266 Demyelinating Disorders
in areas of high MS prevalence. The low risk of conjugal MS Although MS has long been thought to be a CD4+ T-
further supports data suggesting that familial risk is geneti- cell class-II–mediated autoimmune disease, there is
cally determined and not sexually transmitted . strong evidence that CD8+ T cells and class-I molecules
Although the genes that contribute to MS susceptibility also play an integral role, particularly in axonal damage.
have not been identified, genome-wide studies have Importantly, within actively demyelinating MS lesions,
revealed that susceptibility to MS is linked to genes in the MHC class-I–restricted CD8+ T cells outnumber CD4+ T
major hitocompatibility complex (MHC) on chromosome cells by roughly 10-fold [7••]. MHC class-I molecules are
6. Alleles of certain class-II genes, human leukocyte antigen up-regulated on neural cells during most inflammatory
(HLA) DR and HLA DQ, which are known to be involved and degenerative CNS diseases, and may be regulated in
in antigen presentation, confer the strongest degree of MS an activity-dependent fashion. Additionally, in vitro stud-
predisposition, and this has been consistent across many ies have demonstrated that CD8+ cytotoxic lymphocytes
populations. In spite of these associations, the relative risk (CTLs) are capable of transecting neurites in an MHC
provided by HLA is small, increasing by threefold com- class-I peptide-dependent fashion . This evidence
pared with the general population. In addition to suscepti- supports earlier reports that Theiler's murine encephalo-
bility, genetic factors may also govern disease course and myelitis virus (TMEV) infected mice, which are deficient
severity . in MHC class-I, show preservation of axons despite exten-
sive demyelination . Furthermore, blocking CD8+
CTLs using viral-specific peptides also indicates that
Clinicopathophysiology CD8+ cells contribute to neuronal injury, because treated
Although it had been generally accepted that similar mice exhibited improved motor function, despite wide-
pathophysologic mechanisms were operative in all MS spread demyelination [12•].
patients, recent studies indicate heterogeneity at the level
of the MS lesion [6••]. Four fundamentally different pat-
terns of demyelination in acute lesions, which differ Viruses that Have Been Proven to Induce
between, but not within a given patient, have been identi- Demyelination in Humans (Hit-Hit)
fied. Lesions differ in the extent of cellular infiltrates, The concept that viral agents may initiate MS is supported
antibody deposition, demyelination and remyelination, by clear evidence that other viral infections cause CNS
the magnitude of complement activation, and the degree inflammation and demyelination in humans (Table 1)
of oligodendrocyte loss. Patterns I (macrophage-associ- . Viral-induced demyelination is most clearly associ-
ated demyelination) and II (antibody-mediated demyeli- ated with progressive multifocal leukoencephalopathy
nation) resemble experimental autoimmune models of (PML), subacute sclerosing pancencephalitis (SSPE), and
MS, in which the toxic products of activated macrophages human T-lymphotropic virus type-1 (HTLV-1)–associated
(I) or demyelinating antibodies (II) lead to myelin myelopathy/tropical spastic paraparesis (HAM/TSP).
destruction. Patterns III (distal-oligodendrogliopathy) SSPE is an extremely rare, fatal, chronic progressive
and IV (extensive oligodendrocyte loss) mirror a viral- panencephalitis occurring 5 to 10 years after acute mea-
induced or metabolic disturbance, respectively, rather sles virus infection. PML is caused by a ubiquitous human
than autoimmunity. These differing types of lesions and virus acquired early in life. Papopavirus (JC) is also typi-
broad spectrum of structural changes may reflect distinct cally fatal, but predominantly affects immunocompro-
pathogenetic mechanisms involved in different patient mised individuals. In both SSPE and PML, the inciting
subgroups. Although specific correlates have not yet been virus has been identified in oligodendroglia of affected
established, lesion heterogeneity may explain in part the patients (examples of the Hit-Hit hypothesis). TSP is
heterogeneity of MS with respect to clinical presentation caused by the strongly neurotropic retrovirus, HTLV-1,
and response to therapy. and has considerable clinical similarity to primary pro-
There are strong arguments in favor of antigen-specific gressive MS. Although over 20 million people worldwide
mechanisms of immune-mediated demyelination in MS. are infected with HTLV-1, only a small percentage
First, two groups have recently reported extensive clonal develop neurologic disease. As seen in primary progres-
expansion of T cells, predominantly CD8+ T cells, within sive MS, there is a slowly progressive spastic paraparesis,
MS lesions [7••,8]. The clonal expansion of antibody- lesions in magnetic resonance imaging (MRI) scans,
secreting B cells in the CNS and cerebrospinal fluid (CSF) increased CSF immunoglobulin, and oligoclonal band-
of MS patients has also been reported, indicative of ing. Some would argue that HAM/TSP is part of a hetero-
repeated exposure to the same antigen . Together, these geneous MS syndrome with a clearly defined pathogen.
results support the concept of a highly focused immune The association of CSF immunglobulin G (IgG) oligo-
response driving pathogenesis in MS. Because most class- clonal bands that persist in patients unchanged through-
I–restricted CD8+ T-cell responses are triggered by out the course of MS provides at least circumstantial
viruses, these data provide circumstantial evidence for the evidence of an infectious agent. Oligoclonal bands are
viral theory of MS. 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
1) Virus enters the CNS 1) Virus infects periphery
2) Virus persists in the CNS 2) Virus does not persist in the CNS
3) Injury by direct viral replication 3) Injury mediated by a periperal change in the immune milieu,
4) Injury mediated by the immune response to clear through the development of autoimmunity by the activation of the
infection, including toxic cytokines or pathogenic CNS autoreactive T cells (molecular mimicry or bystander
antibodies, by the development of autoimmunity via mechanisms), or directly by toxic proinflammatory agents.
epitope spreading, and/or by the nonspecific activation
of immune T cells by bystander mechanisms.
CNS demyelinating diseases Candidates in MS
PML, SSPE, HTLV-1 (HAM/TSP) Herpesvirus (EBV), self-limiting upper respiratory or
Candidates in MS gastrointestinal tract infections
Herpesvirus (HHV-6), Chlamydia pneumoniae, HERVs
1) Vaccination of predisposed - curative 1) Vaccination of predisposed - curative
2) Antivirals for established patients - 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 founding results. A recent longitudinal study examining
. It is envisioned that CNS infection occurs via the HHV-6 DNA in serum suggested that reinfection or reacti-
blood-brain barrier and is transmitted to CNS cells by vation of a latent HHV-6 infection might be associated
peripheral blood mononuclear cells. Neurotropic viruses with disease exacerbation . Current data suggest a
can persist in the CNS, establishing a CNS-restricted antivi- highly neurotropic variant of HHV-6 (HHV-6A) may be of
ral or autoimmune process. Candidate organisms may ini- considerable importance [17•,18].
tiate MS or trigger relapses in a subset of susceptible
individuals, or may be reactivated due to the disease itself, Chlamydia pneumoniae
without contributing to symptoms. It is clear that Chlamydia pneumoniae infection is com-
monly associated with inflammatory neurologic condi-
tions . Initial studies showed that C. pneumoniae was
Candidate Multiple Sclerosis Pathogens: present in a higher percentage of MS patients by poly-
Hit-Hit Hypothesis merase chain reaction (PCR) testing (97%) relative to con-
Herpesviruses trol subjects (19%) . In addition, immunoblotting
Herpesviruses, including herpes simplex viruses (HSV), experiments have shown that oligoclonal bands in MS CSF
Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV- can be completely adsorbed with purified C. pneumoniae
6), have been described as likely pathogens in MS, in part . However, a recent collaborative effort, in which CSF
due to their ability to cause latent infections that periodi- samples of MS patients were split and sent to several differ-
cally reactivate, mirroring the often relapsing remitting ent laboratories for PCR analysis, produced contradictory
course of MS. Additionally, some human herpesviruses can findings . Kaufman et al.  confirmed earlier results,
be readily identified within the CNS, and some are known but three other laboratories were unable to detect C. pneu-
to be capable of inducing demyelination both in humans moniae in any of the samples examined. A multicenter, col-
and in experimentally infected animals. laborative effort to detect C. pneumoniae in autopsy brain
Human herpesvirus 6 is a T-cell lymphotropic and neu- material of MS patients has also been unsuccessful . If
rotropic virus, generally acquired in early childhood and C. pneumoniae is a cause of MS, it likely would be an exam-
associated with a high incidence of seropositivity in ple of Hit-Hit.
healthy adults. Its association with MS was given support
by Challoner et al. , who demonstrated the presence of Human endogenous retroviruses
HHV-6 DNA in over 70% of both MS and control subject Retroviruses, including HTLV-1, have been intensively
brains, with the caveat that HHV-6 protein was identified studied as potential agents in the pathogenesis of MS. The
only in MS plaques. After this initial observation, several retrovirus visna, which is found in sheep, was an early ani-
other reports were published with confirmatory or con- mal model of MS. This virus can be readily detected in the
268 Demyelinating Disorders
CNS of infected sheep. Another recently identified retrovi- ferons in secondary progressive MS (SPMS), but that they
rus, termed multiple sclerosis retrovirus (MSRV), has been also may aggravate primary progressive MS (PPMS).
reported in MS plasma and CSF and has been cultured Although interferons are known to be immunomodu-
from leptomeningeal cells of an MS patient . In a latory, the initial rationale for use of interferons in MS was
recent study, however, MSRV was identified in nearly half as an antiviral agent. There is recent evidence to indicate
of the CSF samples examined from MS patients at clinical that the treatment efficacy of the β-interferons may indeed
onset and in patients with other neurologic disorders, indi- relate in part to these antiviral properties. Inteferon-β was
cating that MSRV is not MS restricted, but may represent a shown to reduce HHV-6 replication in vitro, to decrease
marker for neurologic diseases of inflammatory origin HHV-6 cell free DNA, and to decrease serum IgM reactivity
. It is important to consider that susceptibility to dis- in MS patients . Other antivirals have also been exam-
ease resulting from infection by a given pathogen may ined in clinical trials. For example, acyclovir, targeting HSV,
reflect underlying genetic predisposition. Therefore, was examined in a placebo-controlled trial in MS patients
excluding a pathogen simply because it is found in both and found to result in a nonsignificant trend toward clini-
MS and control patient groups in similar frequency is cal benefit on relapse rate . Use of a broader-spectrum
likely to be an oversimplification. For example, some stud- antiviral, valacyclovir, which targets varicella zooster and
ies have suggested that MSRV-positive MS patients have a EBV in addition to HSV, showed no differences between
more progressive disease course . the treatment and placebo for any of the clinical endpoints
examined . However, patients with high disease activ-
ity had a 68% reduction in new lesion formation.
Candidate Multiple Sclerosis Pathogens: The other approved treatment for RRMS is glatiramer
Hit-Run Hypothesis acetate . This drug was shown to inhibit experimental
Epstein-Barr virus is a lymphotropic herpesvirus that has autoimmune encephalomyelitis (EAE) in rodents, and has
received considerable attention as a putative MS agent, but been shown to ubiquitously bind MHC class-II DR . If
as for HHV-6 the results remain controversial. The virus is viruses trigger subsequent class-II restricted CD4+ T-cell–
not considered neurotropic. Several studies have detected mediated autoimmunity, then this is likely how glatiramer
EBV antibodies in a higher percentage in MS patients sera acetate works.
relative to control patients . A comprehensive seroepi-
demiologic study, the Nurses Health Study [28•], involving
blood samples from more than 62,000 women, reported Mechanisms of Viral-induced Central Nervous
that higher levels of EBV antibodies were associated with a System Demyelination
fourfold increased risk of developing MS. Owing to the fact Animal models have provided direct evidence that viral
that EBV is effective in activating myeling basic protein infection and/or autoimmune mechanisms can incite
(MBP)-specific T-cell clones, it has also has been suggested inflammatory demyelinating disease resembling MS. There
that periodic EBV reactivation may activate and expand are two primary viral models of MS: TMEV and mouse hep-
self-reactive myelin-specific T cells, thereby exacerbating atitis virus (MHV). Each is a naturally occurring murine
disease. There are no studies to date that have demon- virus that infects the CNS and induces demyelination in
strated EBV nucleic acid or protein in MS plaques, or which genetically susceptible mice (Hit-Hit). Most data indicate
have cultured the virus from affected brains. If EBV is a that demyelination is secondary to the immune response
cause of MS, then the most likely scenario is that the virus targeting CNS viral antigens. The other major animal
alters the immune system in the periphery, which then model of MS is EAE. Similarities between MS and EAE,
transforms with time to autoimmunity. which is inducible by immunization with protein constitu-
ents of CNS myelin such as MBP or proteolipid protein
(PLP) or by adoptive transfer of CD4+ T cells specific for
Current Therapeutic Strategies these proteins, favor an autoimmune model, but do not
Current therapies are mainly directed at the inflammatory exclude the role of an infectious agent. Notably, the induc-
process that characterizes MS, in an attempt to prevent tion of EAE requires the use of Complete Freund's Adju-
clinical relapses and the irreversible damage during pro- vant (CFA), which creates an artificial inflammatory
gression. The approved treatment for long-term therapy is milieu. The best natural adjuvants in nature are viruses that
one of three recombinant interferon β preparations. A large stimulate the immune system (Hit-Run).
body of evidence indicates that type-1 interferons (ie, inter- There are three main mechanisms proposed to explain
feron β-1a and interferon β-1b) reduce exacerbation rates how infectious agents could lead to autoimmunity. The
in relapsing remitting MS (RRMS) by approximately one first suggests that molecular mimicry between pathogenic
third . It is unclear whether β-interferons affect disease and self antigens leads to the activation of T cells that are
progression beyond effects on relapses. Interferon β-1a was cross-reactive with self-epitopes [36,37]. In the epitope
recently reported to also reduce relapse rates in more spreading model, virus-specific T cells cause direct or indi-
severe RRMS . Studies suggest some efficacy of β-inter- rect damage to self, with consequent autoantigen release,
Hit-Hit and Hit-Run: Viruses in the Playing Field of Multiple Sclerosis • Scarisbrick and Rodriguez 269
resulting in de novo activation of autoreactive T cells . tors may render MS patients more susceptible to such
Finally, demyelination may be the result of bystander cross-reactivity, including genetic factors.
mechanisms in which nonspecific infections activate Recent studies also suggest that molecular mimicry
immune T cells [39,40••]. Although there are several pos- between antibodies directed at clearing CNS viruses and
sible mechanisms by which infectious agents may induce CNS antigens may contribute to the pathogenesis of CNS
CNS demyelination, we propose these are initiated in autoimmune disease [45••]. Antibodies isolated from
either a Hit-Hit or Hit-Run fashion. HTLV-1–infected HAM/TSP patients were shown to cross-
react with HTLV-1, to recognize a neuronal nuclear bionu-
Molecular mimicry clear protein-A1 (hnRNP-A1), to specifically stain the neu-
Various viral and bacterial peptides, showing limited rons preferentially damaged in this disease, and to inhibit
sequence homology with myelin self-peptides (HHV-6, neuronal firing in vitro. Notably, hnRNP-A1 was also
influenza, measles, papilloma virus, and EBV), have found to share significant homology to hnRNP-A2, a pro-
been shown to activate autoreactive T-cell clones. Initial tein known to have a critical role in the transport of MBP
studies showed that transgenic mice expressing virus within oligodendroglial processes.
proteins in the context of self-tissues developed autoim-
mune disease following infection with the correspond- Epitope spreading
ing virus. Recently, studies have provided more direct The epitope spreading model suggests that regardless of
evidence that infection-induced molecular mimicry the initial antigenic stimulus (Hit-Hit or Hit-Run), the
could lead to CNS demyelination. For example, CNS specificity of the immune response spreads to include self-
infection with a nonpathogenic variant of TMEV, con- epitopes, which are distinct from that initiating the inflam-
taining a 6 amino acid PLP139-151 mimic present in matory response . For example, PLP-139-151/CFA
Hemophilus influenzae, resulted in early onset demyelina- immunization of SJL mice results in a relapsing remitting
tion and activation of T-helper 1 (Th1) cells cross-reac- demyelinating disease, mediated in the initial phase by
tive with native PLP139-151 [41•]. These results PLP139-151–specific CD4+ Th1-type T cells, with the fol-
demonstrated that infection with a virus expressing a lowing relapses mediated by myelin-specific Th1 cells spe-
mimic of self-epitope, or at least 6 amino acids identical cific for other endogenous myelin epitopes, such as
to a self-epitope, can induce autoreactive T cells, with PLP178-191 and MBP84-104 . The pathogenic signifi-
pathologic potential in the absence of CFA. It is impor- cance of epitope spreading was illustrated by experiments
tant to note that for this to occur, however, the inciting demonstrating that tolerance to PLP178-191, but not to
virus must enter and then persist in the CNS, an exam- PLP139-151, was required to prevent EAE disease relapses.
ple of demyelination in a Hit-Hit fashion. Additionally, T cells specific for relapse-associated epitopes
It has been shown that viral sequence homology is not were shown to transfer disease to naive recipients. A patho-
a prerequisite for activation of T cells specific for myelin logic role for epitope spreading in virus-induced demyeli-
antigens. T-cell receptor (TCR) cross-reactivity has been nation has also been demonstrated. With TMEV infection,
attributed to a high degree of degeneracy in antigen recog- CD4+ T-cell responses are restricted to TMEV. With the
nition by the TCR, requiring only as few as three critical onset of TMEV-induced demyelination, however, CD4+ T-
residues [42•]. Linking molecular mimicry to genetics, the cell responses to the immunodominant PLP139-151 mye-
MBP85-99 cross-reactive human TCR has been linked to at lin epitope develop, which subsequently progress to
least two alleles of the MHC class-II, DR2 haplotype involve CD4 responses to a variety of additional myelin
[43••], a defined genetic risk factor for MS. Lang et al. epitopes . Again, it was shown that induction of toler-
[43••] found that the TCR recognized MBP85-99 in the ance to the encephalitogenic myelin epitopes partially
context of the DRB1*1501 allele, and EBV627-641 in the abrogated disease progression. It is important to note that
context of the DRB5*0101 allele. This functional interac- epitope spreading did not occur in TMEV-infected mice
tion between two of the MHC class-II loci in the DR2 hap- until there was significant demyelination as a result of a
lotype could lead to increased numbers of microbial direct antiviral immune response (Hit-Hit). It has been
pathogen-derived peptides available for presentation to a proposed that epitope spreading to include reactivity to
single cross-reactive TCR. axons might explain the transition from RRMS to SPMS,
The potential contribution of molecular mimicry and a whereas in PPMS, reactivity to axonal antigens may be the
degenerate TCR to autoimmune disease is somewhat tem- primary target .
pered by other recent studies. The capacity of HHV-6 and
MBP to activate T cells isolated from MS patients and con- Bystander-mediated demyelination
trol subjects was examined. T cells cross-reacting with An alternative to the epitope spreading model, the
HHV-6 and MBP were identified; however, cross-reacting T bystander-mediated demyelination model proposes
cells were found in both groups, suggesting that such cross- bystander activation of immune T cells. Notably, numer-
reactivity may not be an important mechanism in MS ous studies have demonstrated the existence of myelin-spe-
pathophysiology . Alternatively, other concurrent fac- cific autoreactive T cells in healthy individuals, and indeed
270 Demyelinating Disorders
these may be part of the normal immune repertoire. It is Acknowledgments
also known that viral infections are associated with sys- Supported by grants RG 3367-A-2-01 from the National
temic immune activation, reflected by the increased pro- Multiple Sclerosis Society and grant P01-NS38468 from
duction of proinflammatory cytokines, which may result the National Institutes of Health.
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 References and Recommended Reading
accepted that nonspecific infections, mostly upper respira- Papers of particular interest, published recently, have been
tory tract infections, are associated with disease exacerba- highlighted as:
tions, and that these exacerbations lead to more sustained • Of importance
•• Of major importance
clinical deficits . Experimental evidence comes from
studies that showed infection of young mice peripherally 1. Noseworthy JH, Lucchinetti CF, Rodriguez M, Weinshenker BG:
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