Hit-Hit and Hit-Run: Viruses in the Playing Field of Multiple Sclerosis I.A. Scarisbrick, PhD, and M. Rodriguez, MD
Address Departments of Neurology and Immunology, Mayo Medical and Graduate Schools, 428 Guggenheim Building, 200 First Street SW, Rochester, MN 55905, USA. E-mail:
[email protected] Current Neurology and Neuroscience Reports 2003, 3:265–271 Current Science Inc. ISSN 1528–4042 Copyright © 2003 by Current Science Inc.
Viruses have been major players in the search for the cause of multiple sclerosis (MS). In support of the viral theory is the predominance of CD8+ T cells and class-I major histocompatibility complex in lesions, the powerful therapeutic effects of β interferons, the ease of inducing demyelination in experimental models following virus challenge, and the documented examples of several human demyelinating diseases conclusively demonstrated to be of viral origin. We propose two hypotheses of how viruses may cause MS. In the "Hit-Hit" hypothesis, the virus persists or may be reactivated in the central nervous system (CNS). Injury is the result of direct viral damage and by an attempt of the immune response to clear the infectious agent. In the "HitRun" hypothesis, virus infects the periphery but never enters the CNS. The virus sets up an abnormal immunologic milieu for subsequent autoimmunity. In both scenarios, knowing the inciting virus would be expected to eliminate disease if the population were vaccinated to prevent infection. In the treatment of patients with fully established disease, the Hit-Hit hypothesis would require that antiviral agents enter the CNS and stop replication. In the case of the Hit-Run hypothesis, treatment of patients with established disease with antiviral agents would be futile.
Introduction Multiple sclerosis (MS) is a common chronic demyelinating disease of unknown etiology that leads to irreversible disability. Whereas there is limited agreement concerning potential initiating event(s), it is agreed the disease process is probably immune mediated. The extent and nature of central nervous system (CNS) inflammation varies and consists of variable degrees of CD8+ and CD4+ T and B lymphocytes, macrophages, and pathogenic antibodies at the leading edge of white matter destruction. Genetic, immunologic, and environmental factors, such as viruses, have each been considered as possible etiologic agents [1].
Fundamental questions concerning the pathophysiology of MS remain unanswered. First, it is unclear what event or events initiate CNS inflammation. Two primary theories exist: the autoimmune and the microbial. In the autoimmune theory, CNS white matter is intact, with the inflammatory insult being mediated by a destructive immune response that is initiated in the periphery by autoreactive T cells. In the microbial theory, demyelination is the consequence of one or multiple infectious agents that persist in the CNS, causing multiple hits ("Hit-Hit"), with direct or indirect damage to myelin and/or oligodendrocytes. Alternatively, demyelination may be caused by an autoreactive immune response, the byproduct of a peripheral microbial or viral infection, a virtual "Hit-Run." There is both clinical and experimental evidence to indicate that infection can drive destructive immunity and demyelination via at least four mechanisms: antigen-specific reactivity, molecular mimicry, epitope spreading, and bystander demyelination. We review recent epidemiologic, clinicopathophysiologic, and experimental evidence of the role that infection plays in MS, and what light this evidence sheds on the potential mechanisms initiating and driving the disease process.
Epidemiologic Studies Epidemiologic studies support the involvement of an environmental agent, possibly infectious, in the etiology of MS, on a background of host genetic factors. These include geographic association of disease susceptibility with evidence of MS clustering [2]. For example, the prevalence of MS is low around the equator, with prevalence increasing both directions, north or south, with migration studies to and from high-risk areas suggesting that timing of exposure is critical to future MS susceptibility. Individuals moving before the of age 15 years acquire the risk of the area to which they move, whereas individuals moving after that age keep their original risk phenotype. It is well accepted that genetic factors play an important role in the pathogenesis of MS, and indeed the lifetime risk of developing MS is higher in biologic relatives of MS patients. For example, the concordance rate is much higher among monozygotic compared with diazygotic twins, even in twins raised separately [3]. Ethnic predisposition also implicates genetic factors. For example, relative susceptibility is greater in northern Eupopeans, as compared with the relative protection of Native Americans, despite each living
266
Demyelinating Disorders
in areas of high MS prevalence. The low risk of conjugal MS further supports data suggesting that familial risk is genetically determined and not sexually transmitted [4]. Although the genes that contribute to MS susceptibility have not been identified, genome-wide studies have revealed that susceptibility to MS is linked to genes in the major hitocompatibility complex (MHC) on chromosome 6. Alleles of certain class-II genes, human leukocyte antigen (HLA) DR and HLA DQ, which are known to be involved in antigen presentation, confer the strongest degree of MS predisposition, and this has been consistent across many populations. In spite of these associations, the relative risk provided by HLA is small, increasing by threefold compared with the general population. In addition to susceptibility, genetic factors may also govern disease course and severity [5].
Clinicopathophysiology Although it had been generally accepted that similar pathophysologic mechanisms were operative in all MS patients, recent studies indicate heterogeneity at the level of the MS lesion [6••]. Four fundamentally different patterns of demyelination in acute lesions, which differ between, but not within a given patient, have been identified. Lesions differ in the extent of cellular infiltrates, antibody deposition, demyelination and remyelination, the magnitude of complement activation, and the degree of oligodendrocyte loss. Patterns I (macrophage-associated demyelination) and II (antibody-mediated demyelination) resemble experimental autoimmune models of MS, in which the toxic products of activated macrophages (I) or demyelinating antibodies (II) lead to myelin destruction. Patterns III (distal-oligodendrogliopathy) and IV (extensive oligodendrocyte loss) mirror a viralinduced or metabolic disturbance, respectively, rather than autoimmunity. These differing types of lesions and broad spectrum of structural changes may reflect distinct pathogenetic mechanisms involved in different patient subgroups. Although specific correlates have not yet been established, lesion heterogeneity may explain in part the heterogeneity of MS with respect to clinical presentation and response to therapy. There are strong arguments in favor of antigen-specific mechanisms of immune-mediated demyelination in MS. First, two groups have recently reported extensive clonal expansion of T cells, predominantly CD8+ T cells, within MS lesions [7••,8]. The clonal expansion of antibodysecreting B cells in the CNS and cerebrospinal fluid (CSF) of MS patients has also been reported, indicative of repeated exposure to the same antigen [9]. Together, these results support the concept of a highly focused immune response driving pathogenesis in MS. Because most classI–restricted CD8+ T-cell responses are triggered by viruses, these data provide circumstantial evidence for the viral theory of MS.
Although MS has long been thought to be a CD4+ Tcell class-II–mediated autoimmune disease, there is strong evidence that CD8+ T cells and class-I molecules also play an integral role, particularly in axonal damage. Importantly, within actively demyelinating MS lesions, MHC class-I–restricted CD8+ T cells outnumber CD4+ T cells by roughly 10-fold [7••]. MHC class-I molecules are up-regulated on neural cells during most inflammatory and degenerative CNS diseases, and may be regulated in an activity-dependent fashion. Additionally, in vitro studies have demonstrated that CD8+ cytotoxic lymphocytes (CTLs) are capable of transecting neurites in an MHC class-I peptide-dependent fashion [10]. This evidence supports earlier reports that Theiler's murine encephalomyelitis virus (TMEV) infected mice, which are deficient in MHC class-I, show preservation of axons despite extensive demyelination [11]. Furthermore, blocking CD8+ CTLs using viral-specific peptides also indicates that CD8+ cells contribute to neuronal injury, because treated mice exhibited improved motor function, despite widespread demyelination [12•].
Viruses that Have Been Proven to Induce Demyelination in Humans (Hit-Hit) The concept that viral agents may initiate MS is supported by clear evidence that other viral infections cause CNS inflammation and demyelination in humans (Table 1) [13]. Viral-induced demyelination is most clearly associated with progressive multifocal leukoencephalopathy (PML), subacute sclerosing pancencephalitis (SSPE), and human T-lymphotropic virus type-1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis (HAM/TSP). SSPE is an extremely rare, fatal, chronic progressive panencephalitis occurring 5 to 10 years after acute measles virus infection. PML is caused by a ubiquitous human virus acquired early in life. Papopavirus (JC) is also typically fatal, but predominantly affects immunocompromised individuals. In both SSPE and PML, the inciting virus has been identified in oligodendroglia of affected patients (examples of the Hit-Hit hypothesis). TSP is caused by the strongly neurotropic retrovirus, HTLV-1, and has considerable clinical similarity to primary progressive MS. Although over 20 million people worldwide are infected with HTLV-1, only a small percentage develop neurologic disease. As seen in primary progressive MS, there is a slowly progressive spastic paraparesis, lesions in magnetic resonance imaging (MRI) scans, increased CSF immunoglobulin, and oligoclonal banding. Some would argue that HAM/TSP is part of a heterogeneous MS syndrome with a clearly defined pathogen. The association of CSF immunglobulin G (IgG) oligoclonal bands that persist in patients unchanged throughout the course of MS provides at least circumstantial evidence of an infectious agent. Oligoclonal bands are associated with very few CNS diseases, and those that are
Hit-Hit and Hit-Run: Viruses in the Playing Field of Multiple Sclerosis • Scarisbrick and Rodriguez
267
Table 1. Viruses in the playing field of multiple sclerosis Hit-Hit
Hit-Run
Mechanism 1) Virus enters the CNS 2) Virus persists in the CNS 3) Injury by direct viral replication 4) Injury mediated by the immune response to clear infection, including toxic cytokines or pathogenic antibodies, by the development of autoimmunity via epitope spreading, and/or by the nonspecific activation of immune T cells by bystander mechanisms. Example CNS demyelinating diseases PML, SSPE, HTLV-1 (HAM/TSP) Candidates in MS Herpesvirus (HHV-6), Chlamydia pneumoniae, HERVs (HTLV-1, MSRV) Treatment 1) Vaccination of predisposed - curative 2) Antivirals for established patients - curative
Mechanism 1) Virus infects periphery 2) Virus does not persist in the CNS 3) Injury mediated by a periperal change in the immune milieu, through the development of autoimmunity by the activation of the CNS autoreactive T cells (molecular mimicry or bystander mechanisms), or directly by toxic proinflammatory agents. Example Candidates in MS Herpesvirus (EBV), self-limiting upper respiratory or gastrointestinal tract infections Treatment 1) Vaccination of predisposed - curative 2) Antivirals for established patients - futile
CNS—central nervous system; EBV—Epstein-Barr virus; HAM/TSP—human T-lymphotropic virus type-1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis; HHV—human herpesvirus; MS—multiple sclerosis; MSRV—multiple sclerosis retrovirus; PML—progressive multifocal leukoencephalopathy; SSPE—subacute sclerosing pancencephalitis.
have been shown to be both inflammatory and infectious [14]. It is envisioned that CNS infection occurs via the blood-brain barrier and is transmitted to CNS cells by peripheral blood mononuclear cells. Neurotropic viruses can persist in the CNS, establishing a CNS-restricted antiviral or autoimmune process. Candidate organisms may initiate MS or trigger relapses in a subset of susceptible individuals, or may be reactivated due to the disease itself, without contributing to symptoms.
Candidate Multiple Sclerosis Pathogens: Hit-Hit Hypothesis Herpesviruses Herpesviruses, including herpes simplex viruses (HSV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV6), have been described as likely pathogens in MS, in part due to their ability to cause latent infections that periodically reactivate, mirroring the often relapsing remitting course of MS. Additionally, some human herpesviruses can be readily identified within the CNS, and some are known to be capable of inducing demyelination both in humans and in experimentally infected animals. Human herpesvirus 6 is a T-cell lymphotropic and neurotropic virus, generally acquired in early childhood and associated with a high incidence of seropositivity in healthy adults. Its association with MS was given support by Challoner et al. [15], who demonstrated the presence of HHV-6 DNA in over 70% of both MS and control subject brains, with the caveat that HHV-6 protein was identified only in MS plaques. After this initial observation, several other reports were published with confirmatory or con-
founding results. A recent longitudinal study examining HHV-6 DNA in serum suggested that reinfection or reactivation of a latent HHV-6 infection might be associated with disease exacerbation [16]. Current data suggest a highly neurotropic variant of HHV-6 (HHV-6A) may be of considerable importance [17•,18]. Chlamydia pneumoniae It is clear that Chlamydia pneumoniae infection is commonly associated with inflammatory neurologic conditions [19]. Initial studies showed that C. pneumoniae was present in a higher percentage of MS patients by polymerase chain reaction (PCR) testing (97%) relative to control subjects (19%) [20]. In addition, immunoblotting experiments have shown that oligoclonal bands in MS CSF can be completely adsorbed with purified C. pneumoniae [21]. However, a recent collaborative effort, in which CSF samples of MS patients were split and sent to several different laboratories for PCR analysis, produced contradictory findings [22]. Kaufman et al. [22] confirmed earlier results, but three other laboratories were unable to detect C. pneumoniae in any of the samples examined. A multicenter, collaborative effort to detect C. pneumoniae in autopsy brain material of MS patients has also been unsuccessful [23]. If C. pneumoniae is a cause of MS, it likely would be an example of Hit-Hit. Human endogenous retroviruses Retroviruses, including HTLV-1, have been intensively studied as potential agents in the pathogenesis of MS. The retrovirus visna, which is found in sheep, was an early animal model of MS. This virus can be readily detected in the
268
Demyelinating Disorders
CNS of infected sheep. Another recently identified retrovirus, termed multiple sclerosis retrovirus (MSRV), has been reported in MS plasma and CSF and has been cultured from leptomeningeal cells of an MS patient [24]. In a recent study, however, MSRV was identified in nearly half of the CSF samples examined from MS patients at clinical onset and in patients with other neurologic disorders, indicating that MSRV is not MS restricted, but may represent a marker for neurologic diseases of inflammatory origin [25]. It is important to consider that susceptibility to disease resulting from infection by a given pathogen may reflect underlying genetic predisposition. Therefore, excluding a pathogen simply because it is found in both MS and control patient groups in similar frequency is likely to be an oversimplification. For example, some studies have suggested that MSRV-positive MS patients have a more progressive disease course [26].
Candidate Multiple Sclerosis Pathogens: Hit-Run Hypothesis Epstein-Barr virus is a lymphotropic herpesvirus that has received considerable attention as a putative MS agent, but as for HHV-6 the results remain controversial. The virus is not considered neurotropic. Several studies have detected EBV antibodies in a higher percentage in MS patients sera relative to control patients [27]. A comprehensive seroepidemiologic study, the Nurses Health Study [28•], involving blood samples from more than 62,000 women, reported that higher levels of EBV antibodies were associated with a fourfold increased risk of developing MS. Owing to the fact that EBV is effective in activating myeling basic protein (MBP)-specific T-cell clones, it has also has been suggested that periodic EBV reactivation may activate and expand self-reactive myelin-specific T cells, thereby exacerbating disease. There are no studies to date that have demonstrated EBV nucleic acid or protein in MS plaques, or which have cultured the virus from affected brains. If EBV is a cause of MS, then the most likely scenario is that the virus alters the immune system in the periphery, which then transforms with time to autoimmunity.
Current Therapeutic Strategies Current therapies are mainly directed at the inflammatory process that characterizes MS, in an attempt to prevent clinical relapses and the irreversible damage during progression. The approved treatment for long-term therapy is one of three recombinant interferon β preparations. A large body of evidence indicates that type-1 interferons (ie, interferon β-1a and interferon β-1b) reduce exacerbation rates in relapsing remitting MS (RRMS) by approximately one third [29]. It is unclear whether β-interferons affect disease progression beyond effects on relapses. Interferon β-1a was recently reported to also reduce relapse rates in more severe RRMS [30]. Studies suggest some efficacy of β-inter-
ferons in secondary progressive MS (SPMS), but that they also may aggravate primary progressive MS (PPMS). Although interferons are known to be immunomodulatory, the initial rationale for use of interferons in MS was as an antiviral agent. There is recent evidence to indicate that the treatment efficacy of the β-interferons may indeed relate in part to these antiviral properties. Inteferon-β was shown to reduce HHV-6 replication in vitro, to decrease HHV-6 cell free DNA, and to decrease serum IgM reactivity in MS patients [31]. Other antivirals have also been examined in clinical trials. For example, acyclovir, targeting HSV, was examined in a placebo-controlled trial in MS patients and found to result in a nonsignificant trend toward clinical benefit on relapse rate [32]. Use of a broader-spectrum antiviral, valacyclovir, which targets varicella zooster and EBV in addition to HSV, showed no differences between the treatment and placebo for any of the clinical endpoints examined [33]. However, patients with high disease activity had a 68% reduction in new lesion formation. The other approved treatment for RRMS is glatiramer acetate [34]. This drug was shown to inhibit experimental autoimmune encephalomyelitis (EAE) in rodents, and has been shown to ubiquitously bind MHC class-II DR [35]. If viruses trigger subsequent class-II restricted CD4+ T-cell– mediated autoimmunity, then this is likely how glatiramer acetate works.
Mechanisms of Viral-induced Central Nervous System Demyelination Animal models have provided direct evidence that viral infection and/or autoimmune mechanisms can incite inflammatory demyelinating disease resembling MS. There are two primary viral models of MS: TMEV and mouse hepatitis virus (MHV). Each is a naturally occurring murine virus that infects the CNS and induces demyelination in genetically susceptible mice (Hit-Hit). Most data indicate that demyelination is secondary to the immune response targeting CNS viral antigens. The other major animal model of MS is EAE. Similarities between MS and EAE, which is inducible by immunization with protein constituents of CNS myelin such as MBP or proteolipid protein (PLP) or by adoptive transfer of CD4+ T cells specific for these proteins, favor an autoimmune model, but do not exclude the role of an infectious agent. Notably, the induction of EAE requires the use of Complete Freund's Adjuvant (CFA), which creates an artificial inflammatory milieu. The best natural adjuvants in nature are viruses that stimulate the immune system (Hit-Run). There are three main mechanisms proposed to explain how infectious agents could lead to autoimmunity. The first suggests that molecular mimicry between pathogenic and self antigens leads to the activation of T cells that are cross-reactive with self-epitopes [36,37]. In the epitope spreading model, virus-specific T cells cause direct or indirect damage to self, with consequent autoantigen release,
Hit-Hit and Hit-Run: Viruses in the Playing Field of Multiple Sclerosis • Scarisbrick and Rodriguez
resulting in de novo activation of autoreactive T cells [38]. Finally, demyelination may be the result of bystander mechanisms in which nonspecific infections activate immune T cells [39,40••]. Although there are several possible mechanisms by which infectious agents may induce CNS demyelination, we propose these are initiated in either a Hit-Hit or Hit-Run fashion. Molecular mimicry Various viral and bacterial peptides, showing limited sequence homology with myelin self-peptides (HHV-6, influenza, measles, papilloma virus, and EBV), have been shown to activate autoreactive T-cell clones. Initial studies showed that transgenic mice expressing virus proteins in the context of self-tissues developed autoimmune disease following infection with the corresponding virus. Recently, studies have provided more direct evidence that infection-induced molecular mimicry could lead to CNS demyelination. For example, CNS infection with a nonpathogenic variant of TMEV, containing a 6 amino acid PLP139-151 mimic present in Hemophilus influenzae, resulted in early onset demyelination and activation of T-helper 1 (Th1) cells cross-reactive with native PLP139-151 [41•]. These results demonstrated that infection with a virus expressing a mimic of self-epitope, or at least 6 amino acids identical to a self-epitope, can induce autoreactive T cells, with pathologic potential in the absence of CFA. It is important to note that for this to occur, however, the inciting virus must enter and then persist in the CNS, an example of demyelination in a Hit-Hit fashion. It has been shown that viral sequence homology is not a prerequisite for activation of T cells specific for myelin antigens. T-cell receptor (TCR) cross-reactivity has been attributed to a high degree of degeneracy in antigen recognition by the TCR, requiring only as few as three critical residues [42•]. Linking molecular mimicry to genetics, the MBP85-99 cross-reactive human TCR has been linked to at least two alleles of the MHC class-II, DR2 haplotype [43••], a defined genetic risk factor for MS. Lang et al. [43••] found that the TCR recognized MBP85-99 in the context of the DRB1*1501 allele, and EBV627-641 in the context of the DRB5*0101 allele. This functional interaction between two of the MHC class-II loci in the DR2 haplotype could lead to increased numbers of microbial pathogen-derived peptides available for presentation to a single cross-reactive TCR. The potential contribution of molecular mimicry and a degenerate TCR to autoimmune disease is somewhat tempered by other recent studies. The capacity of HHV-6 and MBP to activate T cells isolated from MS patients and control subjects was examined. T cells cross-reacting with HHV-6 and MBP were identified; however, cross-reacting T cells were found in both groups, suggesting that such crossreactivity may not be an important mechanism in MS pathophysiology [44]. Alternatively, other concurrent fac-
269
tors may render MS patients more susceptible to such cross-reactivity, including genetic factors. Recent studies also suggest that molecular mimicry between antibodies directed at clearing CNS viruses and CNS antigens may contribute to the pathogenesis of CNS autoimmune disease [45••]. Antibodies isolated from HTLV-1–infected HAM/TSP patients were shown to crossreact with HTLV-1, to recognize a neuronal nuclear bionuclear protein-A1 (hnRNP-A1), to specifically stain the neurons preferentially damaged in this disease, and to inhibit neuronal firing in vitro. Notably, hnRNP-A1 was also found to share significant homology to hnRNP-A2, a protein known to have a critical role in the transport of MBP within oligodendroglial processes. Epitope spreading The epitope spreading model suggests that regardless of the initial antigenic stimulus (Hit-Hit or Hit-Run), the specificity of the immune response spreads to include selfepitopes, which are distinct from that initiating the inflammatory response [38]. For example, PLP-139-151/CFA immunization of SJL mice results in a relapsing remitting demyelinating disease, mediated in the initial phase by PLP139-151–specific CD4+ Th1-type T cells, with the following relapses mediated by myelin-specific Th1 cells specific for other endogenous myelin epitopes, such as PLP178-191 and MBP84-104 [46]. The pathogenic significance of epitope spreading was illustrated by experiments demonstrating that tolerance to PLP178-191, but not to PLP139-151, was required to prevent EAE disease relapses. Additionally, T cells specific for relapse-associated epitopes were shown to transfer disease to naive recipients. A pathologic role for epitope spreading in virus-induced demyelination has also been demonstrated. With TMEV infection, CD4+ T-cell responses are restricted to TMEV. With the onset of TMEV-induced demyelination, however, CD4+ Tcell responses to the immunodominant PLP139-151 myelin epitope develop, which subsequently progress to involve CD4 responses to a variety of additional myelin epitopes [47]. Again, it was shown that induction of tolerance to the encephalitogenic myelin epitopes partially abrogated disease progression. It is important to note that epitope spreading did not occur in TMEV-infected mice until there was significant demyelination as a result of a direct antiviral immune response (Hit-Hit). It has been proposed that epitope spreading to include reactivity to axons might explain the transition from RRMS to SPMS, whereas in PPMS, reactivity to axonal antigens may be the primary target [48]. Bystander-mediated demyelination An alternative to the epitope spreading model, the bystander-mediated demyelination model proposes bystander activation of immune T cells. Notably, numerous studies have demonstrated the existence of myelin-specific autoreactive T cells in healthy individuals, and indeed
270
Demyelinating Disorders
these may be part of the normal immune repertoire. It is also known that viral infections are associated with systemic immune activation, reflected by the increased production of proinflammatory cytokines, which may result in activation and proliferation of immune T cells in a bystander fashion, bypassing TCR engagement. In favor of bystander mechanisms operating in MS, it is relatively well accepted that nonspecific infections, mostly upper respiratory tract infections, are associated with disease exacerbations, and that these exacerbations lead to more sustained clinical deficits [49]. Experimental evidence comes from studies that showed infection of young mice peripherally with a ubiquinated PLP construct, leading to presentation of PLP by class-I MHC, followed by a later nonspecific immunologic stimulus (CFA), resulted in 20% of the mice developing clinical symptoms of EAE [40••]. In a followup experiment, mice were infected peripherally with recombinant vaccinia virus encoding PLP. If these mice were later given CFA, the majority of mice developed CNS inflammation. These studies demonstrate the possibility of bystander demyelination through a mechanism of molecular mimicry in a Hit-Run fashion. Experimental evidence also exists suggesting that bystander mechanisms may contribute to demyelination in a Hit-Hit fashion. Demyelination in response to CNS MHV infection in LCMV gp33 TCR/RAG-deficient mice, which contain T cells unable to recognize MHV, occurred only in mice that had been previously primed with the now "self" gp33 [39]. Thus, CNS infection with MHV resulted in a proinflammatory milieu, capable of promoting demyelination in mice with pre-existing, nonpathogenic, CNS selfreactive CD8+ T cells. Together, these studies demonstrate that it is possible that multiple infectious agents, or periodic reactivation of latent viruses, could expand self-reactive T cells and stimulate or exacerbate disease.
Conclusions Studies in animal models and in MS patients reveal that the mechanisms that ultimately lead to pathogenesis, albeit by autoimmune or infections triggers, may be diverse. With regard to an infectious agent, potential mechanisms may be viewed in terms of an initial Hit-Hit or a Hit-Run. In the HitHit scenario, demyelination can be seen as a direct consequence of infection, with or without the development of autoimmunity. This hypothesis requires that the virus infect the CNS. In terms of a Hit-Run, primary infection in the periphery results in chronic organ-specific autoimmunity, and the inciting pathogen may never enter the CNS. Together, experimental evidence supports the concept that infectious agents may mediate CNS demyelination by several mechanisms, including the induction of autoimmunity; however the identity of that agent or agents has not yet been conclusively demonstrated.
Acknowledgments Supported by grants RG 3367-A-2-01 from the National Multiple Sclerosis Society and grant P01-NS38468 from the National Institutes of Health.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Noseworthy JH, Lucchinetti CF, Rodriguez M, Weinshenker BG: Multiple sclerosis. N Engl J Med 2000, 343:938–952. 2. Ebers GC: Natural history of multiple sclerosis. J Neurol Neurosurg Psychiatry 2001, 71:16–9. 3. Sadovnick A, Yee IM, Ebers GC: Recurrence risks to sibs of MS index cases: impact of consanguineous matings. Neurology 2001, 56:784–785. 4. Ebers GC, Yee IM, Sadovnick AD, Duquette P: Conjugal multiple sclerosis: population-based prevalence and recurrence risks in offspring. Canadian Collaborative Study Group. Ann Neurol 2000, 48:927–931. 5. Kantarci OH, de Andrade M, Weinshenker BG: Identifying disease modifying genes in multiple sclerosis. J Neuroimmunol 2002, 123:144–159. 6.•• Lucchinetti C, Bruck W, Parisi J, et al.: Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000, 47:707–717. Established different patterns of pathology in acute demyelinating multiple sclerosis lesions, suggesting heterogeneity of disease may govern clinical course and response to therapy. 7.•• Babbe H, Roers A, Waisman A, et al.: Clonal expansions of CD8+ T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 2000, 192:393–404. Article demonstrated that the immune response in multiple sclerosis lesions is predominated by CD8+ T cells and is likely antigen driven. 8. Jacobsen M, Cepok S, Quak E, et al.: Oligoclonal expansion of memory CD8+ T cells in the cerebrospinal fluid from multiple sclerosis patients. Brain 2002, 125:538–550. 9. Colombo M, Dono M, Gazzola P, et al.: Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients. J Immunol 2000, 164:2782–2789. 10. Medana I, Martinic MA, Wekerle H, Neumann H: Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am J Pathol 2001, 159:809–815. 11. Rivera-Quinones C, McGavern D, Schmelzer JD, et al.: Absence of neurological deficits following extensive demyelination in a class I-deficient murine model of multiple sclerosis. Nat Med 1998, 4:187–193. 12.• Johnson AJ, Upshaw J, Pavelko KD, et al.: Preservation of motor function by inhibition of CD8+ virus peptide-specific T cells in Theiler's virus infection. FASEB J 2001, 15:2760–2762. Experimental evidence supporting the pathogenic role of class-I CD8+ T cells in axonal injury in an animal model of multiple sclerosis. 13. Soldan SS, Jacobson S: Role of viruses in etiology and pathogenesis of multiple sclerosis. Adv Virus Res 2001, 56:517–555. 14. Gilden DH, Burgoon MP, Kleinschmidt-DeMasters BK, et al.: Molecular immunologic strategies to identify antigens and bcell responses unique to multiple sclerosis. Arch Neurol 2001, 58:43–48. 15. Challoner PB, Smith KT, Parker JD, et al.: Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc Natl Acad Sci 1995, 92:7440–7444. 16. Berti R, Brennan MB, Soldan SS, et al.: Increased detection of serum HHV-6 DNA sequences during multiple sclerosis (MS) exacerbations and correlation with parameters of MS disease progression. J Neurovirol 2002, 8:250–256.
Hit-Hit and Hit-Run: Viruses in the Playing Field of Multiple Sclerosis • Scarisbrick and Rodriguez
17.• Akhyani N, Berti R, Brennan MB, et al.: Tissue distribution and variant characterization of human herpesvirus (HHV)-6: increased prevalence of HHV-6A in patients with multiple sclerosis. J Infect Dis 2000, 182:1321–1325. This paper makes an association of the less well-characterized variant of human herpesvirus (HHV)-6, HHV-6A, with multiple sclerosis. These findings are important because HHV-6A appears to be an extremely neurotropic. 18. Alvarez-Lafuente R, Martin-Estefania C, de Las Hera V, et al.: Active human herpesvirus 6 infection in patients with multiple sclerosis. Arch Neurol 2002, 59:929–933. 19. Sotgiu S, Paiana A, Pugliatti M, et al.: Chlamydia pneumoniae in the cerebrospinal fluid of patients with multiple sclerosis and neurological controls. Mult Scler 2001, 7:371–374. 20. Sriram S, Stratton CW, Yao S, et al.: Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis. Ann Neurol 1999, 46:6–14. 21. Yao SY, Stratton CW, Mitchell WM, Sriram S: CSF oligoclonal bands in MS include antibodies against Chlamydophila antigens. Neurology 2001, 56:1168–1176. 22. Kaufman M, Gaydos CA, Sriram S, et al.: Is Chlamydia pneumonia found in spinal fluid samples from multiple sclerosis patients? Conflicting results. Mult Scler 2002, 8:289–294. 23. Hammerschlag MR, Ke Z, Lu F, et al.: Is Chlamydia pneumoniae present in brain lesions of patients with multiple sclerosis? J Clin Microbiol 2000, 38:4274–4276. 24. Perron H, Garson JA, Bedin F, et al.: Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis. Proc Natl Acad Sci U S A 1997, 94:7583–7588. 25. Dolei A, Serra C, Mameli G, et al.: Multiple sclerosis-associated retrovirus (MSRV) in Sardinian MS patients. Neurology 2002, 58:471–473. 26. Sotgiu S, Serra C, Mameli G, et al.: Multiple sclerosis-associated retrovirus and MS prognosis. Neurology 2002, 59:1071–1073. 27. Wandinger K-P, Jabs W, Siekhaus A, et al.: Association between clinical disease activity and Epstein-Barr virus reactivation in MS. Neurology 2000, 55:178–184. 28.• Ascherio A, Munger KL, Lennette ET, et al.: Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 2001, 286:3083–3088. A large prospective, case-control study demonstrating increased risk for multiple sclerosis correlated with Epstein-Barr virus seropositivity. 29. Beck RW, Chandler DL, Cole SR, et al.: Interferon beta-1a for early multiple sclerosis: CHAMPS trial subgroup analyses. Ann Neurol 2002, 51:481–490. 30. Vermersch P, de Seze J, Stojkovic T, Hautecoeur P: Interferon beta1a (Avonex) treatment in multiple sclerosis: similarity of effect on progression of disability in patients with mild and moderate disability. J Neurol 2002, 249:184–187. 31. Hong J, Tejada-Simon MV, Rivera VM, et al.: Anti-viral properties of interferon beta treatment in patients with multiple sclerosis. Mult Scler 2002, 8:237–242. 32. Lycke J, Svennerholm B, Hjelmquist E, et al.: Acyclovir treatment of relapsing-remitting multiple sclerosis. A randomized, placebo-controlled, double-blind study. J Neurol 1996, 243:214–224. 33. Bech E, Lycke J, Gadeberg P, et al.: A randomized, doubleblind, placebo-controlled MRI study of anti-herpes virus therapy in MS. Neurology 2002, 58:31–36. 34. Johnson KP, Brooks BR, Cohen JA, et al.: Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology 2001, 57:S46–S53.
35.
271
Hafler DA: Degeneracy, as opposed to specificity, in immunotherapy. J Clin Invest 2002, 8:142–154. 36. Fujinami RS: Molecular mimicry that primes for autoimmunity which is triggered by infection. Mol Psychiatry 2002, 7:S32–S33. 37. Wucherpfennig KW: Infectious triggers for inflammatory neurological diseases. Nat Med 2002, 8:455–457. 38. Olson JK, Eagar TN, Miller SD: Functional activation of myelin-specific T cells by virus-induced molecular mimicry. J Immunol 2002, 169:2719–2726. 39. Haring JS, Pewe LL, Perlman S: Bystander CD8 T cell-mediated demyelination after viral infection of the central nervous system. J Immunol 2002, 169:1550–1555. 40.•• Theil DJ, Tsunoda I, Rodriguez F, et al.: Viruses can silently prime for and trigger central nervous system autoimmune disease. J Neurovirol 2001, 7:220–227. Provides experimental evidence suggesting prior viral infection may set the stage for nonspecific immunologic stimuli to activate self-reactive T cells. 41.• Olson JK, Croxford JL, Calenoff MA, et al.: A virus-induced molecular mimicry model of multiple sclerosis. J Clin Invest 2001, 108:311–318. This model was the first to directly demonstrate that a virus encoding a mimic of an encephalitogeic self myelin epitope could induce an autoreactive CD4+ T cell response, leading to central nervous system demyelination. 42.• Hemmer B, Kondo T, Gran B, et al.: Minimal peptide length requirements for CD4(+) T cell clones—implications for molecular mimicry and T cell survival. Int Immunol 2000, 12:375–383. Demonstrated that as few as three critical residues may be required for T-cell receptor recognition. 43.•• Lang HL, Jacobsen H, Ikemizu S, et al.: A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol 2002, 3:940–943. Crystal structure analysis and lymphoproliferative studies were used to demonstrate that the human myelin basic protein (MBP) T-cell receptor may cross-react with both MBP and Epstein-Barr virus in a major histocompatibility class-II DR2 restricted fashion. 44. Cirone M, Cuomo L, Zompetta C, et al.: Human herpesvirus 6 and multiple sclerosis: a study of T cell cross-reactivity to viral and myelin basic protein antigens. J Med Virol 2002, 68:268–272. 45.•• Levin MC, Lee SM, Kalume F, et al.: Autoimmunity due to molecular mimicry as a cause of neurological disease. Nat Med 2002, 8:509–513. These data demonstrate the potential importance of molecular mimicry between pathogenic human T-cell leukemia/lymphoma virus-1 antibodies and neuronal proteins in the development of a human disease resembling multiple sclerosis. 46. Vanderlugt CL, Neville KL, Nikcevich KM, et al.: Pathologic role and temporal appearance of newly emerging autoepitopes in relapsing experimental autoimmune encephalomyelitis. J Immunol 2000, 164:670–678. 47. Katz-Levy Y, Neville KL, Padilla J, et al.: Temporal development of autoreactive Th1 responses and endogenous presentation of self myelin epitopes by central nervous system-resident APCs in Theiler's virus-infected mice. J Immunol 2000, 165:5304–5314. 48. Sadatipour BT, Greer JM, Pender MP: Increased circulating antiganglioside antibodies in primary and secondary progressive multiple sclerosis. Ann Neurol 1998, 44:980–983. 49. Buljevac D, Flach HZ, Hop WC, et al.: Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain 2002, 125:952–960.
