Gender differences in autoimmune disease

Frontiers in Neuroendocrinology 35 (2014) 347–369

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Review

Gender differences in autoimmune disease S.T. Ngo a,b,1, F.J. Steyn a,1, P.A. McCombe b,c,⇑ a

School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, Australia University of Queensland Centre for Clinical Research, University of Queensland, Herston, Queensland, Australia c Department of Neurology, Royal Brisbane & Women’s Hospital, Herston, Queensland, Australia b

a r t i c l e

i n f o

Article history: Available online 2 May 2014 Keywords: Autoimmunity Gender Sex differences Immune system

a b s t r a c t Autoimmune diseases are a range of diseases in which the immune response to self-antigens results in damage or dysfunction of tissues. Autoimmune diseases can be systemic or can affect specific organs or body systems. For most autoimmune diseases there is a clear sex difference in prevalence, whereby females are generally more frequently affected than males. In this review, we consider gender differences in systemic and organ-specific autoimmune diseases, and we summarize human data that outlines the prevalence of common autoimmune diseases specific to adult males and females in countries commonly surveyed. We discuss possible mechanisms for sex specific differences including gender differences in immune response and organ vulnerability, reproductive capacity including pregnancy, sex hormones, genetic predisposition, parental inheritance, and epigenetics. Evidence demonstrates that gender has a significant influence on the development of autoimmune disease. Thus, considerations of gender should be at the forefront of all studies that attempt to define mechanisms that underpin autoimmune disease. Ó 2014 Published by Elsevier Inc.

1. Introduction Autoimmune disease, first recognized by Ian Mackay and Macfarlane Burnet, is characterized by the failure of an organism to tolerate its own cells and tissues, resulting in an aberrant immune response by lymphocytes and/or antibodies (Mackay and Burnet, 1963). This leads to pathological changes and dysfunction of the tissue that is the target of the self-directed immune response. Autoimmune diseases can be systemic or can affect specific organs or body systems including the endocrine, gastrointestinal and liver, rheumatological, and neurological systems. In this review, we discuss systemic and organ-specific autoimmune diseases. In general there is a greater prevalence of autoimmune disease in females than males, although there are exceptions. To demonstrate sex differences in autoimmune disease, we summarize human data to provide an overview of the prevalence in males and females of common autoimmune diseases in countries commonly surveyed. We then discuss possible mechanisms for sex specific differences.

⇑ Corresponding author at: University of Queensland Centre for Clinical Research, University of Queensland, Herston, Queensland, Australia. Fax: +61 7 38327447. E-mail address: [email protected] (P.A. McCombe). 1 Authors contributed equally. http://dx.doi.org/10.1016/j.yfrne.2014.04.004 0091-3022/Ó 2014 Published by Elsevier Inc.

1.1. Autoimmunity and autoimmune disease – key considerations for sexual dimorphism Autoimmune diseases comprise a range of diseases in which the immune response to self-antigens results in damage or dysfunction of tissues (Mackay and Burnet, 1963). Criteria have been developed that allow a disease to be classified as autoimmune (Rose and Bona, 1993). These criteria include the identification of a target antigen, the presence of antibodies and/or T cells in the target organ, and the transfer of disease to animals by cells or antibodies (Rose and Bona, 1993; Witebsky et al., 1957). The immune system is comprised of multiple cell types of a single lineage. Collectively, these cells contribute to acquired and innate immunity. Interactions between acquired and innate immune function may aggravate autoimmune responses. A strong inflammatory component, with infiltration of tissue with macrophages and lymphocytes, is associated with many organ-specific autoimmune diseases, such as in rheumatoid arthritis (RA) and multiple sclerosis (MS). Noninflammatory conditions like myasthenia gravis (MG) are antibody-mediated, although there may be some minor lymphocyte infiltration. Systemic lupus erythematosus (SLE) is another important antibody-mediated disease. The origin of autoimmune disease is a disruption of immune tolerance of self-antigens. This is thought to occur in genetically susceptible individuals after exposure to environmental triggers (Mackay, 2001). Autoimmune diseases are strongly associated with

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human leukocyte antigen (HLA) genes through mechanisms that could involve genetic variability in the immune response and genetic variability in the ability to present antigens (Gough and Simmonds, 2007). Modern genetic studies of autoimmune diseases such as MS, type I diabetes (T1D) and inflammatory bowel disease (IBD) have shown that many other genes, each with small effect, also contribute to genetic susceptibility to autoimmunity (Australia and New Zealand Multiple Sclerosis Genetics, 2009; Barrett et al., 2009; Khor et al., 2011). At times autoimmune diseases run in families (Bias et al., 1986; McCombe et al., 1990). This was once thought to indicate an autosomal dominant inheritance, but it is now thought to be due to the interaction of common genes (Clayton, 2009). However, what is often overlooked is that a very significant component of the genetic contribution to autoimmunity is gender, with the presence or absence of a Y chromosome influencing the risk for autoimmune disease. Environmental factors also predispose to autoimmune disease. This is well illustrated by twin studies, where the risk of developing autoimmune disease cannot be solely explained by genetics. For example, in MS there is greater concordance in monozygotic than dizygotic twins, indicating that genetic factors are important (Willer et al., 2003). However, the concordance in monozygotic twins is incomplete, suggesting a role for environmental factors. In a study from Finland, it was shown that the concordance of MS in dizygotic twins has increased in two decades, with this rapid increase again suggesting a significant role for environmental factors (Kuusisto et al., 2008). Possible environmental factors that predispose to autoimmunity include exposure to infectious agents and to dietary components (Lamb et al., 2008; Pender and Greer, 2007), exposure to chemicals, xenobiotics or toxins (Rieger and Gershwin, 2007), stress (Rieger and Gershwin, 2007), or reduced exposure to factors that protect from the development of autoimmune diseases (e.g. sunlight during childhood and adulthood) (Fraser et al., 2003; Ponsonby et al., 2005). Different exposure or response to these environmental factors could contribute to gender differences in autoimmunity.

2. Sexual dimorphism in autoimmune diseases – prevalence and consequence 2.1. Effect of gender on the prevalence of autoimmune diseases For most autoimmune diseases there are clear sex differences in prevalence whereby females are generally more frequently affected than males (Eaton et al., 2007). This gender bias can be modest, as is seen in MS (Bentzen et al., 2010; Cheng et al., 2009; El Adssi et al., 2012; Hadjimichael et al., 2008; McCombe, 2003; Osoegawa et al., 2009; Pandit and Kundapur, 2014; Ramagopalan et al., 2013), or strong, as is seen in primary biliary cirrhosis (PBC) (Amarapurkar and Patel, 2007; Eaton et al., 2007; Harada et al., 2013; McNally et al., 2011; Shen et al., 2009; Sood et al., 2004). Importantly, prevalence between males and females may be changing. For example, the predominance of MS in females is increasing; initial early reports suggest equal prevalence in males and females (Buckley, 1954), by the 1980’s prevalence was approximately 2:1 (female:male) (Confavreux et al., 1980), and recent reports suggest prevalence in some instances of up to 3:1 (female:male) (Ramagopalan et al., 2013). Such a rapid change is likely to be due to environmental factors. To provide a more detailed assessment of the current status of gender bias in autoimmune diseases, we summarize adult data from recent studies, focusing predominantly (when possible) on the United States (USA), England, France, Denmark, Japan, China, India, and Australia. Measures are further categorized based on systemic, endocrine, gastrointestinal, neurological or rheumatological diseases (Fig. 1).

Data highlight the very high (9:1) gender bias toward females for systemic autoimmune diseases including SLE (Chiche et al., 2012; Eaton et al., 2007; Feldman et al., 2013; Li et al., 2012; Ramagopalan et al., 2013) and Sjögren’s syndrome (SS) (Eaton et al., 2007; Misra et al., 2003; Nannini et al., 2013; Ramagopalan et al., 2013; Seror et al., 2013; Tsuboi et al., 2013; Xiang and Dai, 2009), occurring independent of country of assessment. By contrast, some neurological diseases (including MG (Guptill et al., 2011; Guy-Coichard et al., 2008; Huang et al., 2013; Pedersen et al., 2013; Ramagopalan et al., 2013; Singhal et al., 2008; Suzuki et al., 2011) and Guillain–Barré syndrome (GBS) (Alshekhlee et al., 2008; Chen et al., 2014; Dhadke et al., 2013; Eaton et al., 2007; Mitsui et al., 2013)) had a near equal prevalence in males and females, although recent data suggest a greater prevalence of GBS in males in Asian countries including Japan (Mitsui et al., 2013), China (Chen et al., 2014) and India (Dhadke et al., 2013). In our recent study of GBS in Australia, there was a male preponderance (Blum et al., 2013). However, in MS, the most common neurological autoimmune disease, females accounted for two thirds of all cases (Bentzen et al., 2010; Cheng et al., 2009; El Adssi et al., 2012; Hadjimichael et al., 2008; McCombe, 2003; Osoegawa et al., 2009; Pandit and Kundapur, 2014; Ramagopalan et al., 2013). Again, this occurred mostly independent of country of assessment. The prevalence of endocrine related autoimmune diseases predominantly favored females (including Grave’s Disease (GD) (Carle et al., 2011; Gaujoux et al., 2006; Guo et al., 2013; Phitayakorn et al., 2013) and Hashimoto’s thyroiditis (HT) (Ramagopalan et al., 2013; Zhang et al., 2012)). This was not the case for T1D (Anderson et al., 2012; Bhadada et al., 2011; Eaton et al., 2007; Kawasaki and Eguchi, 2004; Menke et al., 2013), where prevalence was equal in males and females. This varied somewhat between countries, and prevalence slightly favored males in the USA (Menke et al., 2013) and Denmark (Eaton et al., 2007), but females in Japan (Kawasaki and Eguchi, 2004) and Australia (Speight et al., 2012). Prevalence for rheumatological autoimmune diseases varied greatly between countries, however trends remained the same. For ankylosing spondylitis (AS), prevalence favored males in the USA (Reveille, 2011), England (Ramagopalan et al., 2013), China (Xiang and Dai, 2009), India (Aggarwal and Malaviya, 2009), and Australia (Oldroyd et al., 2009). For RA prevalence greatly favored females, with reports ranging from 66% to 86% dominance (Biver et al., 2009; Li et al., 2012; Myasoedova et al., 2011; Pedersen et al., 2011; Ramagopalan et al., 2013; Yamanaka et al., 2013). Of the gastrointestinal diseases that we studied, PBC showed a strong female dominance (values ranging from 80% to 100%), regardless of country (Amarapurkar and Patel, 2007; Eaton et al., 2007; Harada et al., 2013; McNally et al., 2011; Shen et al., 2009; Sood et al., 2004). While celiac disease was generally female dominant (60% to 80% incidence), an exception was the recent observations by Nijhawan et al. (2013) that found a 60% incidence for adult males (Nijhawan et al., 2013). A similar rate of prevalence in male children was reported (Bhattacharya et al., 2013). Incidence of ulcerative colitis (UC) and Crohn’s disease (CD) in males and females did not vary greatly by country, and generally did not favor females or males (Gathungu et al., 2012; Jain et al., 2012; Jess et al., 2007; Nerich et al., 2006; Ng et al., 2013; Ramagopalan et al., 2013; Zhao et al., 2013). Of interest, Asakura et al. (2009) showed a deviation in this trend, with 70% CD subjects in Japan being male (Asakura et al., 2009). The studies detailed above do not consider severity of symptoms. 2.2. Effect of gender on the severity of autoimmune diseases As well as prevalence varying with gender, the severity of autoimmune diseases, meaning the severity of symptoms and the


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Fig. 1. Prevalence of autoimmune disease in USA, England, France, Denmark, Japan, China, India, and Australia. There is a very high gender bias toward females for systemic diseases including systemic lupus erythematosus (Chiche et al., 2012; Eaton et al., 2007; Feldman et al., 2013; Li et al., 2012; Ramagopalan et al., 2013) and Sjögren’s syndrome (Eaton et al., 2007; Misra et al., 2003; Nannini et al., 2013; Ramagopalan et al., 2013; Seror et al., 2013; Tsuboi et al., 2013; Xiang and Dai, 2009). Neurological diseases including myasthenia gravis (Guptill et al., 2011; Guy-Coichard et al., 2008; Huang et al., 2013; Pedersen et al., 2013; Ramagopalan et al., 2013; Singhal et al., 2008; Suzuki et al., 2011) and Guillain–Barré syndrome (Alshekhlee et al., 2008; Chen et al., 2014; Dhadke et al., 2013; Eaton et al., 2007; Mitsui et al., 2013) have near parity distribution between males and females, although recent data suggests a greater prevalence of Guillain–Barré syndrome in males in Japan (Mitsui et al., 2013), China (Chen et al., 2014) and India (Dhadke et al., 2013). In Australia, there is a male preponderance in Guillain–Barré syndrome (Blum et al., 2013). For multiple sclerosis, females account for two thirds of all cases (Bentzen et al., 2010; Cheng et al., 2009; El Adssi et al., 2012; Hadjimichael et al., 2008; McCombe, 2003; Osoegawa et al., 2009; Pandit and Kundapur, 2014; Ramagopalan et al., 2013). The prevalence of endocrine related diseases predominantly favors females (including Grave’s Disease (Carle et al., 2011; Gaujoux et al., 2006; Guo et al., 2013; Phitayakorn et al., 2013) and Hashimoto’s thyroiditis (Ramagopalan et al., 2013; Zhang et al., 2012)). Prevalence is near parity for type 1 diabetes (Anderson et al., 2012; Bhadada et al., 2011; Eaton et al., 2007; Kawasaki and Eguchi, 2004; Menke et al., 2013), although prevalence slightly favors males in the USA (Menke et al., 2013) and Denmark (Eaton et al., 2007), or females in Japan (Kawasaki and Eguchi, 2004) and Australia (Speight et al., 2012). Prevalence for rheumatological diseases varies between countries, however trends remained the same. For ankylosing spondylitis, prevalence favors males in the USA (Reveille, 2011), England (Ramagopalan et al., 2013), China (Xiang and Dai, 2009), India (Aggarwal and Malaviya, 2009), and Australia (Oldroyd et al., 2009). For rheumatoid arthritis, prevalence greatly favors females (Biver et al., 2009; Li et al., 2012; Myasoedova et al., 2011; Pedersen et al., 2011; Ramagopalan et al., 2013; Yamanaka et al., 2013). Primary biliary cirrhosis shows a strong female dominance (Amarapurkar and Patel, 2007; Eaton et al., 2007; Harada et al., 2013; McNally et al., 2011; Shen et al., 2009; Sood et al., 2004). Celiac disease is generally female dominant, although prevalence seems to favor males in India (Nijhawan et al., 2013). Incidence of ulcerative colitis (UC) and Crohn’s disease (CD) in males and females does not vary greatly by country, and generally does not favor females or males (Gathungu et al., 2012; Jain et al., 2012; Jess et al., 2007; Nerich et al., 2006; Ng et al., 2013; Ramagopalan et al., 2013; Zhao et al., 2013), although a deviation in this trend is seen in Japan (Asakura et al., 2009).

degree of disability, may also differ between males and females. However, compared to prevalence, this is not easily defined. The effect of gender on severity varies among autoimmune diseases. For example, psoriasis is more severe in males (Sakai et al., 2005). Men develop autoimmune hepatitis at a younger age and have high relapse rates, but also have better prognosis than women (Al-Chalabi et al., 2008). By contrast, the clinical course in CD is

more severe in girls (Gupta et al., 2007), whereas in diseases like RA, gender does not necessarily predict outcome (Courvoisier et al., 2008). In MS, disease severity, measured as disability progression, appears to be greater in males (Runmarker and Andersen, 1993; Weinshenker et al., 1991). A recent study demonstrates greater disease severity in male SLE patients; male patients were more likely to suffer renal and cardiovascular co-morbidities

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while female patients were more likely to suffer from urinary tract infections, hypothyroidism, depression, esophageal reflux, asthma, and fibromyalgia (Crosslin and Wiginton, 2011). 2.3. Effect of gender on the pathological features of autoimmune disease Gender differences are reported in the T cell and antibody responses that occur in autoimmune disease. In MS for instance, females tend to secrete higher levels of IFNc in response to proteolipid protein (PLP) peptides when compared to control females and males with MS (Pelfrey et al., 2002), and increased T-cell reactivity occurs at a higher frequency (Greer et al., 2004). On the other hand, a small study in SLE patients report that the IgM and IgG reactivity to dsDNA Ro and La follows no gender bias (Ferreira et al., 2005). In diabetes, females have higher levels of antibodies to glutamic acid decarboxylase (Lindholm et al., 2004). There are no systematic studies of the effects of gender on the histopathological features of autoimmune disease, but it has been suggested that autoimmune disease in males is young onset, with acute inflammation and autoantibodies, while in females autoimmune disease is either acute onset and non-inflammatory and/or associated with chronic pathology (Fairweather et al., 2008). Much remains to be studied in this area. 2.4. Effect of gender on survival in autoimmune disease Autoimmune diseases are generally not considered to be fatal, but in many diseases, reduced life expectancy can be demonstrated, compared to the general population. The measure of this is the standarized mortality rate (SMR), which compares the observed mortality in a group with that expected in that population. This has been well studied in MS where survival duration is greater for women than men. However, when survival is considered and adjusted relative to general mortality rates, females with MS have poorer survival outcomes (Grytten Torkildsen et al., 2008). In T1D, relative mortality was found to be higher for Finnish women than for men (Asao et al., 2003). Increased mortality in a large multicentre international cohort of SLE patients have been reported to be associated with female gender (Bernatsky et al., 2006). Similar observations were documented in a Spanish population (Ruiz et al., 2014). For PBC, a higher number of deaths have been observed in English/Welsh women (Hamlyn and Sherlock, 1974). While data suggests that gender can influence the mortality of autoimmune disease, it is important to note that co-morbidities may significantly alter the course of disease. Moreover, survival can be influenced by factors other than severity of disease, such as quality of care, age of onset, and time to diagnosis.

3. Factors underlying sexual dimorphism in autoimmune diseases Above we have described the observable effects of gender on the incidence and severity of autoimmune disease. Now we will consider the possible underlying mechanisms that could lead to these clinical effects. We limit our considerations to human observations and refer to mouse data when human data is restricted. We have previously provided an extensive review of data pertaining to mouse models of autoimmune disease (McCombe et al., 2009). The underlying basis for sexual dimorphism in autoimmune disease is yet to be determined. However, significant research has investigated the impact of differences between males and females in the immune response, organ vulnerability, reproductive function, microchimerism, sex hormones, and the environment on the

Fig. 2. Factors underlying sexual dimorphism in autoimmune disease. While the underlying basis for sexual dimorphism in autoimmune disease is yet to be determined, a number of factors may contribute to gender differences in autoimmune disease. Females show increased immune reactivity, differences in the number or responsiveness of cells that constitute the immune response, and differential resistance to target organ damage, and this may influence propensity to autoimmune disease. Hormonal changes during pubertal maturation, pregnancy, and menopause may alter susceptibility to autoimmunity, and it is generally accepted that pregnancy is associated with improved symptoms in autoimmune disease. The protective effects that are exerted by female (estrogen, progesterone, and prolactin) and male (androgens) hormones may also explain gender differences in specific autoimmune diseases. Differential exposure to environmental factors (including sunlight) can influence the prevalence and risk of developing an autoimmune disease or the severity of disease. Genetic factors that might influence the gender specific development of autoimmune disease may be related to susceptibility genes, chromosomal differences, or epigenetics. When genetic factors are combined with environmental factors, this can influence parental inheritance of autoimmune disease. Epigenetic changes that arise in autoimmune disease can be related to the sex of the parent, or can result from external factors. Genetic imprinting, and in particular, miRNA imprinting, could also contribute to the sexual dimorphism seen in autoimmune disease.

prevalence, susceptibility and severity of autoimmune disease (Fig. 2). These factors are discussed below. 3.1. Differences between female and male immune systems The gender differences in autoimmunity could be due to differences between male and female immune systems (McCombe and Greer, 2013a). Such differences are found in most animal species; males have immune suppression when compared to females and this is linked to male sexual activity (McKean and Nunney, 2005). Females show increased immune reactivity (Hewagama et al., 2009), and this greater immunocompetence may translate to greater resilience to infectious and some non-infectious diseases. However, it is possible that this greater immune reactivity makes women more prone to developing autoimmune disease (Zandman-Goddard et al., 2007). 3.1.1. T lymphocytes, B lymphocytes and natural killer cells T lymphocytes, B lymphocytes and natural killer (NK) cells comprise the lymphocytes of the immune system. T lymphocyte secreted cytokines including IL-2, IL-4, IL-10, IFNc and TNFa underlie cell-mediated adaptive immunity. B lymphocytes produce IgG and IgM antibodies against foreign antigens to mount antibody driven adaptive immune responses. NK cells are effectors of cellmediated, innate immunity. While there are age-associated changes in human lymphocyte subtype numbers (Yan et al., 2010), the overall number of lymphocytes in males and females is the same. However, males have a


lower number of T lymphocytes (Bouman et al., 2004), and postmenopausal women have decreased numbers of B lymphocytes and helper T cells (Th cells) (Giglio et al., 1994; Yang et al., 2000). B lymphocyte counts do not differ between genders, however, women produce higher levels of circulating antibodies than men (Rowley and Mackay, 1969), which could underlie their propensity to produce higher levels of autoantibodies in autoimmune diseases (Whitacre et al., 1999). Indeed, females have increased levels of IgM when compared to their male counterparts (Butterworth et al., 1967; Lichtman et al., 1967). While data on NK cells is limited, when compared to men, fertile females have decreased NK cell cytotoxic activity, but women with premature menopause have higher numbers of NK cells (Giglio et al., 1994). Females produce stronger humoral and cellular immune responses to antigen than males (Ansar Ahmed et al., 1985). Studies in humans suggest that females produce higher levels of CD4 + T cells in response to immunization (Ho et al., 1995). Moreover, the antibody response of females surpasses that of males after vaccination for influenza, hepatitis B, rubella and tetanus (Cook, 2008). In some instances, adverse effects in response to immunization can be observed in females in the absence of a significant humoral response (Shohat et al., 2000). Gender differences are also seen in the outcome of immunity to bacterial, parasitic, and viral infections. With bacterial infections, decreased production of anti-lipoarabinomannan IgM is observed in males with Mycobacterium tuberculosis infections (Demkow et al., 2007). In secondary syphilis, females are more resistant as CD4 + and CD8 + T lymphocytes are both elevated (Ho et al., 1995). The prevalence, severity or susceptibility of parasitic infections, Schistosoma mansoni, Schistosoma haematobiainfections (Degu et al., 2002), and Leishmania donovani (Goble and Konopka, 1973) is greater in males than females. The decreased prevalence and severity of Schistosoma infections in females may be attributed to their ability to secrete greater amounts of anti-inflammatory cytokines and differing antibody isotypes (Demkow et al., 2007), and the decreased susceptibility in females to Leishmania may be due to increased secretion of granulocyte macrophage colony-stimulating factor (Lezama-Davila et al., 2007). In the case of viruses, studies illustrate higher prevalence of herpes simplex virus type 2 in females (Glynn et al., 2008; Howard et al., 2003; Rabenau et al., 2002), and this may be due to higher levels of progesterone in females since progesterone contraceptives hastens herpes simplex virus type 1 (Stringer et al., 2007) (the role of progesterone in autoimmunity will be discussed below). Increased levels of lymphocytes and neutrophils in young females (Pembrey et al., 2008) may underlie their increased susceptibility to hepatitis C virus (European Paediatric Hepatitis, 2005; Zanetti et al., 1998), although chronic adult hepatitis C virus infection results in increased fibrosis in males (Poynard et al., 1997). 3.1.2. Microglia, astrocytes, mast cells, and dendritic cells The immune cells of that are resident in tissues could potentially show gender differences that could influence autoimmune disease. Little is known about gender differences in these cells. To illustrate this issue we will use examples from the CNS. Microglia and astrocytes account for the majority of the brain cell population, and there is no indication of any gender difference with respect to the spatial distribution of these cell types in the male and female brain (Stark et al., 2007). While microglia represent the primary immune cell of the central nervous system, astrocytes are also considered to be immunocompetent, as they possess the ability to synthesize immune molecules in response to insult/ injury (Farina et al., 2007; Gimsa et al., 2013; Jensen et al., 2013; Kaur et al., 2010; Pivneva, 2008; Wirenfeldt et al., 2011). In the context of immunity, mast cells and dendritic cells are also of particular importance. Mast cells are resident in a multitude of tissues

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including the brain (Silverman et al., 2000; St John and Abraham, 2013) and take part in the host innate immune defence by releasing chemoattractants that recruit eosinophils (Wardlaw et al., 1986) and monocytes (Perry et al., 1993). Dendritic cells, which are the antigen-presenting cells of the immune system, are generally present on tissues that are exposed to the environment (Banchereau and Steinman, 1998; Silverman et al., 2000), but they have also recently been suggested to be resident in brain (albeit mouse brain) (Bulloch et al., 2008). A number of in vivo studies provide insight into the roles of microglia, astrocytes, mast cells, and dendritic cells in the neuroimmune response in general. Interestingly, such studies have also generated observations that might be of relevance when considering gender differences in autoimmune disease. For example: estrogen inhibits microglia and astrocyte activation in the striatum of a mouse model of Parkinson’s Disease (Tripanichkul et al., 2006); astrocytes in female mice may be more resistant to oxidative stress-induced toxicity (Giordano et al., 2013), estrogen increases the number and activation of mast cells in the brain (Boes and Levy, 2012), and female mice have increased recruitment of dendritic cells to the brain after stroke (Manwani et al., 2013). In the context of autoimmunity, studies in mice suggest that estrogen may play a key role in the activation of microglia and astrocytes, and the generation of tolerogenic dendritic cells. Myelin basic protein-primed T cells from female mice and castrated male mice induce microglial expression of proinflammatory cytokines (Dasgupta et al., 2005), expression of the RNA binding protein HuR in spinal cord astrocytes provides greater attenuation of disease in female experimental autoimmune encephalomyelitis (EAE) mice (and this is reversed following ovariectomy) (Wheeler et al., 2012), an estrogen receptor alpha ligand reduces inflammation and protects against axonal loss and reactive astrogliosis in EAE mice (Spence et al., 2011), and estriol leads to the generation of splenic dendritic cells that when transferred to mice prior to active induction of EAE leads to protection from the development of EAE (Papenfuss et al., 2011). Data pertaining to human autoimmune disease is currently limited to astrocytes and dendritic cells. Astrocytes in the rim and center of MS lesions in male and female patients have recently been found to upregulate different gender steroid-specific enzymes, suggesting that these responses might underlie genderspecific differences in steroid synthesis and signaling in the brains of MS patients, and thus, the gender bias in MS prevalence and susceptibility (Luchetti et al., 2014). While dendritic cell numbers are reported to be lower in MS (de Andres et al., 2009), primary SS (Vogelsang et al., 2010), and SLE (Henriques et al., 2012), whether there are gender differences in the expression or function of dendritic cells in these diseases remains unknown. Thus, future research that aims to determine whether gender differences in autoimmune disease can be attributed to differential expression and function of microglia, astrocytes, mast cells, and dendritic cells will generate significant interest. 3.2. Sexual dimorphism in target organ vulnerability to damage Autoimmune disease results when an autoimmune attack on target organs leads to dysfunction. Autoimmunity can occur without clinical disease being evident. This means that there are two issues involved in the development of autoimmune disease: the presence of autoimmunity and the ability of the target organ to resist the autoimmune attack. For example, in SLE, the presence of autoantibodies does not always lead to end organ damage (Lewis et al., 2013). The role of the target organ in autoimmunity has been reviewed elsewhere (Hill et al., 2007). To consider gender differences in the target organ that could lead to gender differences in the incidence and severity of autoimmune disease, we need to

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examine gender differences in the ability of different target organs to tolerate damage. The processes that lead to an ability to withstand damage is sometimes referred to as cytoprotection; or neuroprotection or cardioprotection when referring to the ability of the nervous system or the heart, respectively, to withstand damage. A full discussion of this topic is beyond the scope of this review, but the processes involved are fundamental and include susceptibility to apoptosis, autophagy (Lista et al., 2011), mitochondrial function (Martel et al., 2012), and biochemical pathways that promote survival such as the nrf2 pathway (Chen and Kunsch, 2004; Lee et al., 2005). There are some studies that indicate that there are gender differences in the ability to protect cells from damage. In general it is thought that females have greater resistance, because of the cytoprotective properties of estrogen (see below). Much of the work in this area has been done in the nervous system, although estrogen also has protective properties on endothelium (Si et al., 2001). It is generally accepted that females tend to have improved outcome after traumatic brain injury (Groswasser et al., 1998), and although this has been debated (Bayir et al., 2004; Farace and Alves, 2000; Wagner et al., 2000), this is thought to occur in response to the effects of estrogen (Roof and Hall, 2000). While less is known about gender differences in the processes and pathways involved in neuroprotection, there is a study suggesting that there are gender differences in autophagy (Lista et al., 2011). Additional research is needed to determine in more detail whether gender differences that target organ resistance are responsible for gender differences in autoimmune disease. 3.3. Autoimmune disease and reproductive function Reproductive load may significantly alter susceptibility to autoimmunity, particularly in females. Careful consideration relative to pubertal maturation (thus the onset of mature reproductive age), and life events that alter reproductive function (including pregnancy and menopause) should be made. For pregnancy, these considerations extend to that of the fetus. We now survey the data relating to reproductive issues and autoimmune disease. 3.3.1. Puberty The incidence of autoimmune disease varies relative to the onset of reproductive function, although with the exception of epidemiological studies, few studies differentiate between pre-pubertal and post-pubertal incidence, specifically in relation to gender bias. This is surprising, given the impact of puberty on gender bias in autoimmune diseases. For example, while pre-pubertal onset of MS is rare, with only 3–5% of cases reported in individuals under 18 years of age (Chitnis et al., 2009; Duquette et al., 1987; Ghezzi et al., 1997), gender bias within these cases of MS is absent (reviewed in (Chitnis, 2013)). Following the onset of puberty, however, incidence changes rapidly and pubertal girls are found to be at greater risk of developing MS than pre-pubertal girls (Ramagopalan et al., 2010). Moreover, earlier onset of puberty in girls is also associated with increased risk of developing MS (Ramagopalan et al., 2009b). However, in SLE, the male to female ratio of 1:9 may be as low as 1:2 prior to puberty (reviewed in (Tedeschi et al., 2013)). By contrast, the incidence of UC in adolescents is equivalent in males and females, but by early-adulthood the ratio of male to female patients is 4:1 (Bove, 2013). These reports could suggest that exposure to hormonal changes during pubertal development could underlie the gender bias in autoimmune diseases. However, environmental effects may also play a role. For example, relocation from a low-risk geographic to highrisk geographic area during puberty significantly increased MS risk (Dean and Elian, 1997). Although this was not gender specific, it is

an example of how factors other than hormones could influence the effect of puberty on disease. 3.3.2. Pregnancy Pregnancy involves physiological changes in the mother, including elevation of cardiac output, increased basal metabolic rate, increased lipid levels, and weight gain (Forsum and Lof, 2007; Granger, 2002; Lain and Catalano, 2007; Tan and Tan, 2013). In pregnancy there are changes in the levels of hormones such as estriol, progesterone, prolactin, early pregnancy factor (EPF), alpha-fetoprotein (Brunton and Russell, 2010) and leptin (Molvarec et al., 2011), and elevated levels of growth factors such as insulin-like growth factor (IGF) (Lauszus et al., 2003). After delivery, there is a rapid decline in the levels of pregnancy hormones and maternal physiology rapidly returns to normal, although during lactation the levels of prolactin and oxytocin are elevated (Uvnas-Moberg et al., 1990). It is generally thought that the changes in maternal physiology are mediated through the effects of the pregnancy hormones. In pregnancy, the mother plays host to the fetus, which contains foreign antigens. Immune changes in pregnancy tend to suppress the maternal immune system, which is thought to be important in preventing rejection of the fetus (Munoz-Suano et al., 2011; Veenstra van Nieuwenhoven et al., 2003; Yip et al., 2006). 3.3.2.1. Immune responses in pregnancy. Regulatory T cells (Tregs) mediate active immune tolerance to prevent any maternal lymphocyte-mediated damage to the fetus (Aluvihare et al., 2004; Saito et al., 2005). A shift in Th1/Th2 activity in pregnancy favors increased Th2-related and reduced Th1-related activities. This results in an improvement in Th1-mediated diseases and an exacerbation of Th2-mediated diseases (Doria et al., 2002, 2004; Ostensen et al., 2005). Indeed, the remission of the Th1 diseases RA and AS during pregnancy is coupled with an inhibition of Th1-related activities via an upregulation in cytokine inhibitors (Ostensen et al., 2005). These findings are further corroborated by a Th1 phenotype in abortion, and a Th2 phenotype during normal pregnancy (Raghupathy, 2001). While it is accepted that the Th1/Th2 paradigm is a marker for pregnancy success, it has been superseded by the Treg/Th17 paradigm. In 2004, Tregs were found to be elevated during normal pregnancy (Somerset et al., 2004). Elevated levels of Tregs correlate well with decreased activity of Th1-related autoimmune diseases (Forger et al., 2008). The ratio of Treg and IL-17 appears to be of pivotal importance during pregnancy as an imbalance in the Treg/IL-17 proportion is linked to complications during pregnancy, including recurrent pregnancy loss and pre-eclampsia (Darmochwal-Kolarz et al., 2012; Saito et al., 2011). It is likely that steroid hormones drive these immunological changes in pregnancy; improvements in psoriasis (Th1dependent disease) is correlated with higher levels of estrogen (Murase et al., 2005), and the increase in Tregs may be driven by estradiol since low levels of Tregs are positively correlated with low levels of estradiol in patients with missed abortion (Cao et al., 2014). The steroid-associated immunological changes seen in pregnancy may very well contribute to sex differences in autoimmune disease, as discussed below. Another pregnancy-associated change that may underlie gender differences in autoimmune disease is a small protein of the heat shock family, chaperonin 10 (cpn 10) (heat shock protein 10, hsp 10). Cpn 10 is released into blood during early pregnancy (Morton et al., 1977). In line with its immunomodulatory capacity, a 12 week course of cpn 10 treatment improves disease measures in patients with RA (Vanags et al., 2006). Moreover, decreased T lymphocyte-associated secretion of TNFa and interleukin 1b occurs after 12 weeks of cpn 10 in psoriasis (Vanags et al., 2006).


Thus, elevated levels of cpn 10 may contribute to the beneficial effects of pregnancy on autoimmune disease. 3.3.2.2. Autoimmune disease and pregnancy. The effects of pregnancy on autoimmune disease differ for inflammatory autoimmune diseases, which tend to remit, and antibody mediated autoimmune diseases, where the effects are more variable. For instance, the symptoms of MG vary considerably from woman to woman and from pregnancy to pregnancy in the same woman (Hantai et al., 2004), and pregnancy has been reported to worsen, improve, or provide no change in MG symptoms (Batocchi et al., 1999). Likewise, pregnancy with psoriasis can lead to similar variations in disease response (Murase et al., 2005). In AS, pregnancy may not aggravate disease (Lui et al., 2011), but it has been reported to cause remission (Ostensen and Ostensen, 1998). For CD, the activity of disease was significantly lower during pregnancy as determined by the Harvey-Bradshaw index (Agret et al., 2005). In MS (Borchers et al., 2010; Confavreux et al., 1998; McCombe and Greer, 2013b), and RA (Hench, 1983; Nelson and Ostensen, 1997; Ostensen and Villiger, 2007) however, it is widely accepted that pregnancy is associated with the remission of symptoms, although there can be a flare of disease post-partum. In contrast to MS and RA, SLE an antibody mediated disease, is reported to worsen during pregnancy (Ruiz-Irastorza et al., 1996; Stojan and Baer, 2012), and this can vary in the degree of severity (Lateef and Petri, 2012). Pregnancy can also trigger the onset of autoimmune disease. Fulminant autoimmune diabetes can present during pregnancy or in the post-partum period (Inagaki et al., 2002), and other dormant autoimmune diseases, like thyroiditis, can become clinically evident post-partum (Muller et al., 2001; Premawardhana et al., 2004; Thompson and Farid, 1985). With evidence indicating a role of pregnancy in autoimmune disease, it must be noted however that heterogeneous study designs, variable presentation of disease, and patient ethnicity can render the interpretation of pregnancyassociated data difficult. Autoimmune disease during pregnancy can also result in fetal manifestations of disease. This is seen in diseases including MG (Eymard et al., 1991; Gveric-Ahmetasevic et al., 2008), SLE (Lee, 2009; Yildirim et al., 2013), thyrotoxicosis (Batra, 2013; Radetti et al., 2002), autoimmune thrombocytopenic purpura (SukenikHalevy et al., 2008; van der Lugt et al., 2013) and cutaneous lupus (Johnson, 2013). When placental transmission of autoantibodies occurs, a temporary autoimmune disease can occur in the neonate. In more severe cases, passively acquired autoimmunity can result in congenital heart block due to transplacental transfer of anti-Ro and anti-La from mothers with SLE (Brucato et al., 2001; Wahren-Herlenius and Sonesson, 2006), or, from transfer of acetylcholine receptors antibodies, in arthrogryposis multiplex congenita (Donaldson et al., 1981) or pulmonary hypoplasia (Newsom-Davis, 2007). Thus, given fetal complications associated with pregnant mothers with autoimmune disease, due care is required for the management of disease during the gestational period. Autoimmune disease can also appear under conditions of assisted pregnancy and ovarian hyperstimulation. Increased MS activity and relapses of MS can occur after assisted reproductive technology (ART) (Correale et al., 2012; Hellwig et al., 2008; Laplaud et al., 2006), and this may be due to stress, immunological changes in response to hormone therapy, or termination of immune therapy upon the instigation of ART. ART pregnancies have also been associated with exacerbation of SLE (Ben-Chetrit and Ben-Chetrit, 1994; Casoli et al., 1997). Furthermore, complications can arise in autoimmune patients undergoing ART. Women with thyroid antibodies before the first cycle of ART have increased risk of miscarriage (Poppe et al., 2003), and a trend toward worse pregnancy and live-birth rate is becoming evident in SLE mothers undergoing ART (Costa and Colia, 2008).

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As detailed above, current data indicates that the differential effects imparted by pregnancy in autoimmune diseases are very specific to autoimmune disease type. While it has been suggested that some autoimmune diseases are not improved by pregnancy (Adams Waldorf and Nelson, 2008), this is generally only the case for SLE, which is an antibody mediated disease. We note that pregnancy is documented to exert protective effects in AS, CD, MS, and RA, which are inflammatory diseases. In particular, there is overwhelming evidence to demonstrate that pregnancy is associated with improved symptoms in MS and RA. 3.3.2.3. Pregnancy, microchimerism and autoimmunity. Microchimerism, the trafficking of cells from the fetus to the mother and vice versa, occurs during pregnancy (Lo et al., 1996). It is well known that, as a normal phenomenon, fetal cells persist in the maternal circulation years after pregnancy (fetal microchimerism) (Bianchi et al., 1996), and that maternal cells persist in immunodeficient and immunocompetent offspring into adult life (maternal microchimerism) (Evans et al., 1999; Maloney et al., 1999). Microchimerism has been considered to be a possible trigger for autoimmunity and has also been put forward as a protective mechanism (Fig. 3). If microchimerism were indeed linked to the development of autoimmune disease, then chimeric cells may persist as inactive dendritic cells and lymphocytes (McNallan et al., 2007) until an environmental factor, a shift in cytokine proportion, an infection, or a hormonal trigger activates these cells, thereby causing an allograft reaction, and subsequently, autoimmune disease in either the mother or the offspring (Nelson, 1999, 2002). The evidence for a role for fetal microchimerism in the development of autoimmune disease is conflicting. Fetal microchimeric cells have been found in the blood and thyroid of women with autoimmune thyroid disease (Lepez et al., 2012; Renne et al., 2004). Lepez and colleagues have also demonstrated that these fetal cells in women with thyroid disease were cytotoxic T lymphocytes, and hence, may have been capable of initiating a graft-vs-host reaction to elicit autoimmune thyroid disease (Lepez et al., 2011). In line with a role for fetal micochimerism, women with increased odds of developing autoimmune thyroid disease were noted to have had a previous pregnancy (Friedrich et al., 2008), but Bulow-Pederson and colleagues found no association between pregnancy and autoimmune

Fig. 3. Microchimerism and autoimmunity. Microchimerism is the trafficking of cells from the fetus to the mother and vice versa. Fetal microchimerism has been proposed to have a beneficial role in helping a parous woman to recover from injury through the provision of additional mutipotential stem cells that could be used in repair of damage. By contrast, maternal microchimerism may be harmful since maternal cells are a possible source of graft versus host response, as is seen in systemic sclerosis. Since microchimerism occurs during pregnancy, microchimerism may contribute to gender differences in autoimmune disease.

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thyroid disease, and thus argue that there is no association between fetal microchimerism and autoimmune disease (Bulow Pedersen et al., 2006). The disease that has been most studied with respect to a causative role for fetal microchimerism is systemic sclerosis (scleroderma) given that chronic graft-vs-host disease after bone marrow transplantation results in clinical presentations that are similar to systemic sclerosis (Artlett et al., 1998; Gratwohl et al., 1977). Much like the studies for thyroid disease however, those that have investigated microchimerism as an underlying cause for systemic sclerosis have presented variable results (Ichikawa et al., 2001; Murata et al., 1999). Maternal microchimerism may present as tissue-specific maternal microchimerism in neonates, as has been suggested to be the case in neonatal lupus congenital heart block (Stevens et al., 2003). The rate of maternal microchimerism is also higher in twins with MS (Willer et al., 2006). By contrast, maternal microchimerism appears to play no role in PBC (Nomura et al., 2004). Fetal microchimerism has also been proposed to have a beneficial role in helping a parous woman to recover from injury. Microchimeric cells have been demonstrated at sites of tissue inflammation during pregnancy, forming blood vessels. After delivery, microchimeric cells have been found in the maternal liver after liver injury, and many years after pregnancy, microchimeric fetal cells have been found at sites of injury where these cells adopt a variety of phenotypes (indicating their multipotent capacity). This transfer of fetal stem cells could be helpful and provide additional mutipotential stem cells that could be used in repair of damage (Guillot et al., 2007; Johnson and Bianchi, 2004; Khosrotehrani and Bianchi, 2005; Khosrotehrani et al., 2004; Lo et al., 1996). This is speculative, but further investigation could be rewarding. 3.3.2.4. Long-term effects of pregnancy on autoimmunity. Another consideration in autoimmune disease is the long-term effect of pregnancy. There is little information in this area, except in the case of MS. Overall, women with MS who have been pregnant have a better long-term outcome than those who have not been pregnant (D’Hooghe et al., 2010). It seems that the effects are cumulative since multiparous women seem to have a better outcome than women with fewer, or who have no pregnancies (Runmarker and Andersen, 1995; Verdru et al., 1994). Having been pregnant does not increase the risk of secondary progression of disease (Koch et al., 2009). Women who have children with different partners do not have greater risk of disability as might be expected to occur if the immune response to paternal genes was harmful (Basso et al., 2004). Of interest, recent findings suggested that pregnancy frequency lowers mortality in T1D (Sjöberg et al., 2013). This awaits further validation, as it is a difficult topic to evaluate. There may be reverse causation at work, such that women with less severe disease could be more likely to decide to have children. However there are some plausible biological mechanisms for long-term beneficial effects of pregnancy, including fetal microchimerism which could provide a reservoir of stem cells that could aid in repair (as discussed above), and epigenetic changes (as discussed below). 3.3.3. Menopause Menopause is a natural occurrence that marks the end of cyclical changes associated with reproductive function in women. It is characterized by lower levels of estrogens and progesterone, peaking of FSH levels, follicular depletion, and irreversible cessation of menses. There are conflicting reports about the effects of menopause on MS that has developed earlier in life (Holmqvist et al., 2006) (Smith and Studd, 1992; Wundes et al., 2011). In SLE, however, menopausal transition has been reported to decrease the frequency of flares, but to cause more damage in the organs in which individual postmenopausal flares occur (Fernandez

et al., 2005; Sanchez-Guerrero et al., 2001; Urowitz et al., 2006). In RA, postmenopausal women report higher physical disability scores than premenopausal women (Kuiper et al., 2001). Menopause has also been associated with the onset of autoimmune disease. For example, autoimmune hepatitis occurs most frequently in the late teenage years in males, but occurs in women in the late teens and after menopause (Werner et al., 2008). By contrast, menopause is not associated with high occurrence of SLE (Mok, 2008), and SLE after menopause is generally less severe (Boddaert et al., 2004). Early menopause however has shown to be associated with an increased risk of developing SLE and RA (Costenbader et al., 2007; Pikwer et al., 2012a,b). There are a number of immunological changes associated with menopause including increased production and response to pro-inflammatory cytokines, decreased secretion of anti-inflammatory cytokines, decreased lymphocyte levels, and decreased activity of NK cells (Gameiro and Romao, 2010; Gameiro et al., 2010). These changes, coupled with altered endocrine function, may underlie the incidence and risk of autoimmune disease that is associated with menopausal transition. 3.4. Role of hormones in the sexual dimorphism in autoimmunity The strong gender bias in autoimmune disease susceptibility could be due to the differential effects of gender-specific hormones. Indeed, a considerable amount of evidence now demonstrates not only the role of gender-specific hormones in contributing to disease, but also the differential roles of these hormones relative to altered reproductive states (Fig. 4). For example, disease flares for SLE are influenced by the age of onset of menarche, the use of oral contraceptives, the age of onset of menopause, and hormonal treatments in response to menopause (Costenbader et al., 2007). These changes in reproductive function are all characterized by significant changes in the hormonal milieu. The effects of various sex hormones including estrogens, progesterone, androgens, and prolactin are considered below. When possible, we will discuss evidence of contribution to immunity, contribution to autoimmune disease, and outcomes following treatments targeting these hormones. 3.4.1. Estrogens Acting through estrogen receptor subtypes (ERs) alpha (ERa) and beta (ERb), estrogen mediates transcription activity of intracellular machinery to produce genomic effects, whereas the rapid, non-genomic actions of estrogen are triggered through activation of membrane-associated ERs (mER). This results in changes in intracellular activity that occur independent of transcription pathways and protein synthesis. Endogenous estrogens include estrogen (E1), estradiol (E2) and estriol (E3, produced only in pregnancy). These compounds differentially act on intracellular ERs that are present in all cells of the immune system (Deroo and Korach, 2006), including T and B lymphocyte subsets, and peripheral NK cells (Pernis, 2007; Pierdominici et al., 2010). It has become clear that estrogens impact immunity by modulating lymphocyte development and function (Grimaldi et al., 2002; Smithson et al., 1998). Indeed, estrogens may facilitate critical protective effects that negate detrimental changes following inflammatory responses. For example, a decrease in CD4+/ CD8 + T-cell-subset ratios in cultures of human lymphocytes is seen following estrogen treatment (Athreya et al., 1993). Similarly, estrogen enhances immunoglobulin secretion from these cells (Kanda and Tamaki, 1999). Estrogen may also directly affect B lymphocyte subsets. In animal studies, estrogens increase bone marrow progenitor B cells by protecting them from apoptosis (Grimaldi et al., 2002; Medina et al., 2000), and by increasing the survival of B cells (Grimaldi et al., 2002). In humans, estrogens induce polyclonal activation of B cells. Specifically, estrogen


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Fig. 4. The role of hormones in the sexual dimorphism in autoimmunity. The strong gender bias in autoimmune disease susceptibility could be due to the differential effects of gender-specific hormones in contributing to disease, and the differential roles of these hormones relative to altered reproductive states. Estrogen, which is seen in high levels during pregnancy, impacts immunity by modulating lymphocyte development and function, and promoting cytoprotection. These actions of estrogen could lead to improved cell-mediated disease or worsened antibody-mediated disease. Progesterones and androgens exert anti-inflammatory and immunosuppressive effects respectively, and this is generally beneficial in autoimmune disease. Prolactin, which is high during pregnancy, induces pro-inflammatory effects, and this tends to worsen autoimmune disease.

increases IgG and IgM production of peripheral blood mononuclear cells. This occurs regardless of gender (Kanda and Tamaki, 1999; Weetman et al., 1981). The role of estrogen in immunity has been extensively reviewed (Bouman et al., 2005). The potential cytoprotective role of estrogens may explain these effects. Takao and colleagues showed that estrogen treatment dose-dependently reversed the cytotoxic effects of TNFa in T cells. In this study, the ER antagonist ICI-172.780 abolished the cytoprotective effects of 17b-estradiol on T cells (Takao et al., 2005). Numerous reports demonstrate protective actions of estrogens on the EAE mouse model of MS (Bebo et al., 2001; Ito et al., 2001; Jansson et al., 1994). In this model of MS, inflammation is mediated by T lymphocytes that react to CNS and brain-derived autoantigens. To delineate the mechanisms through which estrogen may be cytoprotective, Lélu and colleagues demonstrate that endogenous estrogens limit the recruitment of blood-derived inflammatory cells (CD4 + T cells) into the CNS (Lelu et al., 2010). Thus, estrogen may protect the brain from damage following inflammatory insults. This may underlie the potential cytoprotective effects of estrogen during pregnancy. In females, circulating levels of estrogens change dramatically relative to reproductive function. This is important, as varying levels of exposure to estrogens greatly affects immunity. At high concentrations (such as in pregnancy), estrogen inhibits the Th-1 pro-inflammatory pathways (including TNFa, IL-1b and IL-6) and stimulates Th-2 anti-inflammatory pathways (including IL-4, IL10 and TGFb). Conversely, at low levels (as seen after menopause), estrogen stimulates pro-inflammatory pathways (including TNFa and IL1-b) (Straub, 2007). Relative to autoimmunity, estrogens may differentially impact incidence across age and reproductive capacity. Second to this, the actions of estrogens on inflammatory and immune responses may change relative to the presence of autoimmune diseases. For example, T lymphocytes from patients with SLE, but not from healthy controls, are activated via ERa and ERb-specific agonists (Rider et al., 2006). While evidence confirms the role of estrogens in immunity, suggesting that they may play an important role in autoimmunity, the mechanisms through which estrogens may directly or indirectly mediate autoimmune responses remain unknown. Elucidation of this will require more substantive

evidence demonstrating a direct involvement of estrogen in the incidence of autoimmune disease. The high female to male incidence rate for SLE (Fig. 1), coupled with a dramatic reduction in gender ratios prior to puberty or following menopause (both conditions are associated with a reduction in circulating estrogen levels) has contributed to anecdotal evidence suggesting that estrogen mediate immunity specific to autoimmune diseases. This has been substantiated by studies assessing the effects of estrogens on tissue collected from patients suffering from autoimmune diseases. For example, lymphocytes collected from SLE patients are more sensitive to the actions of physiological levels of E2, whereas E2 may differentially modify signaling pathways coupled to disease onset and severity in T cells from SLE patients (reviewed in (Pierdominici and Ortona, 2013)). Moreover, documented associations between autoimmune diseases and various facets of estrogen signaling provide reason for further assessment of potential causes. For example, in MS, ER expression in the thymus changes dramatically (Zoller and Kersh, 2006), whereas estrogen concentrations in synovial fluid is markedly increased in RA patients (Cutolo et al., 2004). However, this does not necessarily mean that altered levels of endogenous estrogens will increase the risk for developing SLE. For example, the incidence of SLE does not change relative to pregnancy and birth rate (Cooper et al., 2002). Moreover, while the incidence of lupus flares in patients with existing SLE increase during pregnancy (Walker, 2007), this is not necessarily associated with alterations in circulating levels of estrogens. For example, Doria et al. (2006) demonstrated that estrogen levels in SLE patients may not rise during the second and third trimesters of pregnancy, and thus disease flares that occur at this time cannot be directly associated with altered circulating levels of estrogens (Doria et al., 2006). Accordingly, alterations in physiology not coupled to endogenous estrogen may underlie autoimmune disease associations. To this extent, the potential role of estrogen in the development of autoimmune disease may be better identified when considering exogenous estrogens, estrogen-like compounds, or modifiers of estrogen action. Immune responses may be compromised by naturally occurring exogenous estrogens (phyto/myco-estrogens), or by synthetic estrogen-like compounds (xenoestrogens) (reviewed in

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(Chighizola and Meroni, 2012; Pierdominici and Ortona, 2013; Vandenberg et al., 2012)). These compounds are widely found in products used in the production of food and around the home, including detergents, plastics, pesticides, and industrial chemicals. While less potent than endogenous estrogens, these compounds can accumulate in adipose tissue, where they may exert potent effects on immunity (Chighizola and Meroni, 2012). Existing evidence showing an involvement in phyto-, myco- or xenoestrogens in autoimmune disease rely predominantly on epidemiological evidence, or exposure studies conducted on animal models. Thus, it remains unknown to what extent these compounds contribute to autoimmune disease in the real world. Moreover, epidemiological studies, and resulting assessment of the effects of exogenous estrogens on immune function may not necessarily accurately predict direct estrogenic effects on autoimmune disease incidence. Perhaps one of the most revealing cases of associations between autoimmune disease and estrogen replacement therapy comes from the use of Diethylstilbestrol (DES). DES is a synthetic estrogen, historically used to reduce risk of complications to pregnancy, to assist with postpartum lactation, and for the treatment of other postmenopausal symptoms. Not only did DES not improve pregnancy outcomes (Bamigboye and Morris, 2003), it contributed to a number of complications. For example, as a transplacental carcinogen, the exposure to DES contributed to a significant rise in the development of rare vaginal tumors (Herbst et al., 1971). Animal studies showed that DES has a profound effect on immune responses (Luster et al., 1978), confirming fears that DES exposure may have contribute to autoimmune diseases in humans. However, while confirming that females exposed to DES developed a number of autoimmune disorders, the incidence was relatively low (Noller et al., 1988). This was verified in more recent observations (Strohsnitter et al., 2010), where the relative rise in incidence in RA in DES exposed females below 45 years of age was offset by a much lower incidence in older females. Thus, while animal studies demonstrate a significant risk for autoimmunity following DES exposure, data from humans provide little support for an association between the development of an autoimmune disease and exposure to DES. This important case highlights the need for rigorous assessment and careful validation of autoimmune incidence following exogenous estrogen exposure. This is of considerable importance, as estrogen-mediated therapies may effectively alleviate complications with autoimmune diseases. In this instance, unsubstantiated concerns regarding the use of estrogen-containing oral contraceptives may in fact be to the detriment of women suffering from autoimmune conditions, and in particular SLE. While the potential benefits of estrogen therapy in some autoimmune diseases are recognized, it should be noted that conflicting observations make the interpretation of the extent of potential benefits difficult. Moreover, identification of potential beneficial effects of estrogen on autoimmune disease requires careful consideration of the type and severity of the condition. For example, while estrogen therapy in MS (Sicotte et al., 2002) and RA (Bijlsma et al., 1987) may be beneficial, estrogen appears to enhance disease severity in SLE. Thus, blockade of ER in SLE is beneficial (Abdou et al., 2008). Similarly, while the use of contraceptives may protect against RA (Vandenbroucke et al., 1982), some evidence suggest that the beneficial effects are limited to females under 35 years of age (Spector et al., 1990), or to females that used contraceptives earlier in life (Hazes et al., 1990). In this latter study, it was concluded that current use in older females has no benefits. Accordingly, estrogen-containing contraceptives for the prevention of RA may only be of some benefit to females at childbearing age. Studies that directly assess this are however scarce, and current observations are not promising. For example, estrogen treatment (using lynestrenol plus ethinyl estradiol) of

women with RA for 6 months did not significantly improve symptoms (Hazes et al., 1989). As with the use of oral contraceptives, conflicting reports exist regarding the value and risk of hormone replacement therapy (HRT) in women to treat autoimmune diseases. For example, HRT does not appear to impact the ongoing course of disease in MS (Holmqvist et al., 2006), or the risk of developing RA (Walitt et al., 2008). HRT is thought to benefit postmenopausal women with inflammatory bowel disease (Kane and Reddy, 2008), increase bone mineral density in women with PBC (Ormarsdottir et al., 2004), and improve incidence of isolated pulmonary hypertension in post-menopausal women with systemic sclerosis (Beretta et al., 2006). Conversely, in SLE, HRT may increase the risk of thrombosis (Fernandez et al., 2007; Sanchez-Guerrero et al., 2007). Current clinical trials assessing the potential roles of estrogens in preventing or minimizing disease impact for other autoimmune diseases (for example ongoing efforts to assess the impact of estriol in Relapsing Remitting Multiple Sclerosis, ClinicalTrials.gov Identifier: NCT00451204) will shed light on the value of estogen-mediated effects on autoimmunity. 3.4.2. Progesterone Progesterone belongs to the class of steroid hormones known as progestogens, named for their function in gestation (pro-gestation). Progesterone is produced predominantly in the gonads and adrenal gland, and in pregnancy in the placenta. While critically involved in pregnancy, detectable levels of progesterone are in circulation in females throughout the menstrual cycle and in males in levels similar to that seen in females during the follicular phase of the menstrual cycle. The actions of progesterone in reproduction are varied. In addition to directly regulating reproductive function (including oocyte maturation, endometrial differentiation, embryonic implantation, placental growth etc.), progesterone may also alter the actions of other steroid hormones at this time (Steyn et al., 2008). Accordingly, interaction of progesterone with target tissues may occur via indirect mechanisms. Progesterone acts via its cytosolic receptor, the progesterone receptor (PR). This receptor belongs to the nuclear hormone receptor superfamily of transcription factors. Ligand binding of PR induces changes in gene expression through direct binding to promoter elements or through protein–protein interactions with other transcription factors. Of interest, recent observations highlight that actions of progestins (including progesterone) may occur independent of the PR, therefore arguing for non-genomic interactions (Li et al., 2004). As summarized by Hughes (2012), the actions of progesterone on immunity are best described by the wide distribution of PRs on immune cells, including granulocytes, NK cells, dendritic cells, T-cells and B cells (Hughes, 2012), although non-genomic interactions may occur. In general, the effects of progesterone in immunity are antiinflammatory. Of these, known effects include the promotion of apoptosis and inhibition of IFNc production from NK cells (Arruvito et al., 2008), the inhibition of macrophage activity (Pisetsky and Spencer, 2011), the modulation of myeloid dendritic cell activity (reviewed in (Hughes and Clark, 2007)), the inhibition of glucocorticoid-mediated thymocyte apoptosis (McMurray et al., 2000), the reduction of nitric oxide production (Miller et al., 1996) and the expression of toll-like receptors (TLR) by macrophages (Jones et al., 2008), the differentiation of Th2 cells in vitro (Piccinni et al., 1995), and the expression of the co-stimulatory molecules CD80, CD86 and CD40, as well as MHC II (Ivanova et al., 2005; Liang et al., 2006). The role of progesterone in immunity was recently reviewed (Hughes, 2012). As with estrogens the potential actions of progesterone on autoimmunity are more commonly defined in context of fluctuations in endogenous progesterone levels, dictated by changes in


reproductive function. The rise in progesterone in pregnancy is associated with remarkable changes in maternal immunity, and may contribute to changes in immune responses. In general, the effects of progesterone in immunity are anti-inflammatory. As with estrogens, the potential effects of progesterone may also vary relative to disease severity and type. For example, progesterone protects against disease onset in gonadectomised lupus-prone NZB/W mice (a model wherein mice spontaneously develop an autoimmune disorder similar to SLE) (Roubinian et al., 1978), whereas in CIA rats (a common rat model for arthritis), progesterone alone had no effect while reducing the beneficial effects of estrogen (Ganesan et al., 2008). Similarly, continuous progesterone administration to pre-autoimmune NZB/W mice delayed the development of pathogenic serum anti-DNA antibodies and spontaneous autoimmune disease and death (Hughes and Clark, 2007). In humans, combined estrogen and progesterone hormone replacement therapy may cause lupus flares in post-menopausal women (Buyon et al., 2005), whereas a current clinical trial is assessing the potential benefits of progestin treatment to prevent postpartum flares in women with MS (Vukusic et al., 2009) (Results from this trial are pending (ClinicalTrials.gov Identifier: NCT00127075)). Given this variable response, substantive research is needed before we can define the contribution of or treatment of autoimmune diseases using therapies targeting progesterone. 3.4.3. Androgens Androgens are steroid hormones commonly associated with the development of masculine characteristics; implicated in testes formation, spermatogenesis, and the deposition of lean muscle mass at the expense of adipose. In males and females, androgens maintain bone mass while impacting behavior (including aggression). Importantly, androgens are the precursors of all estrogens. While generally present in high levels in males, androgens decline with increasing age (Mitchell et al., 1995), whereas low circulating levels of androgens persist throughout life in females (Davison et al., 2005). As with estrogen and progesterone, androgens may act via genomic (acting through the androgen receptor) and non-genomic mechanisms (Lutz et al., 2003). The actions of androgens on immune function may vary depending on the type of androgen used, the dosage administered, and the timing of administration. For example, some studies report immunosuppressive effects (Fujii et al., 1975; Olsen and Kovacs, 1996; Paavonen, 1994), whereas endogenous androgens are also thought to be immunostimulatory (Calabrese et al., 1989). Testosterone reduces the proliferation and differentiation of lymphocytes (Sakiani et al., 2013; Sthoeger et al., 1988; Wyle and Kent, 1977), and the use of androgens may suppress immunoglobulins, and in particular IgA (Calabrese et al., 1989; Hirota et al., 1976). Androgens, including supraphysiological doses of testosterone may inhibit the cytotoxic activity of NK cells (Callewaert et al., 1991; Marshall-Gradisnik et al., 2008; Sulke et al., 1985). Given that the effects of androgens may vary considerably relative to the level of exposure, and that multiple factors may contribute to the immune profile in females, the potential role of endogenous androgens in gender specific immune function remains unknown. Androgen levels are higher in males, and autoimmune incidence is generally lower. Thus, it is thought that androgens may to some extent protect against autoimmunity. Indeed, gonadectomy of male NZB/W mice result in overt autoimmunity and earlier death, whereas treatment with androgens in ovariectomised female NZB/ W mice reduced mortality (Roubinian et al., 1977). In humans, transdermal treatment with testosterone for 1 year was of some benefit to men with MS, slowing cognitive decline and brain atrophy. Treatment, however, did not affect the number or volume of enhancing lesions (Sicotte et al., 2007). In females with SLE, testosterone administration via skin patches for 12 weeks did not

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significantly improve disease severity (Gordon et al., 2008), whereas the impact of dehydroepiandrosterone (DHEA) treatment in SLE was inconsistent. For example, while initial reports showed that oral DHEA treatment (200 mg/day for 6 months) improved SLE Disease Activity Index (SLEDAI) scores and overall assessment scores in patients (van Vollenhoven et al., 1994), subsequent double-blinded studies from the same group were unable to corroborate these results (van Vollenhoven et al., 1995, 1999). Of interest, a larger multicenter randomized, double-blind placebo controlled trial showed significant improvements in assessment scores from DHEA treated female patients (200 mg/day for 6 months), corresponding with a significant reduction in disease flares (Chang et al., 2002). Importantly, DHEA is a precursor of both androgens and estrogens, and thus these modest effects may not necessarily involve direct androgenic roles. In light of potential negative effects on HDL cholesterol (Casson et al., 1998), coupled with the increased risk of developing atherosclerotic heart disease in SLE patients (van Leuven et al., 2006), it is critical that the longterm ramification on cardiovascular health be considered before recommending DHEA as a treatment option for SLE. 3.4.4. Prolactin While predominantly secreted from the anterior pituitary gland, immune cells including lymphocytes secrete prolactin (ChavezRueda et al., 2005; Vera-Lastra et al., 2002). The prolactin receptor, a member of the cytokine receptor superfamily, is found on monocytes and T lymphocytes, and other cells of the immune system (Jara et al., 1991). Thus, while prolactin predominantly acts on the brain and within the mammary gland to ensure physiological adaptation essential for sustained maternal behavior and lactation (Grattan et al., 2008), it may play an important role in immunity, and thus pregnancy associated changes in autoimmunity. Functionally, the paracrine actions of prolactin produced within lymphocytes may mediate important immunological effects. For example, prolactin is able to induce the proliferation of lymphocytes, whereas inactivation of prolactin action through adminstration of neutralizing antibodies significantly decreases the activation and proliferation of T lymphocytes (Chavez-Rueda et al., 2005). Within the T lymphocytes, prolactin mediates T-bet, an essential transcription factor involved in the production of Th1-type cytokines, including IFN (Tomio et al., 2008). Thus, prolactin may stimulate T-cell mediated inflammatory reactions (Tomio et al., 2008). However, at high concentrations, prolactin may inhibit the proinflammatory activation of T helper cells (Tomio et al., 2008). Prolactin may enhance autoimmune disease, whereas serum levels of prolactin may increase as a consequences of autoimmune disease (Orbach and Shoenfeld, 2007). For example, hyperprolactinemia is seen in autoimmune rheumatic diseases (ARD) including SLE, RA, systemic sclerosis, SS, T1D, GD, HT, celiac disease, and MS (Orbach et al., 2012). Elevated levels of prolactin was found in the CSF in SLE patients with neuropsychiatric lupus (Jara et al., 1998), while hyperprolactinemia is associated with activity of SLE in pregnancy (Jara et al., 2001). Of interest, hyperprolactinemia in patients with pituitary tumors or following therapy with antipsychotic drugs is associated with raised levels of thyroid autoantibodies (Poyraz et al., 2008). Associations between prolactin and autoimmunity are somewhat corroborated by animal studies, wherein prolactin treatment often worsens disease severity. For example, disease severity in NZB/W mice increases following prolactin treatment, and improves following treatment with bromocriptine (an ergoline derivative used to suppress endogenous prolactin production) (McMurray et al., 1991). Attempts to treat human autoimmune disease with bromocriptine have produced some positive results. Notably, in some SLE patients bromocriptine treatment reduces disease flares (AlvarezNemegyei et al., 1998; McMurray et al., 1995). More recently, it

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was found that bromocriptine treatment in postpartum lupus patients reduce disease flares (Yang et al., 2003), whereas this pilot clinical data suggest that bromocriptine treatment may prevent complications in pregnancy including preterm birth and active disease (Jara et al., 2007). Given the potential value of bromocriptine and other prolactin antagonists in the treatment of autoimmunity, further studies to delineate the mechanisms by which PRL affects autoimmune disease activity are of critical importance. 3.5. The environment Environmental exposure can interact with the genotype of (Selmi et al., 2012), and can influence the prevalence and influence the risk of developing an autoimmune disease or the severity of disease. Environmental candidates that have been proposed to play a role in autoimmune diseases include infectious agents and chemicals (Chandran and Raychaudhuri, 2010; Costenbader et al., 2012; Hemminki et al., 2010). Infectious agents are important in the mosaic of autoimmunity (Shoenfeld et al., 2008), and a number of autoimmune diseases have been linked to infection; rheumatic fever presents after Streptococcus pyogenes infection (Fae et al., 2006), primary anti-phospholipid syndrome patients have high levels of IgM antibodies to rubella and Toxoplasma (Zinger et al., 2009), diabetes is associated with Enterovirus (Richardson et al., 2009), and active infections with Helicobacter pylori have been observed in autoimmune gastritis (Annibale et al., 2001). Chemical/drug exposure, and immunotoxicity of such compounds are linked to autoimmune disease. Chemicals that are commonly found in cosmetics are associated with PBC (Rieger et al., 2006), and acetaminophen may underlie the development of PBC by promoting antimitochondrial autoantibodies (Leung et al., 2013). Exposure to pesticides has been suggested to underlie the development of autoantibodies (McConnachie and Zahalsky, 1991, 1992; Thrasher et al., 1993), and lifetime exposure to insecticides is associated with the presence of anti-nuclear antibodies (Rosenberg et al., 1999). More recently, it has been found that exposure to organic solvents is associated with an increased risk of developing an autoimmune trait (Barragan-Martinez et al., 2012). Since these exposures underlie the development of autoimmunity, gender differences could occur if males and females have different types of exposure or different biological response to these agents (Fig. 5). We now discuss several examples.

Vitamin D is an environmental factor that may underlie the development of autoimmunity. Vitamin D has immunomodulatory effects on T lymphocytes, B lymphocytes, and dendritic cells (Arnson et al., 2007; Deluca and Cantorna, 2001). By signaling through the vitamin D receptor, vitamin D reduces the effector T cell response (Adorini, 2005; Gascon-Barre et al., 2003; Godfrey et al., 2000; Lemire, 1992). Vitamin D also interacts with human leukocyte antigen molecules, which predispose to MS (Ramagopalan et al., 2009a). Evidence to support the a role for sun exposure in autoimmunity is seen in SS (Erten et al., 2014), RA (Gatenby et al., 2013), SLE (Kamen et al., 2006), and antiphospholipid syndrome (Andreoli et al., 2012; Piantoni et al., 2012) where vitamin D deficiency is associated with disease or increased risk of developing disease. Indeed, greater vitamin D3 synthetic rate resulting from higher intensity ultraviolet light at high altitudes, may account for lower MS rates at higher altitudes (Hayes et al., 1997). It must be noted however, that within any geographical location, exposure to sunlight between men and women could vary, and this may be dependent on lifestyle factors, or occupational choices. Given that men tend to have more unprotected sun exposure (Hall et al., 1997), gender-specific responses to sunlight may play a role in autoimmune disease. Another example of differences in exposure to environmental triggers is the role of cosmetics in PBC, where the exposure to cosmetics is much greater in women than men. Other environmental agents that are implicated in autoimmunity and that may have differential exposures in males and females are mercury, pesticides and solvents (Pollard, 2012). 4. Genetic aspects of the sexual dimorphism in autoimmunity Genetic factors may contribute to the sexual dimorphism that is seen in autoimmune disease. Such factors that might influence the development of autoimmune disease may be related to susceptibility genes, chromosomal differences, or epigenetics. The presentation of multiple autoimmune diseases in a given individual or family suggests that common genetic factors may prejudice an individual to developing autoimmunity. The clustering of susceptibility genes in conditions like MS and CD suggests that in some cases, autoimmune diseases may be controlled by a set of susceptibility genes (Becker et al., 1998). 4.1. Interaction of genes and gender

Fig. 5. The role of the environment in the sexual dimorphism in autoimmunity. Men and women are exposed to environmental factors to varying degrees (e.g. men tend to get more sunlight than women), and they have different physiological responses to such factors. This differential exposure and response might influence the prevalence and the risk of developing an autoimmune disease, or the severity of disease between men and women.

The HLA genes are located in a region that includes a large number of genes that are involved in the immune response. Associations exist between HLA genes and a number of autoimmune diseases including GD (Li and Chen, 2013), MG (Avidan et al., 2013), MS (Cree, 2014), RA (Jin et al., 2014), and SLE (Deng et al., 2013) amongst many others (Horton et al., 2004). The majority of these associations are with HLA-DR and HLA-DQ genes (Gough and Simmonds, 2007), which encode for proteins that play a central role in presenting antigens to CD4 + T cells (Schendel and Johnson, 1985). The association between HLA genes and autoimmune disease generally shows a gender bias toward females. In MG, single nucleotide polymorphisms in the HLA-locus support the premise that there is a female gender bias for increased risk for MG (Avidan et al., 2013). Similarly, being female may further the risk associated with HLA DR4 alleles in type 1 autoimmune hepatitis, since females have a higher frequency of HLA DR4 than men (Czaja and Donaldson, 2002). In MS, there is a strong association between HLA-DR2, DQ6 in females (Celius et al., 2000), and in chronic inflammatory demyelinating polyneuropathy the association with HLA-DR2 is greater for females (Czaja and Donaldson, 2002). In RA, there is an association between disease and females


with a HLA DRB1 *0401/*0401 genotype (Meyer et al., 1996). In SLE however, there is a reversal in gender bias, with a higher HLA associated genetic risk in men (Hughes et al., 2012). Non-HLA genes are also associated with susceptibility to autoimmune disease. Polymorphisms in cytotoxic T-lymphocyte antigen-4 (CTLA-4), acid phosphatase locus 1 (ACP1), Discs large homolog 5 (DLG5), interleukin-10 (IL-10), and apolipoprotein E (APOE) are commonly observed. Genetic A/G polymorphisms in CTLA-4 have been identified in AS (Huang et al., 2014), GD (Du et al., 2013), and T/C polymorphisms may be associated with SLE risk (Zhu et al., 2013). By contrast, there is no evidence to suggest that CTLA-4 polymorphisms confer susceptibility to MS (Gyu Song and Ho Lee, 2013). While the majority of studies that investigate CTLA-4 polymorphisms in autoimmune disease do not necessarily consider results relative to gender, CTLA-4 A/G polymorphisms can modify maternal inheritance of the HLA-DR3 (Fajardy et al., 2002). Polymorphisms in ACP1 and DLG5 are associated with CD (Browning et al., 2008; Stoll et al., 2004), and there is evidence of a reduced susceptibility to CD in females who possess ACP1*A alleles (Gloria-Bottini et al., 2007), and modest evidence of reduced risk of CD in females with the DLG5 R30Q variant (Browning et al., 2008). Polymorphisms in IL-10 are linked to severity of HT (Inoue et al., 2013), RA (Hee et al., 2007), and primary SS (Qin et al., 2013). While these studies do not stratify risk according to gender, an AA -1087 IL-10 genotype appears to be more common in women with RA (Padyukov et al., 2004). Polymorphisms in APOE are associated with primary SS (Pertovaara et al., 2004) and MS (Cocco et al., 2005; Rafiei et al., 2012). Again, while not considered relative to gender, female carriers of the apolipoprotein E epsilon4 allele had a tendency for earlier onset of primary SS when compared to female non-carriers (Pertovaara et al., 2004). In the case of MS however, presence of the APOE alleles seems to favor females; women carriers of the epsilon2 allele had reduced severity of disease (Kantarci et al., 2004), and cognitive decline is more prominent in males who carry the epsilon4 allele (Savettieri et al., 2004). The observations from these studies provide strong evidence to support the notion that genetic risks underlie susceptibility to some autoimmune diseases. While a large number of studies focus on the involvement of HLA genes, it is becoming strikingly clear that polymorphisms in non-HLA genes should also be taken into account when considering the relationship between genetic factors that predispose to autoimmune disease. Given the strong associations between HLA genes and non-HLA genes and autoimmune disease, future studies that investigate the genetic underpinning of such diseases should be considered relative to gender. 4.2. The X chromosome in autoimmune disease The X chromosome contains a large number of genes that are involved in immunity (reviewed in (Fish, 2008; Libert et al., 2010)). While females carry two X chromosomes, one X chromosome is inactivated early in embryogenesis. This allows for equal gene expression dosage between males and females, but also results in cellular mosaicism (Migeon, 2006). Consequently, females may avoid any effects that arise from harmful gene-mutations, and cellular mosaicism (arising from natural variations in one gene that might result in two different alleles) may result in added advantages in response to immune challenges (Migeon, 2006; Spolarics, 2007). Autoimmune phenomena are observed in X-linked primary immunodeficiencies. Thus it is likely that genes on the X chromosome may also play a role in autoimmunity (Bussone and Mouthon, 2009; Carneiro-Sampaio and Coutinho, 2007; Mackay and Rose, 2001). It has been suggested that X chromosome inactivation, loss of X chromosomes or X monosomy may underlie the

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development of autoimmune disease. Skewed X chromosome inactivation is observed in HT, GD (Brix et al., 2005; Chabchoub et al., 2009; Ozcelik et al., 2006), sclerodoma (Ozbalkan et al., 2005; Uz et al., 2008), RA (Chabchoub et al., 2009), and SS (Ozcelik, 2008), but not in SLE (Huang et al., 1997) and MS (Knudsen, 2009; Knudsen et al., 2007). Data from a number of studies suggest that X chromosome monosomy rates may also underlie the female predominance in autoimmune diseases. In disease such as PBC, HT, and GD, enhanced X monosomy rates have been observed in peripheral blood cells (Invernizzi et al., 2004, 2005), but this is not the case for SLE (Invernizzi et al., 2007). Skewed X chromosome inactivation and monosomy appear to be more common in autoimmune thyroid diseases (Brix et al., 2005; Chabchoub et al., 2009; Invernizzi et al., 2005; Ozcelik et al., 2006). Males with two X chromosomes (Chagnon et al., 2006), or males with two X chromosomes and a Y chromosome have also been known to present with SLE (Lahita, 1999). Interestingly, SLE males that are XXY, are similar to female SLE patients in that they have increased oxidation of testosterone (Lahita, 1999). These observations support a role for the X chromosome in SLE. 4.3. The Y chromosome in autoimmune disease Compared to the X chromosome, the Y chromosome has received little attention in human autoimmunity. The Y chromosome accounts for a small portion of the human genome, and is associated with male fertility and testis formation (QuintanaMurci et al., 2001). While the Y chromosome is linked to the inheritance of human coronary heart disease (Charchar et al., 2012), the majority of studies that have assessed the contribution of the Y chromosome to autoimmunity has been conducted in mouse models of SLE (Lin et al., 2010; Murphy and Roths, 1979; SantiagoRaber et al., 2008; Subramanian et al., 2006) and MS (Palaszynski et al., 2005; Spach et al., 2009; Teuscher et al., 2006) (reviewed in (McCombe et al., 2009)). Recent studies have found an agedependent loss of the Y chromosome in PBC (Lleo et al., 2013), and in HT and GD (Persani et al., 2012). These observations further support the role of the X chromosome in autoimmune disease. 5. Parental inheritance/transmission in autoimmunity Maternal and paternal inheritance occurs in autoimmune disease. While one study in Canada has found that there is equal inheritance of MS from affected fathers and mothers (Herrera et al., 2007), and paternal inheritance in MS has been reported (Marrosu et al., 2004), the majority of studies assessing parentof-origin effects in MS are more indicative of a strong maternal effect for risk of inheritance (Ebers et al., 2004), and predominant maternal inheritance (Chao et al., 2010; Ebers et al., 2004; Herrera et al., 2008; Hoppenbrouwers et al., 2008). Inheritance of autoimmune disease in T1D however, takes on a paternal dominance (MacDonald et al., 1986). Islet autoimmune antibodies are more frequently transmitted via diabetic fathers (Yu et al., 1995), paternal inheritance of the insulin gene B allele confers protection from T1D (Pugliese et al., 1994), while paternal inheritance of the 11p15.5 region of the insulin gene (IDDM2) confers susceptibility to T1D (Bui et al., 1996). 5.1. Causative factors for parental inheritance of autoimmunity The interaction of genetic and environmental factors may underlie parental inheritance of autoimmunity. In the case of maternal inheritance, mitochondrial DNA could play a role. While studies addressing mitochondrial DNA variants with autoimmune disease are limited, MS has been associated with the mitochondrial

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haplotype K (Vyshkina et al., 2008) and haplotype U (Ban et al., 2008). Interestingly, variants in mitochondrial ND2 and ATP6 genes have also been found to be associated with MS and SLE, suggesting that these two diseases may share a common mitochondrial genetic background. In addition to genetic factors, environmental factors may also contribute to parental inheritance of autoimmunity (Hoppenbrouwers et al., 2008). Some of the best examples of environmental influence in parental transmission in autoimmunity have come from studies in MS cohorts. The development of MS in affected offspring may arise from in utero exposure to epigenetic changes that might result from environmental influences on the mother (e.g. timing of birth is associated with risk of MS) (Willer et al., 2005). This is discussed further below. 6. Epigenetics in autoimmunity Epigenetics relates to the stable and heritable patterns of gene expression that are not due to changes in the original DNA sequence. Altered gene expression may be persistent, but not permanent, and the epigenome of the cell can be defined by methylation, histone modification and micro RNA (miRNA) profile (Goldberg et al., 2007; Jiang et al., 2004; Lu, 2013). Epigenetic changes that arise in autoimmune disease can be related to the sex of the parent, or can result from external factors. With respect to parental gender, epigenetic changes occur via genetic imprinting, whereby genes inherited either from the father or mother are imprinted and inactivated, or when transcripts from either the maternal or paternal chromosome are expressed in a monoallelic fashion (Camprubi and Monk, 2011). Extrinsic influences in autoimmune disease include tobacco smoke, exposure to sunlight, and diet (Ellis et al., 2014). Below, we discuss evidence that indicates a role for genomic imprinting and epigenetics in driving sexual dimorphism in autoimmune disease. 6.1. Genomic imprinting as a cause for autoimmunity Genomic imprinting is the allele-specific expression of genes in a parent-of-origin fashion. It has been suggested that the genetics underlying HLA susceptibility in T1D may exhibit parental inheritance; Pani and colleagues suggest that the maternal HLA-DQ2 or DQ8 alleles are risk factors for T1D (Pani et al., 2002). For psoriatic arthritis, genetic linkage analysis suggests that there is imprinted transmission at chromosome 16q that is of paternal origin (Karason et al., 2003). Imprinting of miRNAs may also underlie autoimmunity. Micro RNAs play important roles in the post-transcriptional regulation of gene expression. In this regard, a loss of miRNAs or the deregulation of miRNAs could contribute to altered autoimmune gene expression that would result in the development of autoimmune disease. Indeed, imprinted miRNAs that may regulate autoimmune disease associated genes have been identified for MS, RA, SLE, and T1D (Camprubi and Monk, 2011). Given that there is differential hormonal and chromosomal regulation of miRNAs between males and females (Sharma and Eghbali, 2014), it is highly likely that miRNA imprinting could contribute to the sexual dimorphism seen in autoimmune disease. 6.2. Extrinsically driven epigenetic gene modifications in autoimmunity External stimuli including tobacco smoke, sunlight, and diet that lead to DNA modification could explain gender differences in autoimmune disease. Smoking is associated with an increased risk for RA in both men and women when compared to non-smokers

(Sugiyama et al., 2010), and increased risk of MS (in women studied) (Hernan et al., 2001). Moreover, smoking has been found to be a risk factor for relapsing–remitting MS (Hernan et al., 2005). Exposure to lower levels of sunlight (Hammond et al., 1988; Kurtzke et al., 1979; Taylor et al., 2010; van der Mei et al., 2003; Vukusic et al., 2007), season of birth (Dobson et al., 2013; Willer et al., 2005), low maternal exposure to sunlight (Staples et al., 2010), and low levels of vitamin D (van der Mei et al., 2007) have been well established to be associated with increased risk for MS. Recent studies assessing dietary intake of vitamin D in women with MS report that higher levels of vitamin D are associated with reduced risk (Munger et al., 2004), and assessment of micronutrient intake has provided insight into the geographical blueprint of autoimmune disease in China (Qin et al., 2009). While it is easy to speculate that varying exposure to extrinsic triggers would occur between males and females, earlier adoption of smoking in men (Zang and Wynder, 1996), increased unprotected exposure to sunlight in men (Hall et al., 1997), and different dietary habits between men and women (Dynesen et al., 2003; Ferraro and Vieira, 2010; Friel et al., 2005) would support the notion that differential exposure to extrinsic factors may play a role in gender bias in autoimmune disease. 7. Conclusion The gender differences that exist in autoimmunity tend to follow a female bias. A number of factors may underlie this striking gender difference. The clear differences between the female and male immune systems would suggest that the increased immune reactivity in females might predispose them to developing autoimmune disease. This may be explained in part by the effects of sex hormones since estrogen suppresses Th1-dependent disease, but potentiates Th2-dependent diseases. Accordingly, differences in reproductive function, and pregnancy in women, may also explain gender differences in autoimmunity. While the impact of microchimerism during pregnancy in autoimmune disease remains to be understood, parental inheritance, mitochondrial inheritance, genomic imprinting and chromosomal inactivation could also play a role. Finally, extrinsic epigenetic influences and more specifically, the level of exposure to external factors and the subsequent response to such factors might influence susceptibility to autoimmune disease. In conclusion, the striking evidence of gender differences in autoimmune disease should dictate that future studies considering incidence, prevalence, severity, mortality, disease mechanisms and potential therapies in autoimmunity be stratified according to gender. Acknowledgment Dr. S. Ngo acknowledges the support of the Motor Neurone Disease Research Institute of Australia. References Abdou, N.I., Rider, V., Greenwell, C., Li, X., Kimler, B.F., 2008. Fulvestrant (Faslodex), an estrogen selective receptor downregulator, in therapy of women with systemic lupus erythematosus. clinical, serologic, bone density, and T cell activation marker studies: a double-blind placebo-controlled trial. J. Rheumatol. 35, 797. Adams Waldorf, K.M., Nelson, J.L., 2008. Autoimmune disease during pregnancy and the microchimerism legacy of pregnancy. Immunol. Invest. 37, 631–644. Adorini, L., 2005. Intervention in autoimmunity: the potential of vitamin D receptor agonists. Cell. Immunol. 233, 115–124. Aggarwal, R., Malaviya, A.N., 2009. Clinical characteristics of patients with ankylosing spondylitis in India. Clin. Rheumatol. 28, 1199–1205. Agret, F., Cosnes, J., Hassani, Z., Gornet, J.M., Gendre, J.P., Lemann, M., Beaugerie, L., 2005. Impact of pregnancy on the clinical activity of Crohn’s disease. Aliment. Pharmacol. Ther. 21, 509–513.

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