Cellular and Molecular Mechanisms of Autoimmunity ...

CHAPTER TWO

Cellular and Molecular Mechanisms of Autoimmunity and Lupus Nephritis S.K. Devarapu*, G. Lorenz†, O.P. Kulkarni{, H.-J. Anders*, S.R. Mulay*,1 *Medizinische Klinik und Poliklinik IV, Klinikum der Universit€at M€ unchen, Munich, Germany † Klinikum rechts der Isar, Abteilung f€ ur Nephrologie, Technische Universit€at M€ unchen, Munich, Germany { BITS-Pilani Hyderabad Campus, Hyderabad, India 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. The Phenomenon of Immune Tolerance 2.1 Central Tolerance 2.2 Peripheral Tolerance 3. Factors That Influence the Loss of Immune Tolerance During Autoimmunity 3.1 Genetic Factors and Autoimmunity 3.2 Environmental Factors and Autoimmunity 4. Factors That Induce Autoimmunity 4.1 Epigenetics and Transcription Factors 4.2 Extracellular Vesicles 4.3 Neutrophil Extracellular Traps 4.4 Ion Channels 4.5 Lipids 5. Costimulatory and Coinhibitory Pathways in Autoimmunity 5.1 Costimulatory Pathways 5.2 Coinhibitory Pathways 6. PRRs in Autoimmunity 6.1 PRRs and Autoimmunity 7. Tissue Inflammation and Injury in Autoimmunity 7.1 Immune Complexes 7.2 Lymphocytes 7.3 Monocytes and Macrophages 7.4 Tertiary Lymphoid Organs 8. Genetic Risk Factors for Organ Manifestations in Human Autoimmune Diseases 9. Lupus Nephritis 9.1 Systemic Autoimmunity in SLE 9.2 Autoimmunity and Tissue Inflammation Inside the Kidney 9.3 Animal Models for SLE

International Review of Cell and Molecular Biology, Volume 332 ISSN 1937-6448 http://dx.doi.org/10.1016/bs.ircmb.2016.12.001

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2017 Elsevier Inc. All rights reserved.

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10. Summary Acknowledgments References

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Abstract Autoimmunity involves immune responses directed against self, which are a result of defective self/foreign distinction of the immune system, leading to proliferation of self-reactive lymphocytes, and is characterized by systemic, as well as tissue-specific, inflammation. Numerous mechanisms operate to ensure the immune tolerance to self-antigens. However, monogenetic defects or genetic variants that weaken immune tolerance render susceptibility to the loss of immune tolerance, which is further triggered by environmental factors. In this review, we discuss the phenomenon of immune tolerance, genetic and environmental factors that influence the immune tolerance, factors that induce autoimmunity such as epigenetic and transcription factors, neutrophil extracellular trap formation, extracellular vesicles, ion channels, and lipid mediators, as well as costimulatory or coinhibitory molecules that contribute to an autoimmune response. Further, we discuss the cellular and molecular mechanisms of autoimmune tissue injury and inflammation during systemic lupus erythematosus and lupus nephritis.

1. INTRODUCTION Autoimmunity implies immune responses that are directed against the self. It is usually considered a pathological process that should be avoided by a clear self/foreign distinction of the immune system. Historically, this perspective originates from clinical syndromes of organ destruction by noninfectious triggers for which certain autoantigens and autoantibodies could be identified. However, bioassays used to detect such autoantibodies often display their persistent presence also in healthy people or their transient presence upon infections that provide an unspecific stimulus to clonal lymphocyte expansion—for example, a transient increase of cryoglobulins after mycoplasma infection or persistent levels of low-affinity antinuclear antibodies. Indeed, autoimmunity is a common biological phenomenon that does not always cause a disease. Complex organisms need to maintain their integrity in response to all sorts of threats. For example, threats by infectious organisms require particular host defense mechanisms such as intact barriers, secretory molecules, or local inflammatory responses, referred to as innate immunity. The molecular

Mechanisms of Autoimmunity

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mechanisms of innate immunity have raised considerable attention since the discovery of the Toll-like receptors (TLRs), and the last decade has much increased our knowledge about how infectious organisms alert the immune system in an antigen-independent manner. It is also of note that the vast majority of the past and present species on this planet entirely rely on the innate immune system for host defense. The evolution of the adaptive immune system introduced a completely new way of immune activation that relies on “antigens,” small supramolecular structures of peptides, and lipid or nucleic acid complexes that are presented to the host’s effector cell repertoire. The way in which priming of adaptive immune responses and imprinting of immune memory evolved it holds the risk for misinterpretations in terms of self-foreign discrimination. This was not a new problem. Errors in self-foreign discrimination also exist at the level of the innate immune system and can contribute to considerable tissue destruction, e.g., in sterile forms of inflammation, where danger-associated molecular patterns (DAMPs) activate TLRs to initiate unnecessary inflammation causing additional tissue injury. However, innate immunity-related errors in self-foreign discrimination do not imprint any immune memory. The numerous mechanisms of immune tolerance assure that potentially autoreactive elements of the adaptive immune system are kept to a minimum and hardly activated. However, the genetic variability of the population implies that some people are able to maintain immune tolerance better than others. In the end, autoimmunity presents like most other noncommunicable diseases. Most people do not experience autoimmune diseases during a lifetime. Very few individuals suffer from monogenetic defects of immune tolerance and experience autoimmune disease early in life. However, a small part of the population carries unfortunate combinations of genetic variants that considerably weaken immune tolerance at different levels, which, eventually triggered by environmental factors, primes an immune response and potentially immune memory upon presentation of an autoantigen. This chapter will describe in detail the molecular and cellular mechanisms of immune tolerance and autoimmunity. The presentation is focused on the understanding of diseases in general and may show additional features in specific autoimmune diseases. A detailed description of the pathogenesis of all the different kinds of autoimmune diseases is beyond the scope of this chapter, but it should prepare the reader well for further studying more specific literature.

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2. THE PHENOMENON OF IMMUNE TOLERANCE The immune system identifies and mounts a prompt response to eliminate foreign/nonself-antigens while abstaining the harmful response to self-antigens. This inherent feature of the immune system has been termed as immune tolerance (Burnet and Fenner, 1949; Jerne, 2004). Broadly, immune tolerance can be divided into two categories, viz., natural or self-tolerance and inducible tolerance. Natural or self-tolerance is further subclassified based on the anatomical sites into central and peripheral tolerance (Fig. 1).

2.1 Central Tolerance Of the various immune tolerance methods, central tolerance is the primary event occurring at developmental stages of both T and B cells in the thymus and bone marrow, respectively. The mechanisms of central tolerance involve clonal deletion, clonal anergy, and receptor editing to eliminate autoreactive lymphocytes at maximal efficacy (Fig. 1). 2.1.1 T-Cell Tolerance To achieve tolerance to self-antigens, T lymphocytes undergo two levels of selection processes. After completion of their antigen receptor editing in the thymus, immature T cells with the ability to recognize self-MHC molecule are exposed to self-peptides bound to MHC molecule. Cells that show high affinity for self-peptides MHC complexes are eliminated by clonal deletion, thus negatively selecting the cells with no or low affinity. Thymic dendritic cells (DCs) and cortical and medullary epithelial cells can induce elimination of self-reactive T cells until they reach either CD4+ or CD8+ single-cell stage resulting over 95% of T cells generated in the thymus die by apoptosis (Kappler et al., 1987). The self-antigen-driven thymic B-cell class switching promotes T-cell central tolerance by presenting cognate self-antigens to support the negative selection of CD4+ T cells (Perera et al., 2016). Efficient negative selection is achieved by the display of self-peptides and expression of responsible genes, which are controlled by a transcriptional factor called the autoimmune regulator (AIRE) (Peterson et al., 2008). Medullary thymic epithelial cells (mTECs) selectively express AIRE and drive tissue-specific antigen (TSA) expression to induce negative selection of TSA autoreactive T cells (Anderson et al., 2002). Moreover, CD80hi MHC-IIhi mTECs expressed AIRE and controlled ectopic antigen

Fig. 1 Mechanisms of immune tolerance. The natural immune tolerance is divided into either central or peripheral immune tolerance depending on the anatomical sites in the body. The central tolerance occurs at developmental stages of both T and B cells in the thymus and bone marrow, respectively. The mechanisms of central tolerance involve clonal deletion and either TCR or BCR receptor editing to achieve maximum efficiency to eliminate the autoreactive lymphocytes. The peripheral tolerance primarily occurs in the secondary lymphoid organs such spleens and lymph nodes. The mechanisms of peripheral tolerance involve anergy, immune deviation, immune regulation, and network-mediated suppression, as well as immune privilege.

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expression (Gray et al., 2007). AIRE-deficient humans and mice developed autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APS-1 or APECED), suggesting the involvement of AIRE in the central tolerance (Kyewski and Derbinski, 2004). Furthermore, expression of AIRE is also observed in peripheral lymphoid organs such as spleen and lymph nodes, known as extrathymic AIRE-expressing cells (eTACs) (Gardner et al., 2008). High expression levels of MHC-II molecules by eTACs allow them to interact with CD4+ T cells in an intrinsic and extrinsic manner as well as to maintain central and peripheral immune tolerance (Bour-Jordan et al., 2011; Nurieva et al., 2011). 2.1.2 B-Cell Tolerance In the bone marrow, B cells develop tolerance to self-antigens by means of receptor editing and clonal deletion in order to minimize the risk of autoimmune diseases. In general, B cells upon encountering antigens undergo affinity maturation and produce high-affinity antibodies that eventually avoid the possibility of cross-reactivity with self-antigens. Receptor editing is an essential mechanism that contributes to central tolerance (Tiegs et al., 1993). It is achieved by inducing VDJ recombinase and rearrangements, which produce new Ig light chains (edited) with the ability to modify the specificity of the receptor so that it can no longer recognize self-antigens (Tiegs et al., 1993) (Fig. 1). How does the autoreactive human B cells undergo tolerance was recently addressed by Lang et al. using a humanized mouse model, i.e., mice expressing an antihuman Igκ membrane protein to serve as a ubiquitous neo-self-antigen were transplanted with a human immune system (Lang et al., 2016). They followed the fate of self-reactive human κ + B cells relative to nonautoreactive λ + cells and showed that tolerance of human B cells occurs in the bone marrow via combination of receptor editing and clonal deletion. In addition, they reported that a number of available self-antigens and the genetics of the cord blood donor dictate the levels of central tolerance of the autoreactive B cells in the periphery (Lang et al., 2016).

2.2 Peripheral Tolerance The mechanisms of central immune tolerance operate at the early developmental stages of both T and B cells. However, in certain circumstances, self-antigens are not expressed during early life but rather during the adult life. In addition, certain antigens that are produced in nonlymphoid organs


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are not exposed sufficiently at the primary lymphoid organs and, therefore, are missed during primary tolerance. Such self-antigens might pose a potential threat to the host if not restricted and, hence, must be controlled outside the primary lymphoid organs. These mechanisms are referred to as peripheral tolerance. Peripheral tolerance is maintained primarily in the secondary lymphoid organs such spleens and lymph nodes. Several mechanisms are involved in the regulation of peripheral tolerance such as immune deviation, immune regulation and immune privilege, network-mediated suppression, and co-receptor modulation (Fig. 1). 2.2.1 B- and T-Cell Anergy Although receptor editing and clonal deletion are the primary mechanisms of central tolerance, the maintenance of tolerance is a much more complicated process. The theory of clonal anergy has been evaluated in the maintenance of tolerance. Clonal anergy was first observed in B cells that functionally rest in the nonresponsive state (Nossal and Pike, 1980). In the tolerant animals, anergic lymphocytes have a lower capacity to proliferate and secrete only low levels of antibody upon antigenic or mitogenic stimuli. Moreover, anergic B cells display a reduced life span with delayed deletion state (Goodnow et al., 2009) and a reduced expression of surface immunoglobulin (Ig) M. In addition, impaired signal transduction is attributed as one of the main reasons for the B-cell anergy (Healy et al., 1997). Such anergic B cells have elevated basal levels of intracellular calcium; however, failure to increase it further upon antigenic stimulation due to the increased requirement of B cell-activating factor of TNF family (BAFF) is for the survival of these cells. Hence, anergic B cells are compromised in mounting immune responses owing to the limited/reduced lifespan and impaired signal transduction. Furthermore, T cells also display anergy, although involving different mechanisms compared to B cells. T cells that lack the secondary costimulatory signal undergo anergic state even in the presence of an antigenic signal. Self-antigens presented by the thymic epithelial cells lack secondary signal compelling the reactive T cells into the nonresponsive anergic state. These anergic T cells are incapable of proliferating as well as producing growth factors such as interleukin (IL)-2. As a central theme, cell cycle mediators fail to activate the progression from G1 to S phase in anergic T cells (Subramanian et al., 2006). The biochemical substances such as diacylglycerol, as well as IL-2, play a major role in T-cell anergy (Olenchock et al., 2006; Spitaler et al., 2006; Zha et al., 2006).

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2.2.2 Immune Deviation Upon activation by antigen-presenting cells (APCs), naı¨ve T helper (TH) cells in the peripheral lymphoid tissues differentiate into either TH1 or TH2 effector helper cells, which can be distinguished by the cytokines they secrete. For example, TH1 cells secrete IL-2, interferon (IFN) γ, and tumor necrosis factor (TNF) α. They are involved in the macrophage activation, defend intracellular pathogens, and stimulate B cells to secrete specific subclasses of IgG antibodies that can coat extracellular microbes and activate complement (Alberts et al., 2002). TH2 cells secrete IL-4, IL-5, IL-10, and IL-13. They are involved in the macrophage inactivation, respond to extracellular pathogens, and stimulate B cells to secrete antibodies including IgE and some subclasses of IgG that bind to mast cells, basophils, and eosinophils (Alberts et al., 2002). Recent evidence indicates that preferential activation of T-cell subsets can be a mechanism of tolerance induction. For example, administration of bee venom to NZB/W F1 mice increased CD4+CD25+ Treg cells and delayed the development of lupus nephritis (LN) (Lee et al., 2011), whereas exogenous IL-10 administration inhibited corneal allograft rejection by inducing TGFβ and TH1/TH2 deviation (Li et al., 2014). Furthermore, the TH1/TH2 immune deviation was demonstrated to facilitate islet allograft tolerance in mice (Zhang et al., 2010). 2.2.3 Immune Regulation/Suppression The adoptive transfer of lymphocytes from tolerant animals to naive recipients can induce tolerance in recipients. Such an inducible tolerance was thought to be mediated by suppressor and cytotoxic T cells (Bloom et al., 1992); however, eventually, these cells were identified as regulatory T cells (Tregs). 2.2.3.1 Regulatory T Cells

Tregs are produced in the thymus to maintain immune homeostasis. In addition, they also contribute to immune tolerance due to their ability to suppress the function of other T cells. Tregs are essential in monitoring the immune system and compromising their number or function could result in several autoimmune diseases—for example, multiple sclerosis, rheumatoid arthritis, or type 1 diabetes (Chinen et al., 2010; Kim et al., 2007; Kravchenko et al., 2016; Long and Buckner, 2011; Parackova et al., 2016). Phenotypically, Tregs are identified as CD4+CD25+FoxP3+ T cells, of which Foxp3 is a master regulator shown to drive the regulatory


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activity of Tregs in both humans and mice (Hadaschik et al., 2015). Several studies have explored the functions of Foxp3+ T cells in the immune response. Adoptive transfer of CD4+CD25+FoxP3+ T cells protected FoxP3-deficient mice from the development of autoimmune disease (Hori et al., 2003), in vivo IL-2/anti-IL-2 complex-induced Tregs protected against chronic kidney disease (Polhill et al., 2012). Furthermore, piperlongumine treatment increased the proportion of Tregs and protected MRL/lpr mice from LN (Yao et al., 2014). Additionally, FoxP3 regulatory T cells has also been reported to contribute to immune tolerance—for example, Zohar et al. reported that CXCL-11-dependent induction of FoxP3 regulatory T cells suppressed murine autoimmune encephalomyelitis (Karin and Wildbaum, 2015; Zohar et al., 2014). FoxP3+ Treg cells exert their regulatory function by secreting various immunoregulatory cytokines including IL-9, IL-35, IL-10, and TGFβ that suppress the activity of nearby T cells and APCs by downregulating surface expression of CD80 or CD86 (Wing and Sakaguchi, 2014). Tregs induce the upregulation intracellular cyclic AMP, leading to the inhibition of T-cell proliferation and IL-2 production. Tregs are classified into two groups based on their origin and function into natural Tregs (nTregs) and inducible Tregs (iTregs). The nTregs are generated in the thymus, whereas the iTreg cells develop outside the thymus in various mucosa-associated lymphoid tissues (MALTs). 2.2.3.2 Natural Tregs

Thymus-derived CD4+ cells with high levels of CD25 expression together with the transcription factor FoxP3 (CD4+CD25+FoxP3+) were identified as nTregs. They form approximately 5%–10% of the total CD4+ T-cell population (Walker et al., 2003) and are positively selected thymocytes with a relatively high affinity for self-antigens. The T-cell receptor (TCR) and MHC II with self-peptide interaction signal the development of nTreg in the thymic stroma. Briefly, thymocytes with high affinity for self-antigens undergo clonal deletion, while a small fraction of these thymocytes escape the selection barrier and appear as nTregs moving toward the periphery to patrol along the secondary lymphoid organs. Multiple mechanisms are involved in mediating the immune regulation by nTregs—for example, inhibition of APC’s ability to activate T cells, direct cytotoxicity of T cells, as well as secretion of antiinflammatory cytokines such as IL-10 and TGFβ, which further inhibits T-cell activity. Several recent studies describe the involvement of nTregs and iTregs in various

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disease conditions—for example, lung allergic responses and autoimmune thyroiditis in mice (Joetham et al., 2016; Kong et al., 2015; Lin et al., 2013; Metzker et al., 2016). 2.2.3.3 Induced Tregs

Thymic single-positive CD4+ T cells differentiate into CD25+- and FoxP3+-expressing iTregs (CD4+FoxP3+) in the presence of TGFβ, IL-10, and IL-4. The iTregs mature in peripheral sites—for example, MALT, and exert suppressive function by secreting IL-10 and TGFβ, inducing cell cycle arrest or apoptosis in effector T cells, and blocking costimulation and maturation of DCs. Depending on the cytokine secretion, iTregs identified as T regulatory 1 (Tr1) cells that secrete IL-10 and T helper 3 (Th3) cells that secrete TGFβ. Though Tr1 cells do not express FoxP3, their properties in vitro are very similar to those of FoxP3+ Tregs (Yao et al., 2015). It is reported that in multiple sclerosis patients, memory T cells can be induced to iTreg phenotype and their development and function are precursor dependent (Mohiuddin et al., 2016). 2.2.4 Immune Privilege Sites Certain anatomical regions in the body are more favorable for grafting than others since they are able to tolerate the presence of allogeneic and xenogeneic tissues (antigens) without eliciting an inflammatory immune response. Such sites are called immune privileged sites, implying that in these regions when foreign antigens are introduced, the zone does not mount an autoimmune response. One of the reasons for this nonresponsive state is the effective sequestering of the immune cells in these zones. Several areas have been identified to function as immune privileged sites in the body—for example, the eye, brain, uterus, testis, and the fetus in the pregnant females. Classical experiments done by Medawar PB proved this concept, in which it was believed that tolerance is due to the limited access of lymphocytes to these sites and failure of foreign antigen transportation to secondary lymphoid organs preventing immune response initiation (Medawar, 1948). Immune privilege is achieved by several mechanisms. The major mechanisms operating the immune tolerance are lymphatic drainage and physical barrier between blood and tissues. In addition, the absence or minimal expression of MHC class Ia protein on cells of the eye and brain, which is required for the cytotoxic cells activity, also plays an important role in immune tolerance (Niederkorn, 2012). The constitutive expression of CD95/Fas ligand (FasL) and TRAIL (Griffith et al., 1995) in these sites


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contributes to the immune tolerance by inducing apoptosis of infiltrating lymphocytes, as well as other inflammatory cells, upon their entry into these sites. Furthermore, high expression levels of the antiinflammatory cytokines such as TNFβ and migration inhibitory factor (MIF) contribute to the immune tolerance by inhibiting NK cell-mediated cytolytic activities (Solomos and Rall, 2016; Taylor, 2016).

3. FACTORS THAT INFLUENCE THE LOSS OF IMMUNE TOLERANCE DURING AUTOIMMUNITY 3.1 Genetic Factors and Autoimmunity Genetic variation influences the immune tolerance and autoimmune disease outcomes. The mechanisms that induce genetic variations include sexual reproduction, mutation, migration, random genetic drift, recombination, and natural selection (Ramos et al., 2015). The recombination events mimic the natural selection shaping the diversity of human genome as well as increasing the risk of genetic diseases. For example, lymphocytes achieve their surface receptor diversity by the genomic alterations that occur either(1) at the primary lymphoid organs via somatic VDJ recombination of both B-cell receptors (BCRs) and TCRs or (2) at the secondary lymphoid organs via somatic hypermutations substituting single nucleotides of BCR during the late phase of immune response (Ignatowicz et al., 1996; Laufer et al., 1996; Wardemann et al., 2003). Aberrations in these recombination events lead to autoimmune diseases. Thus, by shaping the diversity of human genome natural selection consistently checks immune function genes and pathways. Many genes have been reported to be associated with autoimmune diseases, for example, Bim, Zap70, Cblb, Ctla4, Fas, and Roquin. How these genes contribute to the loss of immune tolerance and induce autoimmune diseases? When the interaction of immature B cells with self-antigens exceed certain thresholds, they internalize the BCR and halt the maturation process (Hartley et al., 1993). This results in downregulation of CD62 ligand (CD62L) (Hartley et al., 1993) and BAFF (B cell-activating factor) receptors (Mackay et al., 2003) and, however, continues the expression of Rag1 and Rag2, which are required for VDJ recombination for receptor editing (Jankovic et al., 2004; Nemazee and Hogquist, 2003). Failure of receptor editing leads to apoptosis of B cells with self-reactive BCR in either bone marrow or spleen (Hartley et al., 1993). BCL-2-interacting mediator (BIM) of cells death induces B-cell deletion; hence, Bim-deficient mice

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show higher autoantibody production as well as spontaneous autoimmunity (Strasser and Bouillet, 2003). Furthermore, TCR activation by self-peptide/ MHC complex in thymic cortical regions induces positive selection. The positively selected T cells move to the thymic medulla to test TCRs for self-reactivity. Medullary thymic epithelial cells and DCs express B7.1 (CD80) and other costimulatory molecules along with self-peptide/MHC (Palmer, 2003). The TCRs with a strong affinity for self-peptide/MHC molecule undergo cell death. Several molecules have been identified that involve the regulation of self-reactive TCR—for example, ZAP70 (ζ-chain-associated protein kinase of 70 kDa) (Sakaguchi et al., 2003), GRB2 (growth-factor-receptor-bound protein 2) (Gong et al., 2001), and MINK (misshapen-Nck-interacting kinase-related kinase) (McCarty et al., 2005). In addition, BIM, FAS, and Nur77 play essential roles in the autoreactive TCR regulation (Strasser and Bouillet, 2003; Zhou et al., 1996). Furthermore, limitations in central tolerance (of both clonal deletion and receptor editing) are backed by peripheral tolerance with various intrinsic genetic elements. These elements increase BCR threshold irrespective of BCR specificity as well as induce apoptosis of those self-reactive B cells. This involves the recruitment of tyrosine phosphatase SHP1 (SH2-domain-containing protein tyrosine phosphatase 1) and SHIP (SH2-domain-containing inositol-5-phosphatase) to the activated BCR and induction of CD5 receptor that regulates B-cell anergy (Healy and Goodnow, 1998; Hippen et al., 2000; Ravetch and Lanier, 2000). In T cells, CTLA4 (cytotoxic T-lymphocyte antigen 4) induces a high threshold of TCR self-reactivity and inhibits T-cell activation and CTLA4 deficiency or variants of the CTLA4 resulted in autoimmunity in humans and mice (Inobe and Schwartz, 2004; Ueda et al., 2003; Walker and Abbas, 2002). Moreover, TCR internalization is enhanced by ubiquitin ligases such as CBL-B, GRAIL, and ITCH tag (Anandasabapathy et al., 2003; Jeon et al., 2004). Therefore, deficiency of any of these ligases resulted in an autoimmune disease in mice (Liu, 2004; Naramura et al., 2002; Yokoi et al., 2002). These mechanisms are summarized in Fig. 2. Although single-gene defects very rarely lead to autoimmune diseases, single-gene mutations in murine models were employed to understand how such defects in immune system cause autoimmunity. For example, alike experimental DNAse-1 deletion, analysis of Dnase-1-knockout mice revealed that normal DNAse-1 activity protects mice from the anti-DNA autoimmune response (Jacob et al., 2002; Wilber et al., 2003). Similarly, deficiency of caspase-activated DNase resulted in pristane-induced murine


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Fig. 2 Factors that influence the immune tolerance–autoimmunity. Breakdown of immune tolerance results in autoimmunity that involves multiple factors ranging from genetic to the environmental origin. For example, mutations and/or polymorphisms in genes such as Aire, Bim, Zap70, Cblb, Ctla4, Fas, and Roquin are linked to the development of autoimmune diseases in animal models as well as in humans. Other factors that contribute to the breakdown of immune tolerance include upregulation in the surface expression of costimulatory molecules, molecular mimicry by antigens/ adjuvants, the presence of superantigens or modification of proteins into self-antigens, and defective clearance of dead cells exposing the intracellular autoantigens that promote an immune response and, thus, induce autoimmunity.

lupus-like disease owing to the impaired clearance of dead cells in these mice (Frisoni et al., 2007). Deficiency of DNAse-2, that degrades extracellular chromatin, developed a chronic polyarthritis resembling human rheumatoid arthritis in mice (Kawane et al., 2006). Null mutations and hypomorphic variants of the secreted deoxyribonuclease DNASE1L3 are also linked to systemic lupus erythematosus (SLE) since they digest the extracellular microparticle-associated chromatin (Sisirak et al., 2016). Moreover, mice deficient in either NADPH oxidase 2 or rubicon, molecules involved in

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LC3-associated phagocytosis (LAP), a form of noncanonical autophagy that remove dying cells, displayed symptoms of autoinflammatory, lupus-like diseases with kidney pathology (Martinez et al., 2016). In addition, protein kinase C delta deficiency was observed in autoimmune lymphoproliferative syndrome as well as SLE in humans (Belot et al., 2013; Kuehn et al., 2013; Salzer et al., 2013). NADPH oxidase deficiency also renders susceptibility to experimental allergic encephalomyelitis by regulating TH lineage commitment to TH17 in mice (Tse et al., 2010). Defects in the NADPH oxidase enzyme also lead to chronic granulomatous disease that involves recurrent life-threatening infections with bacteria and fungi as well as dysregulated inflammatory mechanisms (Rosenzweig, 2008). Moreover, patients with selective IgA deficiency have a greater risk of concomitant autoimmune diseases (Abolhassani et al., 2015). In addition, combined immunodeficiencies are associated with autoimmune phenomena (Schuetz et al., 2010). For example, (1) common variable immunodeficiency (CVID), which is caused by mutations in the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), is associated with X-linked Agammaglobulinemia and autoimmune cytopenia (Cunningham-Rundles, 2008); (2) Wiskott–Aldrich syndrome, which is caused by mutations in the gene encoding for WASP, is associated with glomerulonephritis and autoimmune hemolytic anemia (Bosticardo et al., 2009); (3) chronic granulomatous disease, which is caused by a defect in NADPH oxidase, is associated with chorioretinitis (Rosenzweig, 2008); and (4) hyper-IgE syndrome is associated with autoimmune cytopenias, glomerulonephritis, and SLE (Yamazaki-Nakashimada et al., 2006). Furthermore, numerous Mendelian disorders are associated with an upregulation of type I IFN, collectively referred as type 1 interferonopathies (Crow, 2011). The common pathomechanism involved in type 1 interferonopathies is the upregulation of IFNα, resulting from either inappropriate stimulation or defective negative regulation of type 1 IFN pathway (Crow, 2011). The genes implicated and resulting type 1 interferonopathies are listed in Table 1.

3.2 Environmental Factors and Autoimmunity 3.2.1 Infection and Tissue Injury In spite of being well endowed with mechanisms of immune tolerance, susceptible individuals still develop autoimmune diseases, suggesting the presence of factors that are capable of breaking tolerance by compromising

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Table 1 Genes Implicated in Type 1 Interferonopathies Gene Autoimmune Disease References

Trex1

Aicardi–Goutie`res syndrome

Livingston and Crow (2016)

Familial chilblain lupus

Rice et al. (2007)

Systemic lupus erythematosus

Fredi et al. (2015)

Rnaseh2 Aicardi–Goutie`res syndrome



Gunther et al. (2015)



Familial chilblain lupus

Ravenscroft et al. (2011)


Ramantani et al. (2011)

Adar1



Ifih1



Singleton–Merten syndrome

Rutsch et al. (2015)

STING-associated vasculopathy

Clarke et al. (2016)

Infantile-onset Familial chilblain lupus

Konig et al. (2017)

Acp5

Spondyloenchrondrodysplasia

Girschick et al. (2015)

Rig1

Singleton–Merten syndrome

Jang et al. (2015)

Isg15

ISG15 deficiency

Zhang et al. (2015)

Usp18

USP18 deficiency

Meuwissen et al. (2016)

Psmb

CANDLE syndrome

Kunimoto et al. (2013)

Pola1

X-linked reticulate pigmentary disorder Starokadomskyy et al. (2016)

Samhd1

Sting

Acp5, acid phosphatase 5; Adar1, adenosine deaminase acting on RNA 1; CANDLE, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; Ifih1, interferon induced with helicase C domain 1; Isg15, interferon-stimulated gene 15; Pola1, polymerase (DNA) alpha 1; Psmb, proteasome subunit beta; Rig1, retinoic acid-inducible gene 1; Rnaseh2, ribonuclease H2; Samhd1, SAM domain and HD domain 1; Sting, stimulator of interferon genes; Trex1, three-prime repair exonuclease 1; Usp18, ubiquitin-specific peptidase 18.

certain checkpoints of immune tolerance (Goodnow, 2007). Indeed, many factors have been identified that can induce a loss of immune tolerance. 1. Superantigens: Superantigens are virulence proteins produced by a variety of pathogens. They bind to MHC II and TCR to stimulate proliferation of autoreactive T cells and cytokine production (Fraser and Proft, 2008). Exposure to superantigens as a result of infection contribute to initiation, as well as exacerbation, of autoimmune diseases including SLE,

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rheumatoid arthritis, multiple sclerosis, psoriasis, and autoimmune type 1 diabetes (Cole and Griffiths, 1993; Conrad et al., 1997; Dar et al., 2016; Kumar et al., 1997; Leung et al., 1995). 2. Molecular mimicry by antigens: Resembles of self-antigens with those of viruses and bacterial epitopes can lead to cross-reacting immune responses known as molecular antigen mimicry. For example, antistreptococcal immunity can cross-react with certain cardiac tissue antigens (Cusick et al., 2012), and the viral RNA recognition receptor TLR7 accelerates murine lupus (Anders et al., 2008). T cells involved in molecular mimicry respond to self-antigens and help autoantibodyproducing B cells to elicit an autoimmune response (Kain et al., 2008; McClain et al., 2005; Ray et al., 1996). 3. Molecular mimicry by adjuvants: During infection and trauma, dying cells release nuclear material such as nucleosomes or U1sn ribonucleoprotein that mimics the structure of viruses. These nuclear materials upon release from dying cell act as autoadjuvants by mimicking viruses and elicit an antiviral-like type I interferon-based immune response, a process typical for SLE (Anders, 2009). 4. Epitope spreading or modification of self-antigen: Modifications of self-antigens such as citrullination increase the potency of self-antigens to induce an immune response (Fig. 2). For example, citrullination of different antigens including fibrinogen, fibronectin, α-enolase, collagen type II, and histones leads to the generation of anticyclic citrullinated peptide antibodies that serve as a biomarker for rheumatoid arthritis (Gavrila et al., 2016; Lipinska et al., 2016; Sakkas et al., 2014). It is proposed that the citrullination of antigens is either a result of smoking, which is associated with increased levels of extracellular peptidyl arginine deiminase 2 (PAD2) in the lungs (Damgaard et al., 2015; Klareskog and Catrina, 2015), or autophagy in synoviocytes in rheumatoid arthritis (Sorice et al., 2016). The molecular mechanisms that assist epitope spreading include endocytic processing, antigen presentation, and somatic hypermutation (Floreani et al., 2016). 3.2.2 Environmental Agents Exposures to physical and chemical environmental agents are also considered as putative causes for the development of autoimmune diseases. For example, exposure to ultraviolet light is associated with SLE since it induces apoptosis of dermal cells resulting in autoantigen production and


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systemic inflammation (Barbhaiya and Costenbader, 2014; Caricchio et al., 2003). Furthermore, drug categories have been associated with drug-induced autoimmunity—for example, procainamide and hydralazine are associated with SLE (Rubin, 2005; Yokogawa and Vivino, 2009), whereas minocycline and nitrofurantoin are associated with autoimmune hepatitis (Hatoff et al., 1979; Lawrenson et al., 2000). Silica, tropospheric pollutants, and solvent/pesticides have also been implicated in autoimmunity; however, the precise mechanisms are not known (Floreani et al., 2016). Moreover, pristine and naturally occurring hydrocarbons can also induce autoimmunity by inducing the formation of tertiary lymphoid organs (TLOs). Pristane-induced lupus is used as a murine model of SLE and LN (Lech et al., 2010; Savarese et al., 2008).

4. FACTORS THAT INDUCE AUTOIMMUNITY 4.1 Epigenetics and Transcription Factors Gene transcription is an essential process for cellular functions and is regulated by epigenetic modifications. Numerous studies reported that epigenetic modifications occur on the gene loci that encode transcription factors and thus act as an additional regulatory factor for biological functions and disease pathogenesis. Epigenetics is one of the promising areas of investigation in the pathogenesis of autoimmune diseases such as SLE, rheumatoid arthritis, and autoimmune diabetes (Ballestar, 2010; Brown and Wedderburn, 2015; Jeffries and Sawalha, 2011, 2015). DNA methylation, histone modification, and microRNA (miRNA) are some of the known important epigenetic mechanisms. The methylation of DNA is a process in which methyl group is added to a cytosine or an adenine at the 50 position of a CpG dinucleotide. DNA methylation represses gene expression and is regulated by a specific set of enzymes like DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b (Denis et al., 2011). Contrary to the DNA methylation, DNA demethylation reactivates gene expression and is regulated by ten–eleven translocation methylcytosine dioxygenase 1 (TET1), TET2, and TET3 (Abdel-Wahab et al., 2009). Methylation influences the function of transcription factors by four different mechanisms, viz.: 1. Transcription factors do not bind to methylated DNA (Jin et al., 2016). 2. Methylated transcription factors cannot bind to DNA (Ivascu et al., 2007).

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3. Transcription factors recruit DNMT1 and repress transcription (Hervouet et al., 2010). 4. Transcription factors regulate transcriptions of methyltransferases and demethyltransferases (Zhang et al., 2006b). Histone modifications are other important epigenetic mechanisms that regulate gene expression and transcriptions factor functions. Histones within nucleosomes can undergo various modifications—for example, methylation, acetylation, deacetylation, and demethylation (Rothbart and Strahl, 2014). The acetylation process is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), and the methylation process is regulated by histone methyltransferases and histone demethylases. There are four known interactions between transcription factors and histone modifications, viz.: 1. Histone modifications influence binding of transcription factors to their target DNA (Gregory et al., 2001). 2. Enzymes that are involved in histone modification also regulate transcription factors (Chuang et al., 2006). 3. Transcription factors recruit HATs and HDACs to their target DNA loci (Yao et al., 2001), and 4. Transcription factors regulate the DNA modification enzymes (Katto et al., 2013). The other important epigenetic modifications are driven by miRNAs, which function as posttranscriptional and posttranslational regulators of gene expression (Chen et al., 2011). miRNAs are, in fact, one of the most important cooperators of transcription factors to various cell functions (Chen et al., 2011). miRNAs and transcription factors regulate the expression of each other in a unilateral negative feedback loop—for example, the expression of transcription factors is negatively regulated by miRNAs, and on the other hand, miRNAs are positively regulated by transcription factors (Krol et al., 2010). Nevertheless, in double-negative feedback loops, the transcription factors regulated miRNAs are directly responsible for the transcriptional activation and inactivation, while the miRNAs themselves are regulated by transcription factors (Arora et al., 2013). Transcription factors and epigenetic modifications that regulate autoimmunity are listed in Table 2. SLE. The transcription factor, regulatory factor X-box 1 (RFX1), recruits DNMT1 and HDAC1 to target gene promoter in CD4+ T cells. During the development of SLE in both humans and mice, RFX1 is found

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Table 2 Transcription Factors and Epigenetic Mechanisms in Autoimmune Diseases Transcription Factor Expression Epigenetic Mechanisms

Disease

References

RFX1

Decreased Recruitment of DNMT1, Systemic Zhao et al. HDAC, and SUV39H1 lupus (2010a,b) to the promoter regions erythematosus

E4BP4/ NFIL3

Increased

Histone acetylation and methylation

CREMα

Increased

Recruitment of DNMT3a Systemic Hedrich et al. to IL-2 promoter lupus (2012) erythematosus

EBF1

Increased

Regulation by miR-1246 Systemic Luo et al. lupus (2015) erythematosus

RelA

Increased

Regulation by SIRT6

DR3

Systemic Zhao et al. lupus (2013b) erythematosus

Rheumatoid arthritis

Klein and Gay (2015)

Decreased Regulation by DNA hypermethylation


Bull et al. (2008); Takami et al. (2006)

HOXA9

Increased

Regulation by DNA hypomethylation

Autoimmune Miao et al. type 1 (2008) diabetes

NF-κB

Increased

Regulation by H3K4 methyltransferase

Autoimmune Brasacchio type 1 et al. (2009) diabetes

FoxP3

Decreased Regulation by hypermethylation

IRF1

Decreased Deacetylation by Sirtuin I Multiple sclerosis

Yang et al. (2013)

FoxP3

Decreased Regulation by hypermethylation

Multiple sclerosis

Guan et al. (2011)

STAT5

Decreased miR-155

Multiple sclerosis

Lu et al. (2009a)

Autoimmune Tan et al. type 1 (2014); Wang diabetes et al. (2013)

CREMα, cAMP-responsive element modulator α; DR, death receptor; EBF, early B-cell factor; Foxp3, forkhead box P3; IRF, interferon regulatory factor; NFIL3, nuclear factor interleukin-3-regulated protein; NF-κB, nuclear factor kappa B; RFX, regulatory factor X; STAT, signal transducer and activator of transcription.

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to be downregulated, which is responsible for DNA hypomethylation and histone H3 hyperacetylation in CD11a and CD70 promoter region in CD4+ T cells, further leading to CD11a and CD70 overexpression (Zhao et al., 2010a,b). Moreover, the transcription factor E4BP4 regulates the expression of CD40L and is overexpressed in CD4+ T cells in SLE patients (Zhao et al., 2013b). Another transcription factor, CREMα, recruits DNMT3a to the IL-2 promoter, regulates chromatin conformation at the IL-17A locus, and contributes to the increased expression of IL-2 and IL-17 in CD4+ T cell in SLE patients (Hedrich et al., 2012). In addition, the transcription factor, Early B-cell factor 1 (EBF1), activates AKT pathway, regulates B-cell functions, and is known to play an important role in B-cell regulation during the development of SLE (Luo et al., 2015). miR-1246 regulates EBF1 expression and contributes the disease pathogenesis in patients (Luo et al., 2015). Rheumatoid arthritis. Epigenetic mechanisms like DNA hypermethylation (Kuchen et al., 2004), aberrant histone modification (Grabiec et al., 2008), and differentially expressed miRNAs (Nakamachi et al., 2009) are also associated with the pathogenesis and progression of rheumatoid arthritis. For example, in mice, SIRT6 suppresses NF-κB-dependent gene expression by deacetylating H3K9 (Kawahara et al., 2009) and thus suppresses the activity of NF-κB target gene-related immune responses that may contribute to the development and progression of rheumatoid arthritis (Klein and Gay, 2015). The death receptor-3 (DR-3) promoter is hypermethylated in experimental rheumatoid arthritis in mice, rendering the synovial cells resistant to apoptosis (Bull et al., 2008; Takami et al., 2006). Autoimmune diabetes. In autoimmune type 1 diabetes, T cells cannot differentiate between self-pancreatic cells from dangerous pathogens and contribute to the disease development (Xie et al., 2014). Epigenetic modifications have been shown to be associated with the pathogenesis of T1D—for example, hypomethylation of the transcription factor HOXA9 in lymphocytes from T1D patients (Miao et al., 2008). The H3K4 methyltransferase upregulates the transcription factor NF-κB and causes an increase in inflammatory gene expression in diabetic mice (Li et al., 2008). Further, an increased H3K4Me1 and a reduced H3K9 methylation also contribute to inflammation by enhanced NF-κB-p65 gene expression in patients (Brasacchio et al., 2009). In addition, the DNA methylation blocked the binding of IRF7 to FoxP3 and thus reduced the number of regulatory T cells, which contributed to the pathogenesis of autoimmune diabetes in patients (Tan et al., 2014; Wang et al., 2013).


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Multiple sclerosis. In multiple sclerosis, autoimmune responses target myelin sheet in CNS and lead to the progressive degeneration. Yang et al. reported that the histone deacetylase sirtuin I deacetylates IRF1 and contributes to the reduction in a number of TH17 cells (Yang et al., 2013). Further, increased DNA methylation is associated with decreased Treg activity in the pathogenesis of multiple sclerosis (Liu et al., 2010). This reduced Treg activity is attributed to a deficiency of miRNA-155 in Tregs (Lu et al., 2009a). Hypomethylation at IL-17A/ifng loci and increased methylation at the IL-4/FoxP3 loci contribute to the TH1/TH17 imbalance, which is also reported in the development of multiple sclerosis in mice (Guan et al., 2011). 4.1.1 MicroRNAs MicroRNAs are short endogenous noncoding RNAs that are evolutionary conserved and regulate gene expression at posttranscriptional level. Along with the wide range of cellular and developmental process, miRNAs also regulate immune tolerance mechanisms as well as pathogenesis of autoimmune diseases (Garo and Murugaiyan, 2016). For example, overexpression of miR-17–92 in lymphocytes induced lymphoproliferation and autoimmunity in mice (Xiao et al., 2008), as well as strong upregulation of miR-155 characterizes murine and human multiple sclerosis and rheumatoid arthritis (Kurowska-Stolarska et al., 2011; Murugaiyan et al., 2011; Paraboschi et al., 2011). miRNAs that regulate autoimmunity are listed in Table 3. 4.1.1.1 Central Tolerance

Central tolerance is induced during the development of T and B cells. During T-cell development, members of the miR-181 family are abundantly expressed and are involved in the regulation of T-cell selection (Li et al., 2007). The miR-181a binds to dual specificity phosphatases-6 and increases TCR signaling promoting clonal deletion of moderate affinity T cells. Thus, it prevents self-reactive T-cell clones evasion to the periphery and promoting autoimmunity (Li et al., 2012). Further, loss of miR-181a-1/b-1 reduced the basal TCR signaling in peripheral T cells and affected their migration from lymph nodes to sites of tissue inflammation, thereby dampening the development of experimental autoimmune encephalomyelitis (EAE), a murine model for multiple sclerosis (Schaffert et al., 2015). Similar to T cells, miRNAs also regulate receptor editing and B-cell clonal deletion to maintain B-cell tolerance. For example, Dicer-deficient mice, which lack

Table 3 MicroRNAs in Autoimmunity Immune Cells miRNA

Function

References

T cells

miR-181a

Clonal selection

Li et al. (2007, 2012)

miR-181a-1/b-1

TCR signaling and migration from lymph node

Schaffert et al. (2015)

Let-7

Costimulation-independent IL-2 production

Marcais et al. (2014)

miR-16

Costimulation-independent IL-2 production

Marcais et al. (2014)

miR-182

Clonal expansion of helper T cells

Stittrich et al. (2010)

miR-155

Treg differentiation

Lu et al. (2009a)

miR-21

Induction of Th-17 differentiation

Murugaiyan et al. (2015)

miR-326


Du et al. (2009)

miR-301a


Mycko et al. (2012); Nakahama et al. (2013)

miR-132/212


Mycko et al. (2012); Nakahama et al. (2013)

miR-20b

Suppression of Th-17 differentiation

Zhu et al. (2014)

miR-185

BCR signaling

Belver et al. (2010)

miR-155

IgG-class switching

Thai et al. (2007); Vigorito et al. (2007)

miR-150

B-cell differentiation

Xiao et al. (2007)

miR-148a

Inhibition of apoptotic death of immature B cells

Gonzalez-Martin et al. (2016)

miR-155

Regulation of Th1- and Th17-polarizing cytokine expression

Murugaiyan et al. (2011)

miR-21

Induction of T helper cells differentiation to Th2 phenotype

Lu et al. (2009b)

B cells

Dendritic cells

Macrophages miR-146a miR-124

Induction of myeloproliferation and leading to loss of peripheral tolerance Boldin et al. (2011) Induction of systemic deactivation of macrophages

Ponomarev et al. (2011)

BCR, B-cell receptor; IgG, immunoglobulin; IL, interleukin; miR, microRNA; TCR, T-cell receptor; Th, T helper cell; Treg, regulatory T cell.


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the dicer enzyme involved in miRNA biogenesis, had high autoantibody titers and immune complex deposition in kidneys (Belver et al., 2010) because the Dicer-deficient B cell had skewed BCR repertoire with increased BCR signaling (Koralov et al., 2008). Dicer-deficient mice have impaired follicular B-cell generation and more transitional and marginal zone B cells (Belver et al., 2010). Further, miRNA analysis in these mice identified loss of miR-185, overexpressed in follicular B cells, responsible for the altered BCR signaling (Belver et al., 2010). The B-cell intrinsic miR-155 regulates the germinal center response by promoting the generation of immunoglobulin class-switched plasma cells (Thai et al., 2007; Vigorito et al., 2007). Mature B cells expressed miR-150 that target the expression of a transcription factor c-Myb and thus control B-cell differentiation (Xiao et al., 2007). Moreover, miR-148a suppresses the expression of Gad45a, Bcl2l11, and Pten to protect immature B cells from apoptosis induced by engagement of the BCR, leading to an acceleration of autoimmune disease development (Gonzalez-Martin et al., 2016). These studies highlight the involvement of miRNAs in the T- and B-cell development, selection, and tolerance to self-antigens. 4.1.1.2 Peripheral Tolerance

Peripheral tolerance is mainly a backup mechanism to control autoreactivity of the cells that have escaped central tolerance. The mechanisms of peripheral tolerance include T-cell anergy and regulatory T cells, as described earlier. Dicer-deficient CD4+ T cells have demonstrated to not distinguish activating and anergic stimuli and produce IL-2 even in the absence of costimulation (Marcais et al., 2014). Further studies revealed that in Dicer-deficient CD4+ T cells, miRNA Let-7 and miR-16 target mTOR and Rictor, which are responsible for costimulation-independent IL-2 production (Marcais et al., 2014). In addition, IL-2-induced miR-182 also promotes clonal expansion of activated helper T cells by posttranscriptionally regulating FOXO1 (Stittrich et al., 2010). Inhibition of miR-182 inhibited T-cell expansion in vitro and ameliorated OVA-induced arthritis in vivo (Stittrich et al., 2010). Tregs also play a crucial role in maintaining peripheral tolerance. miRNAs regulate both kinds of Tregs, i.e., nTregs and iTregs. Selective miRNA disruption in Tregs, e.g., Dicer-deficient Tregs, leads to uncontrolled autoimmunity in vivo and the mice rapidly developed the fatal systemic autoimmune disease, which resembled Foxp3 deficiency in vivo (Liston et al., 2008; Zhou et al., 2008). Further, T cell-intrinsic Foxp3-dependent miR-155 promoted

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IL-2-induced STAT5 signaling and Treg differentiation by targeting SOCS-1 (Lu et al., 2009a). miRNA expression in APCs, e.g., DCs, also regulates the antigen presentation and costimulation (Turner et al., 2011). For example, miR-155 present in DCs positively regulates Th1- and Th17-cytokine expression, which is critical for the development of inflammatory T cells (Murugaiyan et al., 2011). Moreover, miR-155-deficient mice showed a delayed development of an EAE, an animal model of multiple sclerosis, protection from collagen-induced arthritis, as well as reduced autoantibody responses and alleviated lupus-like disease in FAS/lpr mice, suggesting that miR-155 confers susceptibility to multiple sclerosis, arthritis, and SLE (KurowskaStolarska et al., 2011; Murugaiyan et al., 2011; Xin et al., 2015). Furthermore, during an allergic airway inflammation the miR-21, which is upregulated in DCs, induced differentiation of T helper cells to Th2 phenotype by inhibiting p35 subunit of Th1-promoting IL-12 (Lu et al., 2009b). miR-21 also upregulated TH17 cells by inhibiting Smad 7 and mediated development of the EAE (Murugaiyan et al., 2015). Mice deficient in miR-21 were also resistant to SLE, dextran sulfate sodium-induced colitis owing to a defect in TH17 differentiation (Garchow and Kiriakidou, 2016; Shi et al., 2013). Other miRNAs that regulate TH17 differentiation are miR-326, miR-301a, miR-132/212, and miR-20b. The overexpression of miR-326 is demonstrated to be associated with the pathogenesis of multiple sclerosis (Du et al., 2009), whereas the overexpression of miR-301a and miR-132/212 is demonstrated to be associated with the pathogenesis of EAE in mice (Mycko et al., 2012; Nakahama et al., 2013). On the other hand, miR-20b suppresses TH17 differentiation by targeting RAR-related orphan receptor γt and STAT3 and protected mice from multiple sclerosis and EAE (Zhu et al., 2014). Together, miRNAs are implicated in the pathogenesis of many autoimmune diseases. Proper regulation of miRNAs is important in disease prevention and therefore miRNAs serve as a promising approach to treat autoimmune disorders.

4.2 Extracellular Vesicles Extracellular vesicles (EVs) are a group of extracellular structures that are released by all kinds of cells and are found in all body fluids (Raposo and Stoorvogel, 2013). These extracellular structures include nucleic acids from the originating cell within a phospholipid bilayer membrane. EVs are


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subdivided into the exosomes and microparticles based on their size, composition, and mechanism of formation (Raposo and Stoorvogel, 2013). Further, their function varies depending on the origin and microenvironment and may contribute to inflammation, immune signaling, vascular reactivity, angiogenesis, and tissue repair (Turpin et al., 2016). EVs interact with target cells by multiple mechanisms. For example, they regulate cell-signaling pathways by releasing ligands that activate receptors present on the target cells (Pizzirani et al., 2007). EVs also exert their function via a direct membrane contact to target cells, leading to the transfer of intracellular components after fusion or endocytosis (Morelli et al., 2004). Inside the endolysosomal compartments, EVs control antigen presentation or activate endosomal receptors. 4.2.1 The Source of Self-Antigens EVs express peptide–MHC complexes, costimulatory molecules, as well as self-antigens, on the membrane surface. Therefore, EVs might activate autoreactive T cells in the context of MHC. The number of MHC and costimulatory molecules determines an effective autoimmune response (Turpin et al., 2016). Furthermore, microparticles also are a rich source of extracellular DNA, which can bind to lupus DNA autoantibodies (Pisetsky et al., 2011). 4.2.2 Formation of Immune Complexes The binding of soluble antigens to autoantibodies results in the formation of immune complexes. EVs contain autoantigens and therefore participate in the formation of immune complexes. For example, murine monoclonal anti-DNA and antinucleosomal antibodies readily bound to microparticles that are released by dying cells in vitro (Ullal et al., 2011). A similar analysis of plasma from SLE patients showed that microparticles carry IgG, IgM, and C1q, which are associated with autoantibodies and complement activation and their numbers correlate with the anti-DNA levels (Nielsen et al., 2012; Ullal et al., 2011). Interestingly, only the loading of IgG on the microparticles, and not the number of microparticles themselves, is increased in patients with SLE compared to the healthy subjects (Nielsen et al., 2012). In addition to SLE, microparticles also contribute to the immune complex formation in autoimmune arthritis. The collagen receptor glycoprotein VI, present in the synovial fluids of rheumatoid arthritis patients, triggers platelets to release microparticles (Boilard et al., 2010). The levels of platelet-derived microparticles correlated with the rheumatic arthritis

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disease activity (Knijff-Dutmer et al., 2002). These local platelet-derived microparticles interact with the autoantibodies against citrullinated peptides and form proinflammatory immune complexes, which stimulate neutrophils to secrete leukotrienes and induce joint inflammation (Cloutier et al., 2013). Nevertheless, the nature of the association between microparticles and IgG is not studied in detail, raising doubts on their involvement in the formation of immune complexes, and warrants further studies. 4.2.3 Autoantigen Presentation Autoantigen presentation depends on the intracellular components being presented via MHC class I and II molecules on the APCs surface. APCs secrete exosomes that originate from MHC class II peptide compartments of the cell and therefore express very high levels of MHC class II (Clayton et al., 2001). Exosomes can directly activate T cells in the absence of viable APCs (Admyre et al., 2006; Hwang et al., 2003) or indirectly by promoting the exchange of functional peptide/MHC complexes between DCs, therefore increasing the number of a particular peptide bearing DCs (Thery et al., 2002). However, the direct activation of T cells requires that the exosomes coexpress intercellular adhesion molecule-1 (ICAM-1), whereas the mature DCs had to express CD80 and CD86 for such exchanges (Hwang et al., 2003; Thery et al., 2002). Moreover, the exosomes released from immature DCs weakly present the MHC class I peptide to T cells compared to mature DCs, and thus, mature DCs were more efficient in activating T-cell responses (Utsugi-Kobukai et al., 2003). Immature DCs can also internalize and process exosomes in the endocytic compartment to load exosome-derived MHC class II molecules for presentation to T cells (Morelli et al., 2004). 4.2.4 Inflammation and Immunity EVs also contribute to inflammation and immunity—for example, platelet-derived microparticles in the synovial fluids of patients with rheumatoid arthritis induce IL-1β secretion activating synovial fibroblasts, which further secreted IL-6 and IL-8 and contributed to synovial inflammation (Berckmans et al., 2005; Boilard et al., 2010). These platelet-derived microparticles also induce thrombotic events in co-operation with the tissue factor contributing to fibrin deposits in the synovial fluid activating synovial fibroblasts to secrete proinflammatory mediators (Boilard et al., 2010; Muller et al., 2003). In addition to platelet-derived microparticles,


69

macrophage and T cell-derived microparticles also contributed to the matrix metalloproteinase and proinflammatory cytokine production by synovial fibroblasts (Distler et al., 2005). These metalloproteinases are also known to erode the blood–brain barrier, a major pathomechanism in multiple sclerosis (Saenz-Cuesta et al., 2014). On the other hand, synovial fibroblasts secreted exosomes expressing TNFα that bind to autoreactive T cells and render them resistant to activation-induced cell death, therefore promoting their survival (Zhang et al., 2006a). Platelet-derived exosomes also participate in lipid metabolism whereby they deliver arachidonic acid to adjacent platelets and endothelial cells, initiating the production of proinflammatory mediators like thromboxane A2 and cyclooxygenase (Barry et al., 1997). In addition, exosomes derived from macrophages and DCs contain enzymes that regulate leukotriene metabolism. For example, when a leukotriene biosynthesis intermediate LTA4 was incubated with intact macrophages, the major product was LTB4, whereas its incubation with DCs resulted in LTC4 production (Esser et al., 2010). Further, exosomes derived from either cell type produced chemotactic eicosanoids and induced granulocyte migration upon stimulation with Ca2+ ionophore and arachidonic acid (Esser et al., 2010). Several studies reported that the pathogen-infected cells released EVs that carry pathogen-associated molecular patterns (PAMPs), as well as EVs carrying DAMPs that are released by cells during stress conditions (Bhatnagar et al., 2007; Thery et al., 1999). These EVs activate the innate immune response by activating the pattern recognition receptors (PRRs). For example, in SLE EVs carrying RNA, as DAMP, activated endosomal TLR7 in plasmacytoid DCs (pDCs) and induced production of INFα (Pisetsky and Lipsky, 2010). In systemic sclerosis patients, EVs associated with oxidized high mobility group protein B1 (HMGB1) activated neutrophils, leading to microvascular injury and induced inflammation (Maugeri et al., 2014). Furthermore, neutrophils-derived EVs also contribute to the pathophysiology of autoimmune diseases. When human neutrophils are stimulated in vitro with myeloperoxidase (MPO) and proteinase 3 (PR3), antigens involved in ANCA-associated vasculitis, they secrete microparticles that express ANCA antigens (MPO, PR3) and tissue factors (Hong et al., 2012). These microparticles also possessed the capability to activate endothelial cells via ICAM-1 as well as to trigger coagulation cascade involving tissue factor, thus contributing to the pathophysiology of ANCA-associated vasculitis (Hong et al., 2012; Kambas et al., 2014).

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Together, EVs contribute to the development and pathogenesis of several autoimmune disorders and, therefore, offer potential new targets for therapy.

4.3 Neutrophil Extracellular Traps Neutrophils can expel partially decondensed chromatin upon activation by bacteria or phorbol 12-myristate 13-acetate (PMA) in net-like structures known as neutrophil extracellular traps (NETs). NET formation is primarily an early and nonspecific immune response to pathogens or foreign particles build by our body. The major components of NETs include the decondensed chromatin decorated with cytosolic proteins such as neutrophil elastase (NE), myeloperoxidase (MPO), and histones that synergize to kill bacteria (Brinkmann et al., 2004). PMA-induced NET formation was associated with neutrophil death and, therefore, called NETosis, which was morphologically different from apoptosis and necrosis (Fuchs et al., 2007). Recently, it is demonstrated that PMA or crystalline particles indeed induced receptor-interacting protein kinase 3 (RIPK3)- and mixed lineage kinase domain-like (MLKL)-mediated neutrophil necroptosis during NET formation, which is sometimes also referred as suicidal NETosis (Desai et al., 2016a,b; Mulay et al., 2016a). Neutrophils might also be able to release NETs without neutrophil death, which was wrongly termed as vital NETosis (Desai et al., 2016a; Yipp and Kubes, 2013; Yipp et al., 2012). NETs are eventually cleared either by degradation via DNase 1 (Hakkim et al., 2010) or by engulfment by macrophages (Farrera and Fadeel, 2013). 4.3.1 NETs in Autoimmune Diseases NET formation has a potential to play an important role in the pathogenesis of autoimmune diseases since they expose the otherwise intracellular antigens such as DNA, proteases, and histones to APCs that prime specific immune response against these autoantigens (Pruchniak et al., 2015) (Fig. 3). For examples, autoantibodies against double-stranded DNA (dsDNA) and histones are often found in patients with SLE (Fattal et al., 2010). In addition, autoantibodies against citrullinated protein antigens (ACPAs) originating from NETs are considered a key pathogenic event in the pathogenesis of rheumatic arthritis (Khandpur et al., 2013). 4.3.1.1 Systemic Lupus Erythematosus

A key event in the pathogenesis of SLE is the increased production of IFNγ. Denny et al. identified the presence of a distinct subset of

Cytotoxicity, vascular injury Endothelial cells

A U

Histones Type I interferon

Macrophages

LL37–DNA complex, HMGB1

NLRP3 t

b,

-1

IL

en plem

T O I

Plamacytoid Dendritic cells

M

Com

8 -1 IL

Tissue factor

Coagulation, thrombosis

M U

NET formation

N

Platelets

Neutrophils

Cytokines

I Activation

T Y

T cells Autoantibody production B cells

Fig. 3 See figure legend on next page.

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granulocyte population, called low-density granulocytes (LDGs), in the peripheral blood mononuclear cell fraction by density separation of whole blood from SLE patients (Denny et al., 2010). They demonstrated that these LDGs are highly active; secrete increased amounts of proinflammatory cytokines including INFγ; and possessed increased microbicidal and phagocytic capacities compared to their counterparts from the healthy controls, leading to vascular injury (Denny et al., 2010). Moreover, these LDGs have enhanced capacity to form NETs at baseline in vitro, which remains unchanged even after PMA stimulation (Villanueva et al., 2011). These findings suggested that during the development of SLE, these LDGs remain maximally stimulated in vivo, leading to the enhanced externalization of autoantigens and immunostimulatory molecules, e.g., LL-37, MMP9, and dsDNA (Villanueva et al., 2011). Therefore, NET formation attributes to the pathogenesis of SLE. In addition, a substantial proportion of SLE patients also suffer from impaired NET clearance mechanisms. For example, the presence of DNase 1 inhibitors, as well as anti-NET antibodies in the sera of SLE patients, prevented DNAse 1 access to NETs, leading to impaired NET degradation in these patients that correlated with the development of LN (Hakkim et al., 2010). In addition, oxidization of nucleic acids that are released in NETs, as well as NET-induced complement activation, leads to defects in NET clearance, contributing to SLE pathogenesis Fig. 3 Neutrophils and NET formation in the development of autoimmunity. The activated neutrophils expel partially decondensed chromatin in net-like structures known as neutrophil extracellular traps (NETs) along with the secretion of proinflammatory cytokines. This NET formation exposes the intracellular antigens, e.g., histones, peptide (LL-37)–DNA complexes, and HMGB1. The extracellular histones activate Nlrp3 inflammasome in macrophages inducing IL-1β, IL-18 release. These cytokines further promote the recruitment of neutrophils. In addition, extracellular histones kill endothelial cells, resulting in vasculopathy that leads to the development of renal disease in systemic lupus erythematosus and ANCA-associated vasculitis. The LL-37–DNA complexes as well as HMGB1 present in the NETs facilitate the uptake and recognition of dsDNA by plasmacytoid dendritic cells, leading to the production of higher levels of IFNα, and thus contribute to SLE pathogenesis. Activated neutrophils also release inflammatory cytokines that activate T and B lymphocytes, which contribute the development of autoimmunity. Activated B lymphocytes secrete autoantibodies that form immune complexes, which contribute to the pathogenesis of multiple autoimmune diseases. In addition, NETs promote the expression of the tissue factor, which promotes thrombosis. Thrombus formation contributes the development of renal disease in systemic lupus erythematosus and ANCA-associated vasculitis.


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(Leffler et al., 2012; Lood et al., 2016). The oxidized mitochondrial DNA present in the NETs released by LDGs triggered autoimmune responses in SLE by activating the STING pathway to activate type I interferon in myeloid cells (Lood et al., 2016). Furthermore, NETs induce upregulation of CD25 and CD69, activation markers, and phosphorylation of TCR-associated signaling kinase ZAP70 in T cells, leading to lowering of their activation threshold (Tillack et al., 2012). This mechanism also represents an important link between innate and adaptive immune responses. LL-37 and HMGB1 present in the NETs have been demonstrated to facilitate the uptake and recognition of dsDNA by pDCs, leading to the production of higher levels of IFNα in a TLR9-dependent manner, and thus contribute to SLE pathogenesis (Garcia-Romo et al., 2011) (Fig. 3). Moreover, several studies reported that compounds inhibiting in NET formation in vivo—for example, PAD-4 inhibitors and mitochondrial reactive oxygen species (ROS) inhibitors, protect mice from SLE (Knight et al., 2015; Lood et al., 2016). 4.3.1.2 Rheumatoid Arthritis

A key event in the pathogenesis of rheumatoid arthritis is the formation of ACPAs. Neutrophils in the synovial fluid of patients with rheumatoid arthritis are reported to show enhanced NETosis compared to neutrophils from healthy controls. Moreover, the extent of NETosis also correlated with ACPAs levels and systemic inflammatory markers, suggesting that accelerated NETosis plays an important role in the pathogenesis of rheumatoid arthritis (Khandpur et al., 2013). Further, Spengler et al. reported that NETosis leads to the release of active PAD isoforms, viz., PAD2 and PAD4, which generate extracellular autoantigens by citrullinating histones and fibrinogens (Spengler et al., 2015). In addition, NETs also significantly augmented the production of proinflammatory cytokines IL-6, IL-8, chemokines, and adhesion molecules by synovial fibroblasts in rheumatoid arthritis (Khandpur et al., 2013). 4.3.1.3 ANCA-Associated Vasculitis

The presence of autoantibodies against MPO and PR3 is used as serological markers of ANCA-associated vasculitis (Jennette and Falk, 2014). These autoantibodies can also induce NETosis, leading to the release of toxic oxygen radicals and to the development of destructive necrotizing vascular and extravascular inflammation (Falk et al., 1990; Soderberg and Segelmark, 2016). Further, neutrophils from patients with ANCA-associated vasculitis

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have been reported to show enhanced NETosis compared to neutrophils from healthy controls (Tang et al., 2015). In addition, increased levels of the components of NETs, MPO/DNA complex, and calprotectin were found in sera of patients with ANCA-associated vasculitis (Kessenbrock et al., 2009; Pepper et al., 2013). Interestingly, DCs internalize MPO and PR3 present in NETs and can induce ANCA against MPO, PR3, and dsDNA, when injected into mice, leading to autoimmune vasculitis (Sangaletti et al., 2012). NETs have also been implicated in the pathogenesis of other autoimmune diseases. For example, the presence of NETs was detected in the pancreatic islets during type 1 diabetes mellitus, suggesting that circulating NET components could serve as biomarkers for diagnosis of the disease (Wang et al., 2014c). In addition, hypoglycemia in diabetes favors NET formation, a process impairing wound-healing responses and increasing chronic inflammation (Wong et al., 2015). Furthermore, increased levels of antibodies against NETs were also found the serum of patients with antiphospholipid antibody syndrome (Leffler et al., 2014). Together, NETs play a very important role in the development and pathogenesis of several autoimmune disorders and, therefore, offer new targets for therapy. However, whether potential aberrant NETosis inhibitors will ameliorate disease pathology without affecting host defense requires further examination.

4.4 Ion Channels Ion channels are the ubiquitous transmembrane proteins that allow the selective transport of ions and solutes across the plasma membrane. A range of stimuli control the opening and closing of the ion channels— for example, transmembrane potential difference, ligands, pH, temperature, and mechanical stimuli. Ion channels are mainly divided into three broad categories, viz., voltage-gated, ligand-gated, and acid-sensing ion channels (RamaKrishnan and Sankaranarayanan, 2016). In the electrically excitable cells like neurons, cardiomyocytes, and skeletal muscle cells, ion channels regulate the generation and propagation of the action potential, whereas in the nonexcitable cells, ion channels regulate cell volume, proliferation, and differentiation, as well as fluid and ion transport (RamaKrishnan and Sankaranarayanan, 2016). Moreover, ion channels control the differentiation of stem cells into the particular lineage as well as safeguard the pluripotency of stem cells (Li et al., 2015; Lo et al., 2016).


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Hematopoietic stem cells (HSCs) differentiate into both lymphoid and myeloid cells—for example, lymphoid progenitor cells differentiate into T and B lymphocytes, whereas myeloid progenitor cells differentiate into neutrophils, basophils, eosinophils, and macrophages (Pillozzi and Becchetti, 2012). All these cells play an important role in the development and progression of autoimmunity. Ion channels can modulate immune responses indirectly by regulating the differentiation of HSCs into either lymphoid or myeloid cells. In addition, ion channels present in the membrane of the immune cells, driving both innate and adaptive immune responses, can directly regulate their functions and therefore regulate the development and progression of autoimmunity (Table 4). 4.4.1 Role in Innate Immune Response and Autoimmunity Neutrophils and macrophages of the innate immune system provide the first line of defense. As described earlier, NETs released by neutrophils contribute to autoimmunity. Neutrophils undergo a respiratory burst and produce ROS during the process of NET formation (Fuchs et al., 2007). This production of superoxide in neutrophils is highly regulated by the second messenger—calcium, whose intracellular concentration is controlled by the calcium ion channels, e.g., store-operated calcium entry (SOCE), transient receptor potential melastatin subfamily 2 (TRPM2), and transient receptor potential vanilloid 2 (TRPV) (Brechard and Tschirhart, 2008; RamaKrishnan and Sankaranarayanan, 2016). Moreover, recently, it is proposed that NETosis involves neutrophil necroptosis (Desai et al., 2016a,b), and necroptosis involves Ca2+ and Na+ influx via TRPM2/7 and Na+ channels, respectively (Galluzzi et al., 2014; Kunzelmann, 2016). In addition to NETosis, calcium influx also controls other functions of neutrophils like phagocytosis, ROS production, and inflammatory processes involving neutrophils (Burgos et al., 2011). The P2X7 potassium channels, as well as Transient receptor potential (TRP) channels, are known to regulate the neutrophil chemotaxis to the target site (RamaKrishnan and Sankaranarayanan, 2016). Further, TRPM7 mediated the calcium-induced neutrophil chemotaxis, adhesion, and invasiveness, as well as toxicity against bone, and cartilages in rheumatoid arthritis patients (Wang et al., 2014a). The anion channels are also reported to play a role in neutrophil functions—for example, CIC-3 is required for normal neutrophil oxidative function, phagocytosis, and transendothelial migration (Moreland et al., 2006). It is speculated that the activated neutrophils swell due to rapid water entry stimulating the chloride channels (Simchowitz et al., 1993). This leads

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Table 4 Ion Channels in Autoimmunity Name of the Ion Immune Cells Ion Channel

Neutrophils

Function

References

ROS

Brechard and Tschirhart (2008)

TRPM2

ROS


TRPV2

ROS


TRP

Chemotaxis

RamaKrishnan and Sankaranarayanan (2016)

TRPM2/7

Neutrophil necroptosis or NETosis

Desai et al. (2016a); Galluzzi et al. (2014)

TRPM7

Chemotaxis


K+

P2X7

Chemotaxis


Cl

CIC-3

ROS, phagocytosis, migration

Moreland et al. (2006)

Ca2+ SOCE

H+

Rapid water NADPH activation entry-stimulating and NETosis Cl channels

Salmon and Ahluwalia (2009)

VGPC

Fujiwara et al. (2013)

ROS, phagocytosis

Macrophages Na+ VGSC (Nav1.6) Phagocytosis Ca2+ CRAC

Phagocytosis, inflammasome activation, T-cell priming

Craner et al. (2005) Vaeth et al. (2015)

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Table 4 Ion Channels in Autoimmunity—cont’d Name of the Ion Immune Cells Ion Channel Function

K+

References

TRPM2/4/3

ROS, phagocytosis, inflammation


CFTR

ROS, phagocytosis, inflammation


K(Ca)3.1

Secretion of IL-6 and Gao et al. (2010); IL-8 Xu et al. (2014)

Kvi

Inhibition of inflammation

Moreno et al. (2013)

P2X7

Inflammasome activation

Prochnicki et al. (2016)

VGPC (Kv1.3, Induction of apoptosis Leanza et al. Kv1.1, and Kv1.5) (2012) Cl

T cells

ROS, phagocytosis, Intracellular chloride channel inflammation (CLIC 1)

Ca2+ TRPM7


Inhibition of T-cell development

Jin et al. (2008)

TRPV2

Impaired TCR formation

Santoni et al. (2013)

SOCE

Positive T-cell selection

Oh-Hora et al. (2013)

L-type VGCC


Oh-Hora et al. (2013)

TRPV1

Immunotolerance of RamaKrishnan Tregs and Sankaranarayanan (2016) Continued

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K+

B cells

References

VGPC (Kv1.3)

Proliferation and cytokine production


K(Ca)3.1

Memory T-cell development


P2X7

Baricordi et al. Maturation, proliferation, cytokine (1996) production

Na+ VGSC


Lo et al. (2012)

Ca2+ TRPV2

Inhibition of B-cell development

Santoni et al. (2013)

CRAC

Activation, selection, RamaKrishnan and differentiation and Sankaranarayanan (2016)

T-type calcium channel

Proliferation


Mg2+ TRPM6/7

B-cell growth


K+

VGPC (Kv1.3)

Proliferation and class Amigorena et al. switching of memory (1990) cells

K(Ca)3.1

Proliferation and class Amigorena et al. switching of memory (1990) cells

P2X7

Proliferation


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H+ Dendritic cells

References

Kvi

Mitogenesis and DNA Amigorena et al. synthesis (1990)

HVCN1

Antibody production Capasso et al. (2010)

Ca2+ TRPM4

Migration to lymph nodes


TRPV2

Migration to lymph nodes


L-type calcium Antigen presentation RamaKrishnan channel (Cav1.2) and Sankaranarayanan (2016) CFTR

DC differentiation


Na+ VGSC (Nav1.7) Cytokine secretion Zsiros et al. (2009) and T-cell activation K+

Cl

VGPC (Kv1.3)

Cytokine secretion Zsiros et al. (2009) and T-cell activation

K(Ca)3.1

Chemokine-induced Shao et al. (2015) migration

P2X7

Cytokine secretion


Chloride channel Chemokine-induced Shao et al. (2015) (CCL3) migration

CFTR, cystic fibrosis transmembrane conductance regulator; CRAC, Ca2+ release-activated Ca2+; HVCN1, hyperpolarized voltage-gated proton channel; K(Ca)3.1, CRAC-activated K+ channel; Kvi, voltage-dependent inward rectifier K+ channels; SOCE, store-operated calcium entry; TRPM, transient receptor potential melastatin; TRPV, transient receptor potential vanilloid; VGCC, voltage-gated calcium channel; VGPC, voltage-gated potassium channels; VGSC, voltage-gated sodium channels.

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to activation of NADPH oxidase, an enzyme that regulates neutrophil migration, phagocytosis, and NETosis (Salmon and Ahluwalia, 2009). The nicotinic acetylcholine receptor, as well as cAMP, activated chloride channel, and cystic fibrosis transmembrane conductance regulator (CFTR) also regulate the neutrophil functions (RamaKrishnan and Sankaranarayanan, 2016). In addition, voltage-gated proton channels also controlled the neutrophil phagocytosis by regulating cytosolic acid concentration (pH) and superoxide anion production (Fujiwara et al., 2013). Macrophages are involved in phagocytosis of pathogens as well as clearance of NETs and are responsible for both innate and adaptive immune responses. Ion channels also regulate the functions of macrophages. Craner et al. have reported that the voltage-gated sodium channel, Nav1.6, is important for the phagocytosis activity of microglia, residential macrophages in the brain and spinal cord. Therefore, inhibitors of this channel ameliorated the axonal degeneration and inflammatory reactions in an animal model of EAE and multiple sclerosis (Craner et al., 2005). In contrast, expression of human Nav1.5 in mouse macrophages enhanced the recovery in multiple sclerosis (Rahgozar et al., 2013). Furthermore, Ca2+ release-activated Ca2+ (CRAC)-induced Ca2+ influx is important for many effector functions of macrophages including phagocytosis, inflammasome activation, and priming of T cells (Vaeth et al., 2015). Such CRAC-induced Ca2+ influx regulated calcium-activated K+ channel (K(Ca)3.1)-mediated secretion of proinflammatory cytokines IL-6 and IL-8 by activation of NF-ĸB (Gao et al., 2010; Xu et al., 2014), and therefore, chemical inhibition of these channels attenuated the inflammatory reactions of macrophages (Tsai et al., 2013). The antiinflammatory action of 15-epi-lipoxin A4 is also attributed to the inhibition of voltage-dependent and inward rectifier potassium channels (Kv) in macrophages (Moreno et al., 2013). K+ efflux via P2X7 receptors activates NLRP3 inflammasome in macrophages, leading to secretion of IL-1β and IL-18 (Prochnicki et al., 2016). In addition to phagocytic and inflammatory functions by macrophages, the voltage-gated potassium channels also regulate their apoptosis. The Kv1.3, Kv1.1, and Kv1.5 are demonstrated to interact with Bax to induce apoptosis in macrophages, and subsequently, siRNA knockdown of these channels protected macrophages from undergoing apoptotic cell death (Leanza et al., 2012), as well as the Kv1.3-deficient mice showed decreased susceptibility to the development of EAE (Gocke et al., 2012). The presence of anti-IgG antibodies against Kir4.1 in the sera of patients of multiple sclerosis has been reported (Srivastava et al., 2012). Furthermore, macrophage functions are


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also regulated by Ca2+ influx through TRPM2, TRPM4, and TRPC3; intracellular chloride channel (CLIC 1); and CFTR (RamaKrishnan and Sankaranarayanan, 2016). CFTR acidified the phagolysosomes in macrophages and therefore contributed to increased oxidative burst as well as bacterial clearance (Di et al., 2006). Along with neutrophils and macrophages, ion channels also regulate the functions of basophils and natural killer cells that are involved in innate immune responses during the development of autoimmunity (RamaKrishnan and Sankaranarayanan, 2016). 4.4.2 Role in Adaptive Immune Response and Autoimmunity T and B lymphocytes are the major arms of adaptive immune responses. Ion channels have been implicated in the T-cell development and proliferation. T cell-specific deletion of TRPM7 caused a block in T-cell development at the double-negative (CD4CD8) stage, leading to fewer numbers of double-positive (CD4+CD8+) and single-positive (CD4+) T cells in spleen and thymus (Jin et al., 2008). The TRPV2 orchestrates Ca2+ signal in T-cell activation, proliferation, and effector functions since knockdown of TRPV2 in T cells impaired calcium signaling and TCR formation (Santoni et al., 2013). The rise in the intracellular concentration of calcium activates nuclear factor of activated T cells, leading to lymphocyte activation (Gwack et al., 2007). Accordingly, increased expression of CRAC in T lymphocytes of patients with rheumatoid arthritis was reported recently (Liu et al., 2014). Furthermore, the positive selection of T cells also depends on the SOCE as well as on voltage-gated Na+ channel and L-type voltage-gated calcium channel (Lo et al., 2012; Oh-Hora et al., 2013); thus, any alterations in their functions may lead to the development of autoimmune diseases. In addition to calcium channel, potassium channel also regulates T-cell proliferation and cytokine production—for example, increased expression of Kv1.3 and K(Ca)3.1 has been observed on T lymphocytes associated with autoimmune type 1 diabetes (RamaKrishnan and Sankaranarayanan, 2016), whereas inhibition of Kv1.3 on T lymphocytes protected severe combined immunodeficient mice from psoriasis (Gilhar et al., 2011). Recent evidence also suggests that curcumin inhibits Kv1.3 on T effector lymphocytes isolated from patients with rheumatoid arthritis and multiple sclerosis and, therefore, may serve as a potential treatment option for these patients (Lian et al., 2013). Intracellular Ca2+ concentration also plays an important role in B-cell activation, selection, and differentiation into plasma and memory B cells (Scharenberg et al., 2007). Similar to T cells, TRPV2 is expressed in

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B cells where it regulates Ca2+ release during B-cell development and activation (Santoni et al., 2013). In addition, potassium channels are also involved in B-cell proliferation and IgG-class switching associated with SLE (RamaKrishnan and Sankaranarayanan, 2016). Moreover, the influx of K+ activated B-cell mitogenesis and DNA synthesis at G1 and S phases (Amigorena et al., 1990). The voltage-gated proton channel HVCN1 that associated with the BCR is involved in mitochondrial ROS production in B cells (Capasso et al., 2010). 4.4.3 Antigen Presentation DCs process the antigens and present the antigenic peptides to T and B cells. It is demonstrated that the immature DCs express sodium channel Nav1.7, which is downregulated with concomitant upregulation of voltage-gated Kv1.3 potassium channel expression during maturation of DCs, and therefore, Kv1.3 blockers can inhibit various functions of mature DCs such as cytokine secretion and T cell-activating potential (Zsiros et al., 2009). Furthermore, intermediate conductance calcium-activated potassium channel K(Ca)3.1 and chloride channel (CIC-3) regulate the chemokine-induced migration of DCs to the lymph nodes where they stimulate adaptive immune responses (Shao et al., 2015). Other ion channels that regulate the DCs migration include TRPM4, TRPV1, and TRPV2 (RamaKrishnan and Sankaranarayanan, 2016). In addition to this, the water-transporting channels AQP-7, AQP-5, and AQP-3 are involved in antigen presentation (RamaKrishnan and Sankaranarayanan, 2016). The voltage-gated potassium and calcium channels also act as an autoantigen and stimulate immune responses during the development of autoimmune type 1 diabetes (Fierabracci and Saura, 2010; Messinger et al., 2009). Together, ion channels extensively regulate both innate and adaptive immune response, and therefore, an aberration in the expression of ion channel might lead to autoimmune disorders. Understanding their functions in more detail will offer multiple new targets as potential novel therapies autoimmune diseases.

4.5 Lipids Lipid mediators are other important molecules that influence the autoimmunity. They are divided into following three classes—class I, arachidonic acidderived eicosanoids—prostaglandins and leukotriene; class II, lysophospholipids and their derivatives; and class III, omega-3-polyunsaturated fatty acid-derived


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antiinflammatory mediators (Murakami, 2011). Lipids are important and complex component of the plasma membrane. The lipid raft controls protein interactions following the ligand–receptor binding and, thus, promotes the signaling in immune cells (Katagiri et al., 2001). While the complexity of lipids in the plasma membrane is appreciated for long, only recently the developments in lipidomics have increased our knowledge of their dynamics in plasma membrane (Wu et al., 2016). Aberration in lipid functions has been associated with development and complications of several autoimmune disorders—for example, patients with SLE show increased levels of oxidized lipids, viz., oxidized LDL and phospholipids, leading to generation of antibodies against them, which contribute to thrombosis resulting in increase in atherosclerosis and coronary artery events in SLE (Hahn and McMahon, 2008). Abnormalities in lipid-binding proteins of myelin and sphingolipid content that confer increased immunogenicity have been implicated in the development of multiple sclerosis (Reale and Sanchez-Ramon, 2016). Furthermore, the presence of lipid-specific antibodies against sulfatide, sphingomyelin, and oxidized lipids in cerebrospinal fluid derived from individuals with multiple sclerosis has been identified by a large-scale multiplex microarray analysis of lipids present in the myelin sheath, including ganglioside, sulfatide, cerebroside, sphingomyelin, and total brain lipid fractions (Kanter et al., 2006). Lipids also serve as an antigen and regulate immunity via lipid-reactive T cells. Such lipid antigens are presented to T cells by proteins of CD1 family (Dowds et al., 2014). Such lipid-reactive T cells’ number and functions were reduced in patients with SLE as well as mouse models of SLE (Jacinto et al., 2012). These CD1d-reactive T cells, also called invariant natural killer T (NKT) cells, inhibit autoreactive B cells since they express more CD1d than the nonautoreactive B cells (Yang et al., 2011). Therefore, CD1d deficiency in mice leads to exacerbated autoantibody production and developed a lupus-like disease (Yang et al., 2011). Furthermore, the NKT cell levels and functions are also reduced in SLE patients, which correlated with the disease activity (Cho et al., 2011). In particular, the CD4+ T cells from SLE patients display an altered profile of lipid raft-associated glycosphingolipids (GSLs), e.g., lactosylceramide, globotriaosylceramide, and monosialotetrahexosylgangliosi de (McDonald et al., 2014). Interestingly, normalizing GSLs restored function in CD4+ T cells from SLE patients (McDonald et al., 2014).

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Together, these observations indicate that lipids and lipid-reactive T cells contribute to autoimmunity via different mechanisms, and therefore, represent potential therapeutic targets for autoimmune diseases.

5. COSTIMULATORY AND COINHIBITORY PATHWAYS IN AUTOIMMUNITY Activation of naive T cells requires two signals acting simultaneously. Interaction of TCR with MHC-peptide molecules comprises signal 1, while costimulation via costimulatory receptors and their corresponding ligands on APCs requires signal 2 for activation of naı¨ve T cells (Lafferty and Cunningham, 1975; Mueller et al., 1989). These costimulatory mechanisms provide molecular checkpoints to ensure that the immune system produces a controlled response to foreign antigens while avoiding pathology and destruction of the host tissue and provide potential avenues for therapeutic intervention. These costimulatory mechanisms regulate Tregs, which are important for self-tolerance (Sakaguchi et al., 2008; Vignali et al., 2008). In fact, as mentioned earlier, either overactivation of costimulatory pathways or loss of coinhibitory mechanisms leads to loss of the self-tolerance. Apart from APCs, B cells and other immune cells also require costimulation for their activation, maturation, and function (Bretscher and Cohn, 1970). Thus, costimulatory and coinhibitory receptors and their signaling pathways regulate overall immune response. We have reviewed these costimulatory and coinhibitory pathways in four important autoimmune diseases including SLE, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes (Table 5).

5.1 Costimulatory Pathways One of the most important costimulatory receptors is CD28, which is activated by its ligands B7.1 (CD80)/B7.2 (CD86). This CD28 stimulation, along with TCR-MHC-II signaling, promotes the proliferation of T cells, as well as their survival, during T-cell priming. Several studies reported attenuation of autoimmune diseases in Cd28-deficient mice— for example, MRL/lpr mice, an animal model for SLE (Tada et al., 1999a); in DBA/1 mice with collagen-induced arthritis (Tada et al., 1999b); and in Cd28-deficient-MBP1–17 TCR transgenic mice, a model of EAE (Oliveira-dos-Santos et al., 1999). Interestingly, other reports suggest that the B7.1 and B7.2 act in a redundant manner in the development of SLE. For example, the dual blockade of B7.1 and B7.2 using antibodies resulted in a significant decrease in autoantibody production compared to the blockade using either of the antibodies alone in MRL/lpr mice

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Table 5 Costimulatory and Coinhibitory Pathways in Autoimmunity Autoimmune Pathway Disease References

Costimulatory CD28–B7.1/ B7.1 axis


Liang et al. (1999); Tada et al. (1999a)

Autoimmune type 1 diabetes

Lenschow et al. (1996); Salomon et al. (2000)


Tada et al. (1999b); Webb et al. (1996)

Encephalomyelitis Chang et al. (1999); Oliveira-dos-Santos et al. (1999) ICOS–ICOSL axis


Hu et al. (2009); Odegard et al. (2008); Teichmann et al. (2015)


Iwai et al. (2002)

Encephalomyelitis Sporici et al. (2001)

CD40–CD40L axis

Autoimmune type 1 diabetes

Ansari et al. (2008); Hawiger et al. (2008)


Early et al. (1996); Ma et al. (1996)


Kyburz et al. (1999); MacDonald et al. (1997); Tellander et al. (2000)

Encephalomyelitis Gerritse et al. (1996); Howard et al. (1999) Autoimmune type 1 diabetes OX40–OX40L Systemic lupus axis erythematosus Rheumatoid arthritis

Baker et al. (2008); Bour-Jordan et al. (2004); Green et al. (2000) Cunninghame Graham et al. (2008); Jacquemin et al. (2015); Manku et al. (2013) Gwyer Findlay et al. (2014); Yoshioka et al. (2000)

Encephalomyelitis Carboni et al. (2003); Weinberg et al. (1996) Autoimmune type 1 diabetes

Pakala et al. (2004) Continued

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Table 5 Costimulatory and Coinhibitory Pathways in Autoimmunity—cont’d Autoimmune Pathway Disease References

Coinhibitory

CTLA4–B7.1/ B7.2 axis

PD1–PDL1/ PDL2 axis


Butte et al. (2007); Finck et al. (1994); Mihara et al. (2000)


Ko et al. (2010); Quattrocchi et al. (2000); Webb et al. (1996)


Butte et al. (2007); Laufer et al. (1996); Okazaki and Honjo (2007)


Raptopoulou et al. (2010)

Encephalomyelitis Ansari et al. (2003); Bodhankar et al. (2013); Carter et al. (2007) Autoimmune type 1 diabetes

Ansari et al. (2003); Liang et al. (2003); Wang et al. (2008)

Rheumatoid Levin et al. (2011) TIGIT– CD112/CD155 arthritis axis Encephalomyelitis Joller et al. (2011); Levin et al. (2011) TIM3–galectin 9 axis


Pierer et al. (2009); Seki et al. (2008)

Encephalomyelitis Podojil et al. (2013); Zhu et al. (2005) Autoimmune type 1 diabetes

Sanchez-Fueyo et al. (2003); Wang et al. (2011)

CD, cluster of differentiation; ICOS, inducible T-cell costimulator; PD, programmed cell death protein; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; TIM3, T-cell immunoglobulin and mucin domain-containing 3.

(Liang et al., 1999). The similar redundancy of B7.1 and B7.2 was observed in DBA/1 mice (Webb et al., 1996) as well as in the MOG35–55-induced EAE model in mice (Chang et al., 1999). Further, O‘Neill et al. showed that expression of B7 molecules on B cells is essential for autoreactive T-cell priming in the development of murine proteoglycan-induced arthritis


87

(O’Neill et al., 2007). In contrast to the above observations, both Cd28-deficient NOD mice and B7.1/B7.2-double deficient NOD mice showed an acceleration in the development of autoimmune diabetes, along with a significant reduction in the number of Tregs and enhanced IFNγ production (Lenschow et al., 1996; Salomon et al., 2000). The Inducible T-cell COStimulator (ICOS) or CD278 also induces T-cell activation and the humoral immunity. The function and generation of follicular and extrafollicular T helper cells are dependent on ICOS in NZB/NZW.F1 and MRL/lpr mouse models of SLE (Hu et al., 2009; Odegard et al., 2008; Teichmann et al., 2015). Furthermore, pharmacological blockade of the ICOS–ICOSL pathway with anti-ICOSL inhibited development of arthritis in a mouse model of collagen-induced arthritis (Iwai et al., 2002). In the EAE, selective ICOS blockade exacerbated disease in the priming phase (1–10 days after immunization), whereas it ameliorated the disease in the efferent phase (9–20 days after immunization) (Sporici et al., 2001). However, the Icos-deficient mice developed more severe disease with enhanced production of Th1 and Th17 cell cytokines (Dong et al., 2001; Galicia et al., 2009). In contrast, the Icos-deficient NOD mice, as well as NOD mice treated with anti-ICOSL, showed a delayed development of autoimmune diabetes (Ansari et al., 2008; Hawiger et al., 2008). In addition to the costimulatory receptors, the CD40–CD40L costimulatory pathway also drives the humoral immune responses during the development of autoimmunity. Studies in NZB/NZW.F1 and MRL/lpr mice with the loss of CD40–CD40L axis demonstrated that the B and T cells interact with each other via CD40–CD40L axis and drive the humoral immunity in SLE (Early et al., 1996; Ma et al., 1996). For example, anti-CD40L blockade in combination with CTLA4 antibody in NZB/ NZW.F1 mice has shown synergistic effects by suppressing B- and T-cell activation (Daikh et al., 1997; Wang et al., 2002). Furthermore, in rheumatoid arthritis patients, CD4+ T cells present in synovial fluid express CD40L, and the CD40–CD40L axis contributes to the production of autoantibodies (MacDonald et al., 1997). The pharmacological blockade of CD40–CD40L axis attenuated the progression of murine collagen-induced arthritis (Kyburz et al., 1999; Tellander et al., 2000), as well as anti-CD40L antibody slowed the progression and development of EAE by inhibiting T-cell activation, as well as IFNγ production (Gerritse et al., 1996; Howard et al., 1999). In addition, CD40–CD40L costimulation plays an essential role in the initiation of insulitis and autoreactive T-cell priming during the development of autoimmune diabetes since both CD40L antagonization and Cd40l

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deficiency in NOD mice completely abrogated the development of the disease (Baker et al., 2008; Balasa et al., 1997; Bour-Jordan et al., 2004; Green et al., 2000). Another costimulatory pathway that contributes to the development of autoimmune diseases is the OX40–OX40L axis. Several polymorphisms at Tnfsf4, a gene encoding OX40L, are associated with the development of SLE (Cunninghame Graham et al., 2008; Manku et al., 2013). Further, OX40L was reported to contribute to human lupus pathogenesis by promoting T follicular helper response (Jacquemin et al., 2015). Very high expressions of OX40 and OX40L were observed on activated T cells and APCs, respectively, in the inflamed joints in collagen-induced arthritis mouse model (Gwyer Findlay et al., 2014). Moreover, mice deficient in OX40–OX40L signaling show less IFNγ and autoantibody production in the pathogenesis of rheumatoid arthritis (Gwyer Findlay et al., 2014; Yoshioka et al., 2000). Similarly, OX40 is overexpressed on autoreactive T cells during the development of EAE, and therefore, the selective depletion of T cells attenuated the disease pathology (Carboni et al., 2003; Weinberg et al., 1996). However, although the deficiency of OX40 or OX40L delayed the development, it did not result in complete protection from the disease, suggesting a minor role of this axis in the pathogenesis of EAE (Carboni et al., 2003; Ndhlovu et al., 2001; Nohara et al., 2001; Weinberg et al., 1999). The OX40–OX40L axis also demonstrated to contribute to the development of autoimmune diabetes in NOD mice at a late stage (Pakala et al., 2004).

5.2 Coinhibitory Pathways The coinhibitory molecule B7.1 plays an important role in the regulation of immune response in SLE. For example, the B7.1-deficient mice showed exacerbation of SLE in MRL/lpr (Liang et al., 1999). As mentioned earlier, the B7.1 and B7.2 molecules interact with costimulatory CD28 on T-cell surface to transduce stimulatory signal, whereas they can also interact with CTLA4, as well as PD-L1, to transduce the inhibitory signals (Butte et al., 2007). Therefore, an exacerbation in disease pathology in B7.1-deficient MRL/lpr mice can be attributed to the preferential interaction of CTLA4 and PDL1 with B7.1 over B7.2 (Butte et al., 2007). The important evidence of the coinhibitory role of CTLA4–B7 interaction comes from the observation that treatment of CTLA4 antibody attenuated the disease progression in NZB/NZW.F1 mice (Finck et al., 1994; Mihara et al., 2000) as well as in


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mouse model of collagen-induced arthritis (Knoerzer et al., 1995; Ko et al., 2010; Quattrocchi et al., 2000; Webb et al., 1996). On the contrary, the NOD mice expressing the CTLA4 antibody or treated with CTLA4 antibody showed exacerbation in autoimmune diabetes (Lenschow et al., 1996; Salomon et al., 2000). Another coinhibitory pathway that contributes to the development of autoimmune diseases is the PD1–PDL axis. Polymorphisms at PDCD1 are associated with SLE, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes (Okazaki and Honjo, 2007). The C57BL/6J mice that are deficient in Pdcd1 have higher expression of IgG2b, IgA, and IgG3 in plasma along with reduced expression of CD5, leading to the spontaneous development of SLE (Nishimura et al., 1998; Nishimura et al., 1999). Moreover, pharmacological blockade of PD1 in NZB/NZW.F1 mice resulted in an expansion in the population of Tregs and therefore protected the mice from the development of SLE and associated renal injury (Kasagi et al., 2010; Wong et al., 2013; Wong et al., 2010). Similarly, the Pdcd1-deficient mice exhibited exacerbated rheumatoid arthritis, and pharmacological activation of PD1–PDL axis attenuated the progression of rheumatoid arthritis (Raptopoulou et al., 2010). Further, the PD1–PDL axis also plays an important role in the development of EAE. Both PDL1 and PDL2 were observed on the infiltrating cells. However, the PD1 interaction with PDL1 but not PDL2 on B cells protected mice from EAE (Bodhankar et al., 2013; Carter et al., 2007). Pancreatic β cells also express PDL1; however, its involvement in the development of autoimmune diabetes is ambiguous (Ansari et al., 2003; Liang et al., 2003). For example, PDL1 overexpression on β cells in NOD mice protected them (Wang et al., 2008), whereas in C57Bl6 mice PDL1 overexpression caused the activation of autoreactive T cells, leading to the aggravation of autoimmune diabetes (Subudhi et al., 2004). Similar to the EAE, pharmacological blockade of PD1–PDL1 axis, but not the blockade of PDL2, leads to aggravation of autoimmune diabetes in NOD mice (Ansari et al., 2003). Apart from the coinhibitory pathways discussed earlier, there are some pathways, which also participate in the regulation of immune response— for example, the signaling pathways associated with TIGIT (VSIG9 or VSTM3). The TIGIT interacts with ligands like CD112 and CD115 and suppresses T-cell responses in rheumatoid arthritis (Levin et al., 2011). Further, both the treatment with TIGIT agonist and mice overexpressing TIGIT inhibited the progression, while mice Tigit-deficient mice exhibited exacerbation of EAE (Joller et al., 2011; Levin et al., 2011). Moreover,

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coinhibitory receptors, TIM3 and B7-H4, play an important role in the progression of rheumatoid arthritis (Pierer et al., 2009; Seki et al., 2008), EAE (Monney et al., 2002; Podojil et al., 2013; Prasad et al., 2003; Sabatos et al., 2003; Zhu et al., 2005), as well as autoimmune diabetes (Sanchez-Fueyo et al., 2003; Wang et al., 2011). Together, several costimulatory receptors, as well as coinhibitory pathways, regulate the immune responses during the development of autoimmune diseases. Understanding such pathways in detail will provide novel therapeutic options for autoimmune diseases.

6. PRRs IN AUTOIMMUNITY Pioneers like Beutler, Janeway, Medzhitov, and colleagues initiated scientific interest in the field of innate immunity over the past decades (Beutler, 2000; Janeway and Medzhitov, 1999). It is now clear that immune cells use a set of evolutionarily conserved PRRs to detect foreign microorganisms via PAMPs (Cao, 2016). However, these PRRs can also sense mammalian motifs that are delivered by stressed or dying cells (Cao, 2016). Such signals include the release and intracellular engagement of ATP; endogenous TLR ligands, e.g., modified mammalian nucleic acids, are cumulatively termed DAMPs (Cao, 2016; Park et al., 2004). This so-called danger hypothesis not only implies broadened competence of the innate immune system in terms of host defense but also suggests a role for these PRRs in the pathogenesis of autoimmunity and autoimmune disease (Anders and Fogo, 2014; Lech and Anders, 2013; Lech et al., 2015; Lorenz and Anders, 2015; Marshak-Rothstein, 2006; Nickerson et al., 2010; Pawar et al., 2007). Currently, PRRs can be divided into three main families, namely: TLRs, RIG-I-like receptors (RLRs), and NOD-like receptors (NLRs) with different (sub)cellular localizations (Cao, 2016). TLRs can be subdivided into surface expressed (TLR1, 2, and 4–6) and endosomal receptors (TLR3, 7, 8, and 9). RLRs (e.g., MDA5, RIG-I) and NLRs (e.g., AIM2, NLRP3) on the contrary reside in the cytosolic compartment (Cao, 2016; Lorenz et al., 2017). Surface and endosomal TLRs cover the detection of extracellular bacterial wall components, e.g., LPS. They further sense endolysosomal RNA and DNA derived from pathogens or the host cell itself (Wu and Chen, 2014). Whereas these receptors are practically blind to cytosolic pathogens, RLRs like RIG-I or MDA5 and NLRs like AIM2 can detect viral RNA and DNA in the cytosol, respectively (Wu and


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Chen, 2014). This ubiquity awareness of nuclear acids and other PAMPs and DAMPs is double edged. Indeed, it allows the detection of a broad variety of pathogens independently of their intrusion pathway (Wu and Chen, 2014). However, under autoimmune conditions, NLR ligation by self-nuclear acids can promote autoimmunity and autoimmune tissue inflammation (Cao, 2016). In the following sections, we will discuss how PRRs can influence the pathogenesis of autoimmunity and autoimmune tissue inflammation and discuss their involvement in clinical autoimmune disease such as SLE systemic sclerosis.

6.1 PRRs and Autoimmunity How PRRs contribute to autoimmunity. The self-nucleic acids become immune stimulatory by engaging endolysosomal TLRs. For example, in SLE failure to clear apoptotic blebs on the surface of dying cells containing nuclear material and associated proteins renders these initially inert particles immune stimulatory (Casciola-Rosen et al., 1994; Lorenz and Anders, 2015). After engulfment, nuclear material containing immune complexes can stimulate autoreactive B cells to secrete autoantibodies and APCs to release proinflammatory cytokines and type I interferons in a TLR7- or a TLR9-dependent manner (Anders, 2010; Demaria et al., 2010; Lau et al., 2005; Leadbetter et al., 2002; Lorenz and Anders, 2015). Hence, it is not surprising that overexpression of RNase in TLR7 transgenic mice confers protection against TLR7-driven lupus-like disease (Sun et al., 2013). Within immune cells, ligation of most TLRs results in the recruitment of MyD88 and consequently the activation of NF-κB and mitogen-activated protein kinases (Cao, 2016). In turn, APCs produce inflammatory cytokines, enhance their antigen-presenting capability, and stimulate T- and B-celldependent adaptive immune responses (Lorenz et al., 2017). Different from this is the signaling via TLR3 and TLR4, which alternatively signal via the adapter protein TRIF to induce the production of type I interferons via interferon regulatory transcription factor (IRF) 3–7 (Cao, 2016). In addition, parenchymal cells—for example, renal mesangial cells, also express a restricted set of TLRs (e.g., TLR1–4, TLR6). Upon TLR engagement of endogenous ligands, these cells can produce chemoattractants and interleukins to recruit immune cells and promote autoimmune tissue inflammation (Lorenz et al., 2017). RLRs, like RIG-I and MDA5, detect invading virus via double-stranded or single-stranded cytosolic RNA. Consequently, type I interferon secretion

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boosters the antiviral host response (Cao, 2016). However, increased type I interferon production is also prominent in some autoimmune diseases (Lorenz and Anders, 2015). A gain-of-function mutation in the gene coding for MDA5 triggers the spontaneous onset of autoimmunity in mice, which partially depends on exaggerated type I interferon production by DCs (Funabiki et al., 2014). Interestingly, a gain-of-function mutation of the human MDA5 gene locus IFIH1 has also been identified in patients suffering from Aicardi–Goutie`res syndrome (Oda et al., 2014). The IFIH1 rs1990760 T-allele of the human IFIH1 (MDA5-coding) gene has been associated with SLE, rheumatoid arthritis, and other autoimmune diseases (Cen et al., 2013). These data indicate that aberrant RLR activity is involved in the onset of autoimmunity. In addition, parenchymal cells express MDA5 and RIG-I. After activation by RNA motives, these cells produce proinflammatory mediators and enhance inflammation on the tissue level (Hagele et al., 2009; Imaizumi et al., 2012). Activation of NLRs, like NLRP3 and AIM2, can form large molecular complexes with the adaptor protein ASC to recruit caspase-1, which results in the proteolytic activation and secretion of proinflammatory IL-1β and IL-18. Moreover, inflammasome formation can trigger a programmed proinflammatory cell death with necrotic features in macrophages, which is known as pyroptosis (Fernandes-Alnemri et al., 2009; Lorenz et al., 2014a). Further, AIM2 senses cytoplasmatic double-stranded DNA and mediates macrophage activation in response to apoptotic DNA under autoimmune conditions (Fernandes-Alnemri et al., 2009; Zhang et al., 2013). In contrast, the NLRP3 inflammasome can respond to a much broader spectrum of different DAMPs, thereby acting as a sensor of cellular homeostasis (Martinon et al., 2009). NLRP3 inflammasome activation usually comprises a two-step process. First, there is TLR or death receptormediated transcriptional upregulation of pro-IL-1β and pro-IL-18. Second, cellular potassium efflux, ROS generation, or extracellular ATP increase triggers the assembly of the NLRP3-inflammasome and caspase1-dependent IL-1β and IL-18 secretion (Lorenz et al., 2014a). Interestingly, U1-sn RNP and NETs can also stimulate NLRP3 activation (Kahlenberg et al., 2013; Shin et al., 2012). Inadequate secretion of IL-1β and IL-18 not only fosters local inflammatory responses as seen in arthritis but also skews adaptive immune responses—for example, by promoting Th17 T-cell expansion. These cells have been implicated in several autoimmune diseases (Ji et al., 2016; Zhang et al., 2016).


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6.1.1 PRRs in SLE TLR involvement in autoimmunity is most apparent in murine models of lupus-like disease. TLR7, which senses single-stranded RNA, is required for the production of anti-RNA-targeted autoantibodies in different murine models (Christensen et al., 2006; Savarese et al., 2008). Abrogation of the signaling molecule MyD88 or simultaneous deletion of TLR7 and TLR9 in MRL/lpr completely abrogates ANA production (Nickerson et al., 2010). Further, TLR7 signaling promotes systemic cytokine production, lymphoproliferation, memory T-cell formation, and severity of glomerulonephritis in these mice (Nickerson et al., 2010). In mice, bearing autoimmune susceptibility mutations such as Sle1 overexpression of TLR7 aggravates pathologies (Subramanian et al., 2006). For humans, SNP in the TLR7 gene or UTR has been associated with risk of SLE in different ethnic populations (Kawasaki et al., 2011; Lee et al., 2016; Shen et al., 2010; Wang et al., 2014b). Moreover, overexpression of TLR7 gene has been found in PBMCs from SLE patients (Lyn-Cook et al., 2014). Normalizing TLR7 expression solely in CD19+ B cells significantly decreases anti-RNA autoantibody production and severity of nephritis (Hwang et al., 2012). In accordance with this, in MRL/lpr mice, B-cell intrinsic TLR/MyD88 is required for ANA formation and full-blown nephritis, whereas DC-intrinsic signaling affects different disease features like autoimmune skin inflammation and type I interferon production by pDCs (Teichmann et al., 2013). Thus, TLR7/MyD88 signaling differentially promotes innate and adaptive immune responses in B cells and DCs. Nevertheless, nuclear acid-sensing TLRs do not promote autoimmunity uniformly and show a complex regulatory interplay. TLR9 is a sensor for CpG rich DNA that is able to sense endogenous DNA-containing immune complexes and to induce type I interferon secretion by pDCs (Leadbetter et al., 2002; Lech and Anders, 2013). TLR9 expression in peripheral blood leukocytes correlates with anti-DNA-targeted autoantibody titers and TLR9 upregulation on B cells has been correlated with increased serum creatinine in humans (Chauhan et al., 2013; Nasr et al., 2015). Although TLR9 inhibition reduced lymphoproliferation and renal inflammation upon CpG challenge in murine lupus, deletion of TLR9 in several murine models goes along with exaggerated disease (Nickerson et al., 2010; Patole et al., 2005; Bossaller et al., 2016). The Tlr9-deficient MRL/lpr mice show reduced titers of antinucleosome antibodies, but produce increased amounts of antiRNA-mediated antibodies and present with increased lymphoproliferation and aggravated renal disease (Nickerson et al., 2010). These effects can be

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abrogated by simultaneous deletion of TLR7 (Nickerson et al., 2010). Thus, TLR9 negatively regulates TLR7 in this model of systemic autoimmunity (Nickerson et al., 2010). A possible molecular mechanism for this regulatory function of TLR9 may be that TLR9 and TLR7 compete for endosomal trafficking via Unc93B1 (Fukui et al., 2011). Consequently, in the absence of TLR9, TLR7 trafficking to the endosome may be increased (Fukui et al., 2011; Lorenz et al., 2017). Like TLR9, the role of TLR8 is difficult to predict in SLE and autoimmunity. In 564Igi mice that express an anti-RNA-antibody, TLR8 contributes to autoantibody production and type I interferon production. However, in C57BL/6 mice, loss of TLR8 results in lymphoproliferation, anti-dsDNA autoantibody production, and glomerulonephritis (Demaria et al., 2010; Tran et al., 2015). Interestingly, myeloid cell TLR7 signaling is exaggerated in Tlr8-deficient animals and simultaneous deletion of TLR7 can rescue the phenotype of Tlr8-deficient animals (Demaria et al., 2010; Tran et al., 2015). Thus, both TLR8 and TLR9 differentially regulate TLR7-mediated autoimmunity in murine lupus. Besides that, also TLR2 and TLR4 have been implemented in the pathogenesis of autoimmunity. Pristane-induced nephritis as well as nephritis in C57BL6lpr/lpr mice partially depends on the presence of TLR2 and TLR4 and responsiveness of PBMCs to TLR2 and TLR4, in terms of cytokine production, is increased in SLE patients (Klonowska-Szymczyk et al., 2014; Lartigue et al., 2009; Nasr et al., 2015; Summers et al., 2010). Murine macrophages in lupus-prone MRL/lpr mice display defects in lysosomal maturation and acidification. This goes along with prolonged and heightened ROS production and reduced elimination of internalized IgG immune complexes (Monteith et al., 2016). Internalized IgG immune complexes stimulate endolysosomal TLR7 and TLR9 to increase type I interferon production (Monteith et al., 2016). Most importantly, dsDNA from immune complexes was shown to leak into the cytosol and to drive AIM2 inflammasome assembly in macrophages (Monteith et al., 2016). This might explain how knockdown of AIM2 in an apoptotic DNA-induced lupus model decreases systemic inflammation and nephritis (Zhang et al., 2013). The AIM2 expression in human PBMCs is upregulated in SLE patients and correlated to clinical disease severity (Zhang et al., 2013). Therefore, AIM2 might be an important sensor for self-DNA in SLE and contribute to renal inflammation via aberrant activation of infiltrating macrophages (Monteith et al., 2016; Zhang et al., 2013). However, New Zealand Black (NZB) mice, which spontaneously develop autoimmune


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hemolytic anemia and lupus-like disease, present defective NLRP3 and AIM2 inflammasome signaling (Sester et al., 2015). This implies that other genetic alterations can substitute for aberrant NLR signaling in order to promote SLE pathogenesis. Further, there is the possibility that like TLR9, NLRs have additional negative regulatory functions via interfering with other signaling pathways. In this context, Nlrp3-deficient B6lpr mice have been shown to display exaggerated lymphoproliferation and autoimmune kidney and lung injury, eventually due to decreased immunosuppressive TGFβ signaling in these mice (Lech et al., 2015). On the contrary, inhibition of NLRP3 inflammasome activation reduced Th17 T-cell polarization and beneficially influenced nephritis and lifespan in MRL/lpr and NZM2328 mice (Zhao et al., 2013a). Intensive research is needed to further dissect the complex regulatory interplay among different PRRs to exploit these receptors as therapeutic targets in the future. SLE patients show elevated production of type I interferons similar to a (pseudo)antiviral immune response (Lorenz et al., 2017). In addition to the endosomal TLR3, TLR7 and TLR9 as well as RLRs, e.g., RIG-I and MDA5, are potent triggers of type I interferon and proinflammatory mediator production (Allam et al., 2008; Lorenz and Anders, 2015). In fact, a gain-of-function mutation in MDA5 has been identified in both murine and human lupus-like disease (Funabiki et al., 2014; Van Eyck et al., 2015). Mice expressing a constitutively active MDA5 mutant develop anti-dsDNA autoantibodies, systemic inflammation, and glomerulonephritis, which in part depends on type I interferons (Funabiki et al., 2014). In brief, there can be no doubt aberrant TLR, NLR, and RLR activations are deeply involved in murine and human SLE pathogenesis. Here, they influence both adaptive and innate immunity. 6.1.2 PRRs in Systemic Sclerosis Systemic sclerosis is another clinical example of autoimmunity. The exact pathogenesis of this condition remains elusive. However, it can be characterized by small vessel abnormalities, aberrant innate, and adaptive autoimmunity ultimately ending in fibrosis of the skin and inner organs (Fuschiotti, 2016). Monocytic cell infiltration in the skin precedes the onset of fibrosis in patients (Ishikawa and Ishikawa, 1992; Kraling et al., 1995). Interestingly, Broen and colleagues demonstrated that a TLR2 polymorphism (Pro631) that renders myeloid DCs prone to proinflammatory mediator production correlated with antitopoisomerase positivity, disease severity, and the development of pulmonary hypertension in systemic sclerosis patients

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(Broen et al., 2012). In addition, dermal fibroblasts of systemic sclerosis patients express increased surface TLR2 and, therefore, show increased IL-6 production when exposed to the endogenous TLR2 ligand, serum amyloid A (O’Reilly et al., 2014). In analogy, Bhattacharyya et al. found increased TLR4 expression on fibroblasts and vascular cells within dermal or pulmonary lesions of systemic sclerosis patients. They also showed a simultaneous increase of endogenous TLR4 ligands such as the alternative spliced fibronectin domain A in five skin biopsy speciesism (Bhattacharyya et al., 2013, 2014). In vitro TLR4 activation of systemic sclerosis dermal fibroblasts resulted in an increased TGFβ response and profibrotic capacity (Bhattacharyya et al., 2013). Thus, enhanced TLR4 responsiveness for endogenous DAMPs may tip the scales toward uncontrolled fibrosis in systemic sclerosis (Bhattacharyya et al., 2013). Additional data suggest an involvement of endosomal nucleic acid-sensing TLRs in the pathogenesis of systemic sclerosis. Similar to SLE, an involvement of increased type I interferon-responsive gene expression has been demonstrated for dermal fibroblasts in systemic sclerosis (Farina et al., 2010). In this context, chronic activation of TLR3 via subcutaneous Poly(I:C) application in mice was shown to induce interferon and TGFβ depending on the gene expression in dermal fibroblast. Consequently, Poly(I:C)-treated mice developed inflammation and fibrotic remodeling of the skin, which was in part dependent on the TLR3/TRIF axis (Farina et al., 2010). Moreover, similar to the induction of type I interferons in SLE by RNA-containing immune complexes, systemic sclerosis-specific autoantibodies such as antitopoisomerase can induce type I interferon production in PBMCs (Eloranta et al., 2009; Kim et al., 2008). Combined DNase and RNase treatment of patients’ sera or blockage of Fc gamma receptors (FcyR) II on test PBMCs was able to reduce the type I interferon inducing properties of antitopoisomerase antibodies of patients sera (Kim et al., 2008). Therefore, similar to SLE, interferon induction in systemic sclerosis by autoantibodies requires FcyR-mediated uptake and eventually TLR7 or TLR9 engagement (Kim et al., 2008; Santegoets et al., 2011). In brief, these data indicate that dysregulated TLR signaling is an early event in the pathogenesis of systemic sclerosis promoting local tissue inflammation as well as systemic disease features. Although data on the involvement of NLRs and RLRs in systemic sclerosis are rare, an involvement in this disease seems likely. In fact, the NLR, especially NLRP3, is overexpressed in skin biopsies of systemic sclerosis patients and correlates with skin thickening and profibrotic


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mediator expression (Martinez-Godinez et al., 2015). Inhibition of downstream caspase-1 activation reduced secretion of the proinflammatory mediators IL-1β and IL-18 as well as the production of collagens by systemic sclerosis fibroblasts (Artlett et al., 2011).

7. TISSUE INFLAMMATION AND INJURY IN AUTOIMMUNITY 7.1 Immune Complexes The binding of autoantibodies to soluble autoantigens results in the formation of immune complexes. Immune complexes are involved in several immune responses—for example, phagocytosis, opsonization, and complement activation. Mononuclear phagocytes or red blood cells that bear the complement and Fc receptors usually efficiently clear the immune complexes from the body. However, impairment in their clearance machinery leads to their deposition and subsequent tissue injuries resulting in autoimmune diseases. Such autoimmune responses are classified as type III autoimmune responses. Immune complex-mediated inflammation and tissue injury primarily depend on the Fcγ receptors (FcγRs) that bind to Fc-binding domain of IgG. They are further classified into activating or inhibitory FcγRs and are present in immune cells, e.g., neutrophils, which upon activation by inflammatory mediators shed inhibitory FcγRs and modulate activating FcγRs (Selvaraj et al., 2004). Therefore, the activities of FcγRs at the site of inflammation determine the magnitude of neutrophil responses. In fact, mice lacking the activating FcγRs were protected from SLE, whereas mice lacking inhibitory FcγRs showed exacerbated SLE disease (Mayadas et al., 2009). In addition to FcγRs, the immune complex deposition in tissues activates the complement cascade, which mediates inflammation and tissue injury. Complement C1Q binds to the Fc part of the antibody, leading to activation of anaphylatoxins C5a and C3a (Mayadas et al., 2009). This results in secretion of proinflammatory cytokines and chemokines that activate endothelial cells. Further, activated endothelial cells increase the expression of adhesion receptors on the surface, subsequently leading to enhanced recruitment of neutrophils at the target site (Kim and Luster, 2015; Mayadas et al., 2009). In addition, the complement factor C3a also possesses the potential to induce NETosis. NETosis results in release of complement components C3a and C5a along with the DAMPs (Guglietta et al., 2016; Yuen et al., 2016). These extracellular DAMPs, along with C3a and C5a,

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activate other immune cells to secrete proinflammatory cytokines. Some proinflammatory cytokines, e.g., TNFα, possess the potential to induce regulated necrosis and, therefore, cause further DAMPs release from the dying cells. In addition, neutrophils recruited at the site of inflammation can directly induce cytotoxicity via FcγRs, complement receptors, and ROS generation (Mayadas et al., 2009). This sets up an autoamplification loop between cell death and inflammation, which is referred as necroinflammation (Linkermann et al., 2014; Mulay et al., 2016b,c,d) (Fig. 4). Furthermore, the FcγRs bearing neutrophils signal macrophage recruitment at the inflammatory site (Tsuboi et al., 2008), which also contribute to immune complex-mediated inflammation and tissue injury.

Fig. 4 Schematics of immune complex deposition-mediated tissue injury. The binding of autoantibodies to soluble autoantigens results in the formation of immune complexes. Impairment in their clearance machinery leads to their deposition in tissues, where the Fc part of the antibody binds to complement C1Q, and leads to the activation of C3a as well as C5a. These anaphylatoxins then activate the immune cells to secrete proinflammatory cytokines and chemokines as well as increase the recruitment of immune cells, viz., neutrophils in the injured tissues. In addition, C3a and C5a can induce cell necrosis as well as neutrophil extracellular trap (NET) formation and, therefore, induce DAMP release. DAMPs activate other immune cells to secrete proinflammatory cytokines that may possess the potential to induce regulated necrosis (e.g., TNFα), resulting in a further DAMP release. This sets up an autoamplification loop between inflammation and cell death, known as necroinflammation, which subsequently contributes to the tissue injuries resulting in autoimmune diseases.


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The more common examples of immune complex-mediated autoimmune diseases are SLE (discussed in detail later), all forms of immune complex glomerulonephritis, e.g., IgA nephropathy (Fabiano et al., 2016), and cryoglobulinemic vasculitis. Cryoglobulinemic vasculitis is a form of vasculitis that is caused by the cryoglobulin-containing immune complexes. Cryoglobulins are immunoglobulins that form solid precipitates at low temperature and redissolve at body temperature (Takada et al., 2012). Cryoglobulinemia, presence of cryoglobulins in serum, is often observed in lymphoproliferative disease (type I cryoglobulinemia), or collagen disease and infections of hepatitis C virus (type II and III cryoglobulinemia) (Takada et al., 2012). The disease affects skin, muscles, nerves, lungs, kidneys, and bone marrow (Takada et al., 2012).

7.2 Lymphocytes The key feature of most of the autoimmune diseases is the presence of autoreactive T and/or B lymphocytes in the periphery. Usually, lymphocytes have less affinity toward antigens as such, and therefore, they are unable to react to the antigen directly. However, they become activated when the APCs, which also express high levels of costimulatory molecules, present the antigen to them. 7.2.1 T Lymphocytes T lymphocytes that are present in the inflamed tissues contribute to the inflammatory processes in tissue damage. For example, their presence in the kidney of SLE patients is linked to the decreased renal function (Tsokos, 2011). T cells sense antigen via the T-cell receptor (TCR) in conjunction with the CD3-defined complex of transmembrane proteins (ε, δ, γ, and ζ) to activate a signaling process that decides the effector cell function (Moulton and Tsokos, 2015). Aberrations in this signaling pathway during autoimmune diseases lead to hyperactivated T-cell responses causing defective gene transcription, increased cytokine production, e.g., IL-17 and IFNγ, as well as excessive help to B cells to produce more autoantibodies, e.g., anti-dsDNA autoantibodies in SLE (Moulton and Tsokos, 2015). Furthermore, T cells also express several costimulatory molecules that promote B-cell differentiation, proliferation, and autoantibody production in autoimmune diseases (Kow and Mak, 2013). The TCR complex as well as the costimulatory molecules is present in the lipid rafts on T-cell membrane. Therefore, alterations in the T-cell lipid rafts in

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autoimmune diseases lead to a reduction in their activation threshold (Jury et al., 2004). T cells are subdivided depending on the expression of CD4, CD8, and TCR chains (α, β, γ, δ) into: A. Double-negative (CD4CD8) T cells. Although the origin of these cells is still not so clear, the populations of TCRαβ+CD4CD8 T cells are increased in blood of patients with SLE as well as autoimmune lymphoproliferative syndrome (Konya et al., 2014). They produce proinflammatory IL-17 and augment the production of pathogenic anti-DNA autoantibodies associated with LN (Shivakumar et al., 1989). B. TH17 cells. CD4+ T cells undergo a specific differentiation to become TH17 cells that produce IL-17 (Wilson et al., 2007). IL-17 is considered as an important cytokine that contributes to the development of autoimmune inflammation. Mice deficient in IL-17 are protected from SLE (Amarilyo et al., 2014). In addition, the IL-17 blockade was beneficial in ameliorating inflammation in autoimmune diseases like psoriasis, rheumatoid arthritis, and uveitis (Hueber et al., 2010). C. T follicular helper cells. These are activated T helper cells that migrate from thymic extrafollicular area to germinal center where they stimulate the activated B cells to produce autoantibodies and then differentiate into T follicular helper cells expressing CXCR5 (Konya et al., 2014). They are increased in blood of patients with SLE (Yang et al., 2014) and are demonstrated to contribute to the development of lupus in Fas-deficient mice (Futatsugi-Yumikura et al., 2014). D. Tregs. Regulatory T cells are the CD4+ T cells that express the transcription factor Foxp3. They are important for maintaining the self-tolerance and thereby control the immune system. These CD4+Foxp3+ Tregs are decreased in patients with SLE, which contributes to lack of self-tolerance (Konya et al., 2014). 7.2.2 B Lymphocytes B lymphocytes contribute to the development of autoimmune diseases by different cellular functions—for example, A. Secretion of autoantibodies. B cells secrete autoantibodies against DNA, chromatin peptides, and ribonucleoproteins in SLE (Iwata and Tanaka, 2016); against ribonucleoprotein antigens in Sj€ ogren’s syndrome (Shen et al., 2016); and against DNA topoisomerase I, RNA polymerases, and fibrillin-1 during systemic sclerosis (Sakkas and Bogdanos, 2016).


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B. Presentation of autoantigens. B cells stimulate antigen-specific CD4+ T-cell proliferation after naı¨ve T-cell priming by DC (Giles et al., 2015; Ronchese and Hausmann, 1993). C. Secretion of inflammatory cytokines. B cells secrete cytokines such as IL-6, TNFα, and IL-10 as well as other immunoregulatory cytokines such as IL-2, IFNγ, IL-12, and IL-4 when stimulated with Th cells and antigens (Harris et al., 2000). D. Generation of ectopic germinal centers. B cells help in the process of ectopic germinal center formation during the chronic inflammatory condition. Such ectopic germinal centers are observed in SLE, rheumatoid arthritis, Sj€ ogren’s syndrome, multiple sclerosis, and type 1 diabetes (Aloisi and Pujol-Borrell, 2006; Hampe, 2012). B cells are activated when the antigen binds to the BCR (Yuseff et al., 2013). Other lymphoid cells that cause cytotoxicity and contribute to inflammation by secreting cytokines include NK cells, CD56+ T cells, NKT cells, gamma/ delta (γδ) T cells, and mucosal-associated invariant T cells (Doherty, 2016).

7.3 Monocytes and Macrophages Monocytes and macrophages are involved in various important functions that regulate innate immunity—for example, cytokine production, antigen presentation to T cells, and phagocytosis. They recognize and remove pathogens as well as dead or damaged host cells. Abnormalities in these functions of monocytes and macrophages are linked to the pathogenesis of several autoimmune diseases (Brunini et al., 2016; Hamerman et al., 2016; Katsiari et al., 2010; Roberts et al., 2015). The immune responses by these cells are governed by the expression of surface markers, which help them to sense the environment and respond to it. For example, abnormalities in the FcγRs, involved in phagocytosis as well as inflammatory cytokine production, contributed to the development of LN in NZB/WF1 murine model of lupus (Bergtold et al., 2006; Clynes et al., 1998). The antibodies that form immune complexes have been demonstrated to interact with the FcγRs present in the immune cells (Bergtold et al., 2006; Nimmerjahn and Ravetch, 2008). Such aberrant activation of monocytes and macrophages causes increased production of inflammatory cytokines in SLE, rheumatoid arthritis, as well as Sj€ ogren’s syndrome (Katsiari et al., 2010; Roberts et al., 2015; Tsokos, 2005). These cytokines further contribute to aggravation of the autoimmune disease—for example, IL-6 and IL-10 promoted IgG production; IL-6 and IFN-1 together can

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induce B-cell maturation in SLE patients (Jego et al., 2003); whereas IL-6, IL-23, TNFα, IL-1β, and TGFβ have been implicated in the pathogenesis of rheumatoid arthritis (Estrada-Capetillo et al., 2013; Roberts et al., 2015). Recently, it is reported that in healthy individuals an autoregulatory feedback mechanism exists between DCs and regulatory B cells that are mediated by IFNα, and alteration in this mechanism results in SLE (Menon et al., 2016). Monocytes are instrumental in both inductions and maintenance of the immune tolerance. A phenotypic analysis of monocyte-derived DCs from SLE patients in the presence of IL-10 revealed enhanced levels of HLA-DR, CD80, CD9, and CD151 tetraspanins, FN1 (a class II MHC-tetraspanin epitope), CD85j/ILT2, and CD69, suggesting that these cells have an enhanced capacity of antigen representation (Figueroa-Vega et al., 2006). Furthermore, the expression of costimulatory molecules is critical for antigen presentation. Monocytes from SLE patients express high levels of CD40, ICAM-1, STAT-1, and CD69 at the baseline, suggesting their activation status; they indicate an increased costimulatory potential (Kuroiwa et al., 2003). Monocytes and macrophages also play a crucial role in host defense by phagocytosing pathogens as well as dying cells. Increased apoptosis and deficiency in clearing apoptotic cells are considered an important pathomechanism, leading to autoimmune diseases (Biermann et al., 2014). Impaired clearance of dying cells promotes the abundance of autoantigens derived from necrotic cells and thus increased antigen presentation to T and B lymphocytes resulting in increased autoantibody production, chronic inflammation, and severe tissue damage (Biermann et al., 2014).

7.4 Tertiary Lymphoid Organs The persistence exposure of antigens increases the continuous need for extravasation of leukocytes during an autoimmune attack, leading to the formation of the TLOs (Jones and Jones, 2016). The term TLOs is referred to: A. The anatomically distinct infiltrates those are adjacent to T- and B-cell compartments. B. T-cell compartment rich in fibroblasts reticular cells. C. T-cell compartment rich in PNAd+ or MECA79+ high endothelial venules.


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D. Evidence of B-cell class switching and germinal center reactions in B cells. E. The presence of activation-induced cytidine deaminase enzyme. F. The presence of follicular DCs (Neyt et al., 2012). The formation of TLOs at the site of chronic inflammation is induced by the cytokines and chemokines. For example, overexpression of IL-22, IL-7, LTα, CCL21, and CXCL13 promoted the formation of TLOs (Barone et al., 2015; Marinkovic et al., 2006; Neyt et al., 2012), whereas deletion of CXCL13, CXCR5, and CCR7 inhibits the formation of TLOs (Rangel-Moreno et al., 2007; Wengner et al., 2007; Winter et al., 2010). TLOs allow the activation of naive T cells and B cells by DCs within the germinal centers as well as induce self-reactive T lymphocytes and antibodies (Lee et al., 2006; Moyron-Quiroz et al., 2004). The formation of TLOs is observed in various autoimmune diseases including type 1 diabetes, SLE, rheumatoid arthritis, as well as autoimmune thyroiditis (Armengol et al., 2001; Chang et al., 2011; Lee et al., 2006; RangelMoreno et al., 2006).

8. GENETIC RISK FACTORS FOR ORGAN MANIFESTATIONS IN HUMAN AUTOIMMUNE DISEASES Loss of organ-specific tolerance can be attributed to either lack of thymic presentation of organ-specific antigen or altered antigenicity within the target organ. The identification of the common genetic risk variants, their frequencies in the population (risk allele frequency), and the risks of disease they confer (odds ratio) by the genome-wide association studies (GWASs) have revealed very important information on the genetic risk factors for human autoimmune diseases (Goris and Liston, 2012; Iles, 2008). We have summarized the genetic loci associated with lack of organ-specific tolerance and development of organ-specific autoimmune diseases later. Genetic defects affecting the negative selection process increase the susceptibility to autoimmune disease. For example, the APS-1 is monogenic autoimmune disease because of mutations in gene AIRE (Finnish-German, 1997; Nagamine et al., 1997). Multiple mechanisms of action for AIRE have been suggested, viz.: (1) Aire protein has a transcriptional activity (Kumar et al., 2001; Pitkanen et al., 2000) and is directly involved in the expression

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of self-antigen within thymus (Ruan et al., 2007), (2) Aire may function via intermediates, viz., cofactors (Ilmarinen et al., 2008), or indirectly recruits transcriptional components required for target gene expression (Org et al., 2008; Tao et al., 2006). Aire deficiency interacts with the loci associated with the common autoimmune diseases and alters the disease progression in APS-1 patients (Halonen et al., 2002; Kogawa et al., 2002). The Aire pathway is very sensitive, and a slight reduction in Aire expression leads to reduced expression of Aire-dependent antigens. This indicates that small changes in the thymic expression of Aire-dependent antigens may contribute to autoimmune susceptibility in a disease-specific manner (Kont et al., 2008; Liston et al., 2004). For example, the susceptibility alleles of the INS locus cause a two- to threefold decrease in AIRE-dependent thymic expression of the insulin gene (Taubert et al., 2007; Vafiadis et al., 1997). Furthermore, Chrna1 is an organ-specific gene expressed in an AIRE-dependent manner in the thymus. CHRNA1 has allelic variants with reduce thymic expression of the antigen resulting in the autoimmune disease, myasthenia gravis (Giraud et al., 2007). Other susceptibility gene variants with reduced thymic expression are MBP that is associated with multiple sclerosis, and TSHR and TG that are associated with autoimmune diabetes. The common factor involved in all these cases is the organ-specific expression of target antigens. However, in some cases the putative genes might also be associated with imbalance between thymic and peripheral expression—for example, PADI4 locus with rheumatoid arthritis (Yamada and Yamamoto, 2007) and the TREX1 and DNASE1 loci with SLE (Lee-Kirsch et al., 2007; Shin et al., 2004). The PADI4 encodes for peptidyl citrulline, TREX1, and DNASE1 producing DNA fragments. Association of the PDS locus, which produces pendrin, with autoimmune type 1 diabetes explains the synergy between genetic and environmental factors. Pendrin contributes to the iodination of thyroglobulin and increases its antigenicity (Barin et al., 2005). Apart from the expression and antigenicity of the antigen, the other aspect of the immune tolerance revolves around the efficient antigen presentation and that makes MHC-II gene within the HLA locus an important factor. For many autoimmune diseases, HLA is the most important genetic contributor (Chung et al., 2014; Fernando et al., 2008; Goris and Liston, 2012). Two alternative mechanisms exist for the association of altered peptide presentation to autoimmunity, viz., the reduced thymic presentation of major target autoantigens for tolerogenic purposes, and the enhanced peripheral presentation of major target autoantigens. Substitution of aspartic residue at position 57 of HLA-DQ8 with serine, alanine,


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or valine increases the binding of insulin peptide to HLA-DQ and may elicit an autoimmune response (Faas and Trucco, 1994). Similarly, HLA-DR2 variants have an increased ability to display a dominant epitope of MBP to CD4+ T cells and contribute to the development of multiple sclerosis (Li et al., 2005; Maynard et al., 2005). In addition, some variants of class II HLA-DRB1 are biased toward recognizing a cartilage-specific protein CII in rheumatoid arthritis (Burkhardt et al., 2006). Furthermore, recent GWASs of LN identified multiple LN-susceptibility loci that are independent of HLA regions. For example, the MHC locus rs9263871 located within HCG27 had strongest association with LN (Chung et al., 2014). Other loci that are associated with LN include rs1364989 on 4q11–q13, upstream of PDGF receptor α; rs274068 on 16p12.1 within an intronic region of sodium-dependent glucose cotransporter SCL5A11; and rs7834765 on 8q24.12 as well as other two regions on 6p22 and 9p21 (Chung et al., 2014). Apart from loss of immune tolerance in an antigen-specific manner, other mechanisms can also participate in organ-specific autoimmune disease, viz., increased immune trafficking in the target organ. Multiple genes associated with Crohn’s disease are suggestive of increased leukocyte trafficking, including Atg16l1, Irgm, Mdr1, Mst1, Ncf4, and Nkx-2.3 (Ellson et al., 2006; Rioux et al., 2007; Singh et al., 2006; Suh et al., 2006). In autoimmune diabetes, gene TNFR2 is responsible for increased damage to the islet cells due to prolonged signaling through TNFR2 (Walter et al., 2000). Moreover, GWASs revealed the contribution of PTPN22 to autoimmune type 1 diabetes and rheumatoid arthritis (Begovich et al., 2004; Bottini et al., 2004), as well as NOD2 and IL-23R to Crohn’s disease (Duerr et al., 2006; Hugot et al., 2001; Ogura et al., 2001). In conclusion, the development of autoimmune disease is, therefore, an additive effect of defects in multiple immune tolerance mechanisms being directed toward a specific target organ by additional organ-specific defects, heavily modified by environmental influences.

9. LUPUS NEPHRITIS SLE and its most common organ manifestation, LN, strikingly reflect the implications of systemic autoimmunity and autoimmune tissue injury in clinical reality. In this chapter, we will recapitulate the factors involved in breaking tolerance against self during SLE and describe the mechanisms acting inside the nephritic kidney.

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9.1 Systemic Autoimmunity in SLE Genetic susceptibility predisposes to SLE. SLE is rather a clinical syndrome than a defined disease entity. Patients present with variable symptoms and organ involvement can differ among them. Yet, they share serological features like ANAs that document the loss of tolerance against self-nuclear acids. However, what are the reasons for this? Familial aggregation studies support a genetic predisposition to SLE (Alarcon-Segovia et al., 2005; Ghodke-Puranik and Niewold, 2015). In general, SLE follows a polygenetic inheritance pattern, meaning that many risk alleles of moderate effect size (odds ratio 1, 5-2, 5) are present in one individual prone to developing SLE (Ghodke-Puranik and Niewold, 2015). GWASs have identified over 40 risk loci that correlate with an increased risk to develop SLE (Ghodke-Puranik and Niewold, 2015). Strong associations have been found for HLA loci and SLE (Ghodke-Puranik and Niewold, 2015). In addition, genetic alterations in genes promoting type I IFN responses or reducing clearance of apoptotic materials such as IRF5, DNase I, or complement deficiencies have been identified as risk loci in SLE (Ghodke-Puranik and Niewold, 2015; Niewold et al., 2008; Truedsson et al., 2007; Yasutomo et al., 2001). SLE is a heterogeneous disease. In order to understand the heterogenicity of SLE, Banchereau et al. profiled the blood transcriptome of a longitudinal cohort of pediatric lupus patients and have identified a plasmablast signature as a biomarker of disease activity (Banchereau et al., 2016). They also identified neutrophil-related immune signatures with progression to LN (Banchereau et al., 2016). This approach of personalized immunomonitoring also enabled patient stratification into groups that might facilitate implementation of personalized therapies in SLE (Anders and Kretzler, 2016; Anders et al., 2015; Banchereau et al., 2016). 9.1.1 Apoptotic Material Triggers an Inappropriate Immune Response In order to prevent inappropriate immune reactions against self-nuclear acids and associated proteins, the apoptotic material is usually rapidly cleared from the environment (Lorenz et al., 2014b). DNase and RNase degrade extracellular nuclear material (Lorenz et al., 2014b; Yasutomo et al., 2001). C1q marks apoptotic bodies for SCARF1 receptor-dependent clearance by phagocytes (Ramirez-Ortiz et al., 2013). In SLE patients, genetic alterations weaken these defense mechanisms. As a consequence,


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nuclear material persists in the tissue compartment and can undergo changes rendering it immune stimulatory (Lorenz et al., 2017). In addition, defects in lysosomal degradation of nuclear material lead to prolonged persistence of nuclear material within phagocytes and may facilitate the recycling of DAMPs to the cell membrane (Monteith et al., 2016). Additional sources of extracellular immunogenic material are netting neutrophils (Leffler et al., 2015; Lindau et al., 2014). Interestingly, SLE patients that present with a reduced ability to degrade those NETs also have a reduced ability to degrade secondary necrotic particles and have an increased likelihood of nephritic involvement (Leffler et al., 2015). Cell necrosis in response to injuries or sunburns also increases the load of necrotic material that has to be cleared. Failure of clearance of these intracellular autoantigens induces SLE (Lorenz et al., 2017; Munoz et al., 2010). The deficiency of the tyrosine kinase c-Mer and the Milk fat globule protein factor 8, which are involved in recognition and clearance of early apoptotic cells, results in anti-DNA autoantibodies and SLE (Cohen et al., 2002; Hanayama et al., 2004). The extracellular chromatin because of cell necrosis as well as neutrophil extracellular trap formation is cleared efficiently by endonucleases such as DNase 1, and therefore, the loss of function of DNAse 1 has been associated with renal manifestations in murine SLE (Seredkina and Rekvig, 2011). Furthermore, defects in LAP, a form of noncanonical autophagy to remove dying cells, also contribute to the pathogenesis of murine SLE (Martinez et al., 2016). 9.1.2 Mistaking Self-Nuclear Components for Invading Virus High titer ANA production implies an inappropriate innate and adaptive immune response against self-nuclear acids and associated proteins. Prolonged presence of nuclear particles in the extracellular matrix can reverse epigenetic modifications that normally inhibit self-nuclear acid recognition by PRRs (Kariko et al., 2004; Lorenz et al., 2014b). Some drugs, e.g., procainamide, were also shown to inhibit DNA methylation, thereby enhancing immune simulative properties of self-DNA (Cornacchia et al., 1988). Consequently, after engulfment into phagocytes, secondary necrotic material gains the ability to stimulate innate immune responses via TLR3, 7, 8, and 9, NLRs like AIM2, or RLRs like MDA5, as discussed earlier (Allam et al., 2008; Lorenz et al., 2014b; Zhang et al., 2013). Similar to an infection with intracellular virus innate immune cells, pDCs produce large amounts of type I interferons and initiate

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proinflammatory cell response programs (Lorenz et al., 2014b; Savarese et al., 2006). In this context, DNA-containing immune complexes and U1snRNP were shown to activate TLR9 or TLR7 in pDCs, respectively (Leadbetter et al., 2002; Savarese et al., 2006). Since cellular responses to improperly cleared nuclear material mimic those during viral infection, it is likely that viral infection in SLE patients delivers a potent stimulus of active disease flares (Theofilopoulos et al., 2005). These analogies between SLE and viral infectious diseases have led to the concept of pseudo antiviral immunity as a model for SLE pathogenesis (Lorenz et al., 2017). 9.1.3 Directing Adaptive Immunity Against Autoantigens APCs, i.e., DCs, represent the link between innate and adaptive immunity. Due to persistent activation by endogenous immune stimuli, DC’s life span is prolonged in SLE (Guiducci et al., 2010). The pDCs in SLE exhibit increased expression of the IRF3, which goes along with increased type I IFN production in patients (Santana-de Anda et al., 2014). The DCs further show increased expression of costimulatory molecules like CD40 and CD86, as well as an increased activating/inhibitory FcγR expression ratio, which might contribute to a break in self-tolerance in SLE pathogenesis (Carren˜o et al., 2009; Mackern-Oberti et al., 2015). Although the precise mechanisms in breaking T-cell tolerance remain elusive, reduced ability to induce PD1L expression on DCs, which can mediate T-cell suppression via ligation of PD1 on T cells, could promote autoreactive T-cell expansion in SLE (Mackern-Oberti et al., 2015; Mozaffarian et al., 2008). Activated DCs can directly stimulate B-cell proliferation, maturation, and autoantibody production in murine models of SLE (Wan et al., 2008). Furthermore, in SLE, RNA- and DNA-containing autoantigens can directly activate autoreactive B cells via dual engagement of TLR7 or TLR9 and the BCR (Lau et al., 2005; Leadbetter et al., 2002). TLR7 overexpression solely in B cells is sufficient to trigger autoantibody production and lupus progression in Sle1 lupus-susceptible mice (Hwang et al., 2012). The long-lived autoreactive plasma cells rather than the short-lived plasmablasts produce autoantibodies and contribute to chronic humoral autoimmunity in BZB/W mice (Hoyer et al., 2004; Moser et al., 2006). In summary, aberrant stimulation of B cells by DCs and continuous exposure to endogenous PRR ligands foster the selection of self-reactive B cells and promotes autoantibody production.


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9.2 Autoimmunity and Tissue Inflammation Inside the Kidney 9.2.1 Immune Complex Formation Inside the Kidney LN manifests because of systemic autoimmunity. The formation of immune complexes rather than their passive deposition in different glomerular compartments is a diagnostic hallmark of LN (Lorenz et al., 2017). Immune complexes can harm glomerular cells in different ways. Resident renal cells and immune cells can bind Immunoglobulins via FcR. Immune complexes have the potential to activate the C1q-dependent classical complement pathway. In turn, the proteolytic product C5a serves as a chemoattractant for infiltrating immune cells that cause inflammation and injury (Lorenz et al., 2014b; Yung and Chan, 2015). However, the contribution of complement pathway in the development of SLE is paradoxical. For example, the classical complement C1q participated in phagocytosis of apoptotic cells and its deficiency leads to the development of SLE (Botto, 2001). The anti-dsDNA antibodies may also cross-react within renal cell antigens, such as Annexin II or α-actinin (Yung and Chan, 2015). Last, nuclear material can ligate innate PRRs on resident renal cells and infiltrating immune cells to stimulate local tissue inflammation and cytokine production (Allam et al., 2009; Flur et al., 2009). Immune complexes contain IgM, IgA, and IgG and seem to form in the kidney after binding to renal matrix components (Krishnan et al., 2012; Tojo et al., 1970). Immune complexes can be located in the mesangium, the subendothelial, or the subepithelial space. Outside the glomerular immune complexes can be found along peritubular capillaries (Yu et al., 2010). The histopathological classification of LN reflects their distribution within the renal compartments. Class I and II LN means the presence of mesangial immune complexes. Subendothelial and subepithelial immune complexes can be found in class III and IV or V LN, respectively (Weening et al., 2004). 9.2.2 Innate Immune Signaling Inside the Nephritic Kidney As mentioned earlier, immune complexes have the potential to activate innate PRRs within renal parenchymal cells and infiltrating immune cells. Mesangial cells are reactive to DNA or RNA antigens that aggravate LN (Allam et al., 2008, 2009). Activation of MDA5 in mesangial by exogenous RNA triggers potent type I interferon responses (Flur et al., 2009). Ligation of TLR3 in mesangial cells can upregulate the expression of CXCL1, a strong neutrophil chemoattractant that is enriched during LN (Imaizumi et al., 2014). Glomerular endothelial cells were shown to depend on RIG-I

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rather than MDA5 to produce type I interferons and proinflammatory mediators such as IL-6 in response to double-stranded RNA (Hagele et al., 2009). TLR4 is also expressed on podocytes during nephritis. Ligation of TLR4 results in the production of chemokines by podocytes (Banas et al., 2008). Overall, sensing of DAMPs via PRRs in renal parenchymal cells promotes intrarenal inflammation and tissue injury. Furthermore, Stamatiades et al. demonstrated the presence of kidney-specific macrophages that monitor the transport of proteins and particles into the renal interstitium. These kidney macrophages also detect and scavenge the immune complexes in the interstitium and trigger an FcγRIV-dependent inflammatory response and the recruitment of monocytes and neutrophils (Stamatiades et al., 2016). 9.2.3 Immune Cell Infiltration Into Renal Tissue Inflammatory mediators lure a great variety of cells into the nephritic kidney. In some cases, there even is TLO formation inside the tubulointerstitial compartment. Here, B cells can proliferate and undergo somatic hypermutation stimulated by T cells (Chang et al., 2011). In NZB/W mice, autoreactive long-lived anti-dsDNA-specific plasma cells were shown to reside in the kidneys in large numbers (Espeli et al., 2011; Moser et al., 2006). In humans, intrarenal plasma cells correlate with disease severity (Espeli et al., 2011). Among T cells, TH17 cells are currently under intensive investigation in the context of SLE. Increased numbers of these cells along with a skewed TH17/Treg balance have been demonstrated for SLE patients. Th17 T cells infiltrate the renal tissue and promote tissue damage (Koga et al., 2016). Although LN and interstitial infiltrates can develop in the absence of DCs, they promote the progression of nephritis in MRL/lpr mice via stimulating local and systemic inflammatory responses (Sahu et al., 2014; Teichmann et al., 2010). Several different subtypes of DCs and macrophages have been identified inside the kidney and indicate poor prognosis (Bethunaickan et al., 2011). Murine macrophages during nephritis display neither a classical pro- nor an antiinflammatory phenotype. Sahu et al. suggest that this could indicate the missing resolution of inflammatory responses (Sahu et al., 2014). Further research is needed to exactly define the roles of different DC and macrophage subsets during LN. Finally, neutrophils can promote tissue injury by releasing cytokines or ROS inside the kidney (Worthmann et al., 2014). Additionally, they deliver DAMPs to the extracellular space when undergoing NETosis (Lorenz et al., 2014b). Together, immune complexes, aberrant pattern recognition, and misdirected cellular


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responses trigger recurrent flares of renal inflammation and consecutive tissue injury. The latter can trigger excessive proliferation of renal progenitor cells and exaggerated extracellular matrix production (Smeets et al., 2009). Ultimately, this leaves sclerosing lesions inside most of the glomeruli, which is defined as class VI LN (Weening et al., 2004).

9.3 Animal Models for SLE Most mechanistic data on the etiology and progression of SLE originate from murine models of lupus-like autoimmunity. Similar to human SLE, murine models reflect different modalities of disease pathogenesis, which result in different phenotypes (Peng, 2012). Animal models have been successfully used to identify genetic aberrations associated with disease development and to test therapeutic strategies (Peng, 2012). Nevertheless, translational scientists have to keep several limitations and features of the murine lupus model in mind. The following section will briefly introduce widely used mouse models of SLE and their resulting phenotype. We will further highlight some similarities and differences to human disease. In general, we distinguish spontaneous models (MRL/lpr, NZB/NZW.F1, BXSB/ Yaa) from pharmacologically induced models (e.g., pristane-induced) (Peng, 2012). The latter can be used to study the onset of disease, whereas spontaneous models reveal insight into how genetic alterations predispose to the development of SLE (Peng, 2012). 9.3.1 NZB/NZW.F1 The F1 hybrid from phenotypically mostly unaffected NZB and New Zealand White (NZW) mice results in NZB/W F1 mice (Peng, 2012). In comparison to their ancestors, these mice develop an exaggerated lupus-like phenotype including lymphoproliferation, splenomegaly, ANA production, and immune complex-mediated glomerulonephritis (Table 6) (Peng, 2012). Life expectancy is reduced due to renal failure. Similar to human SLE, severity of the disease is depending on the gender in these mice. Analysis of similarly diseased NZM2410 mice derived from backcrossed NZB/W F1 with NZW mice revealed several lupus susceptibility loci (Sle1-Sle3) linked to MHC-II-related and -nonrelated genes. Subsequent experiments revealed that introduction of these risk alleles into nonautoimmune background (C57BL6) leads to autoantibody production; however, it failed to trigger nephritis (Peng, 2012). This ancestral history resembles the concept of human SLE, where the combinations of several risk loci rather than a monogenetic aberration are needed to

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Table 6 Comparison of Phenotypical Features and Cause of Disease in Animal Models of SLE NZB/W F1 MRL/lpr BXYB/Yaa Pristane Phenotype

Spontaneous

+

+

+

Gender

Female

Male/female

Male

Female > male

Arthritis

+

+

Vasculitis

+

+

+

+

Nephritis

+

+

+

+/ *

Mortality (average)

9 months 6 months

5 months

*

Anti-dsDNA Ab

+

+

+

+

Anti-Smith Ab

+

+

Anti-U1snRNP Ab

+

+

Cause

c LSL

Fas/ > c LSL

Yaa (TLR7") > LSL

TLR7/type I

Skin involvement

LSL, combined lupus susceptibility loci; * depends on background: + in BALB/c, weak in C57BL/6, strong in lupus-prone backgrounds (e.g., MRL/lpr); +, positive; –, negative.

enable disease development. Nevertheless, NZB/W F1 mice fail to develop humoral immunity against U1snRNP, a common human lupus autoantigene (Peng, 2012). 9.3.2 MRL/lpr The MRL/lpr mice develop lymphoproliferation, accumulation of CD4CD8 T cells, a broad variety of autoantibodies, and severe immune complex nephritis (Peng, 2012) (Table 6). Unlike other models, both males and females develop the disease (Peng, 2012). Skin involvement is a special characteristic of this model. The main cause of the phenotype relates to deficiency in Fas receptor, which belongs to the TNFR superfamily, and induces lymphocyte apoptosis upon ligation by FasL (Peng, 2012). Defective clearance of autoreactive lymphocytes and innate immune cells is considered the main cause of the phenotype. Interestingly, selective


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deletion of Fas in DCs was sufficient to trigger autoimmunity in C57BL6 mice (Stranges et al., 2007). Additionally, lupus susceptibility loci have been identified within the MRL background that predispose to autoimmunity and associate with disease features (Vidal et al., 1998). Interestingly, deletion of Fas in humans does not classically result in SLE, but rather induces an autoimmune lymphoproliferative disorder without nephritis (Teachey et al., 2010). In addition, the main mechanism of disease induction is a defect in lymphocyte apoptosis (Reap et al., 1995). However, peripheral T lymphocytes from patients demonstrate increased apoptosis, which has been correlated to disease severity (Dhir et al., 2009). 9.3.3 BXSB/Yaa The BXSB/Yaa strain represents the strongest phenotype. On average male mice die after 5 months due to proliferative GN (Peng, 2012). In this model the BXSB bears several different lupus susceptibility loci (BXS1–6) on chromosomes 1, 2, 13, some of which per se confer lupus phenotypes (Haywood et al., 2004). However, in this background, Y-linked autoimmune accelerator (Yaa) has been shown to be the main driver of disease. Yaa is caused by a translocation of X chromosomal ends to the Y chromosome, thereby increasing the gene dose of several genes including TLR7. In this model, increased TLR7 gene expression accounts for many immune cell aberrations, lymphoproliferation, glomerulonephritis, and mortality (Fairhurst et al., 2008). As expected, only male BXSB/Yaa mice develop full-blown disease. Interestingly, in Chinese and Japanese patients an SNP within the TLR7 gene has first been linked to human SLE selectively in male patients (Shen et al., 2010). Meanwhile, TLR7 risk alleles have also been identified in female patients with SLE (dos Santos et al., 2012). As a limitation, monogenetic Lupus is rare in humans. 9.3.4 Pristane The pristane model is a pharmacologically induced model of SLE. It works within several different backgrounds including Balb/c and C57BL6. After i.p. injection with isoprenoid alkane, pristine, mice develop autoantibodies, including U1snRNP, and depending on the background show renal involvement and develop a mild erosive arthritis (Table 6) (Leiss et al., 2013). As such, pristane represents the influence of environmental triggers on SLE development (Peng, 2012). Further, although C57/BL10 mice injected with pristane developed hemorrhagic pulmonary capillaritis (Chowdhary et al., 2007), whether it mimics rare pulmonary capillaritis

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in human SLE remains elusive (Zamora et al., 1997). In its function as an autoadjuvant, pristane-induced SLE depends on type I interferon signaling of peritoneal Ly6Chigh monocytes and on the TLR7 signaling axis since the ablation of any of those factors rescues the phenotype (Lee et al., 2008a,b). A type I interferon signature is a common finding in SLE patients, which generates a value for the pristane model to study this aspect. However, in patients, pDCs are the main source of these mediators (Lorenz and Anders, 2015).

10. SUMMARY Unlike autoinflammation and alloimmunity, autoimmunity originates from a spontaneous loss of tolerance against self-proteins and other structures. A number of environmental factors such as drugs, infections, and acquired epigenetic modifications altering gene regulation determine and enhance the susceptibility to the loss of tolerance. Gene variants can weaken or break the checkpoints that maintain immune tolerance in the immune system. Beyond extremely rare monogenetic forms of autoimmunity, the combinations of genetic and environmental factors need to pass a threshold that compromises the safeguard mechanisms of immune tolerance. Infections are common triggers of breaking this threshold in susceptible patients. Although autoimmunity is often transient and potentially harmless, it holds the risk of persistent autoimmunity whenever autovaccination occurs and immune memory is imprinted, implying a potentially lifelong persistence of autoreactive lymphocyte subsets. Consequently, curing of chronic autoimmune disease is hardly possible unless eradicating immune memory that is laid down in long-lived plasma cells in the bone marrow. Hence, the management of autoimmune diseases focusses largely on the control of lymphocyte proliferation to limit the size of autoreactive lymphocyte clones. Indeed, the driving force of autoimmune tissue injury is underlying autoimmune mechanisms located in lymphoid organs. Clonal expansion of the autoreactive lymphocyte clones leads to humoral and cellular immune responses. Immune complex disease, infiltration of autoantigen-specific T cells, and TLO formation contribute to autoimmune tissue injury, inflammation, atrophy, and subsequently organ dysfunction. Currently, the strategy for therapy includes modulating the systemic and peripheral pathomechanisms of autoimmune disease. Inducing remission, maintaining a sufficient suppression of disease activity, and preventing relapsing disease are three different treatment targets to consider. Another


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treatment target is tissue inflammation, where the problem is to identify nonredundant elements of tissue injury, e.g., complement factors, FC receptors, or Jak/STAT-mediated cytokine signaling. These are currently addressed by steroid therapy for most autoimmune diseases, but more specific targets that allow selective inactivation of lymphocyte cytokines and proinflammatory mediators are approaching the clinic or have already been implemented in the treatment of rheumatoid and psoriatic arthritis. Indeed, novel therapies also help to better understand the pathophysiology. For example, rheumatoid arthritis was considered as a T cell-driven disease up to the moment where anti-CD20 therapies became available and demonstrated profound effects on clinical outcomes of rheumatoid arthritis. This observation implied an unexpected but a central role of CD20+ B cells in the pathogenesis of rheumatoid arthritis and shifted the research interest in this direction. Therefore, we conclude that both bench-to-bedside and bedside-to-bench researches are important approaches to understand immune tolerance and to unravel the pathophysiology of autoimmune diseases. However, several studies often present variable or contradictory results especially while understanding the involvement of EVs, as well as NETs, in the disease pathology, the most probable reason being in the difficulties in their characterization and standardization of the analytical techniques. Whether EVs, as well as NET components, can be used as biomarkers in patients with autoimmune diseases remains to be studied.

ACKNOWLEDGMENTS S.R.M. is supported by the Deutsche Forschungsgemeinschaft (MU 3906/1-1). H.-J.A. is supported by the European Union’s Horizon 2020 research and innovation program under Grant Agreement No. 668036 (RELENT). The views expressed here are the responsibility of the author(s) only. The EU Commission takes no responsibility for any use made of the information set out. Conflict of interest statement: None.

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