Virus-induced Demyelination Research Articles

Migration of engrafted neural stem cells is mediated by CXCL12 signaling through CXCR4 in a viral model of multiple sclerosis

Multiple sclerosis (MS) is a human demyelinating disease characterized by multifocal regions of inflammation, progressive myelin loss within the central nervous system (CNS), and eventual failure to remyelinate damaged axons. These problems suggest deficiencies in recruiting and/or maturation of oligodendrocyte progentior cells (OPCs) and highlight cell replacement therapies to promote remyelination. We have used a model of viral-induced demyelination to characterize signaling cues associated with positional migration of transplanted remyelination-competent cells. Although successful transplantation of rodent-derived glial cell types into models of MS has been performed, the mechanisms by which these cells navigate within an inflammatory environment created by a persistent virus has not been defined. Infection of the mouse CNS with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in an immune-mediated demyelinating disease with clinical and histologic similarities to MS. Surgical engraftment of GFP+ neural stem cells (NSCs) into spinal cords of JHMV-infected mice with established demyelination results in migration, proliferation, and differentiation of the cells into OPCs and mature oligodendrocytes that is associated with increased axonal remyelination. Treatment with anti-CXCL12 [stromal derived factor-1alpha, (SDF-1alpha)] blocking serum resulted in a marked impairment in migration and proliferation of engrafted stem cells. Moreover, small molecule-mediated antagonism of CXCR4, but not CXCR7, impaired migration and proliferation, to an extent similar to that with anti-CXCL12 treatment. These data highlight the importance of the CXCL12:CXCR4 pathway in regulating homing of engrafted stem cells to sites of tissue damage within the CNS of mice persistently infected with a neurotropic virus undergoing immune-mediated demyelination.

Regulatory T cells inhibit T cell proliferation and decrease demyelination in mice chronically infected with a coronavirus.

Mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) develop acute and chronic demyelinating diseases with histopathological similarities to multiple sclerosis. The process of demyelination is largely immune-mediated, as immunodeficient mice (RAG1(-/-) mice) do not develop demyelination upon infection; however, demyelination develops if these mice are reconstituted with either JHMV-immune CD4 or CD8 T cells. Because myelin destruction is a consequence of the inflammatory response associated with virus clearance, we reasoned that decreasing the amount of inflammation would diminish clinical disease and demyelination. Given that regulatory T cells (Tregs) have potent anti-inflammatory effects, we adoptively transferred Tregs into infected C57BL/6 and RAG1(-/-) mice. In both instances, transfer of Tregs decreased weight loss, clinical scores, and demyelination. Transferred Tregs were not detected in the CNS of infected RAG1(-/-) mice, but rather appeared to mediate their effects in the draining cervical lymph nodes. We show that Tregs dampen the inflammatory response mediated by transferred JHMV-immune splenocytes in infected RAG1(-/-) mice by decreasing T cell proliferation, dendritic cell activation, and proinflammatory cytokine/chemokine production, without inducing apoptosis. By extension, decreasing inflammation, whether by Treg transfer or by otherwise enhancing the anti-inflammatory milieu, could contribute to improved clinical outcomes in patients with virus-induced demyelination.

A critical role for virus-specific CD8+ CTLs in protection from Theiler's virus-induced demyelination in disease-susceptible SJL mice

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) is a relevant mouse model of multiple sclerosis. Infection of susceptible SJL/J mice leads to life-long CNS virus persistence and development of a chronic T cell-mediated autoimmune demyelinating disease triggered via epitope spreading to endogenous myelin epitopes. Potent CNS-infiltrating CD8(+) T cell responses to TMEV epitopes have previously been shown to be induced in both disease-susceptible SJL/J and resistant C57BL/6 mice, in which the virus is rapidly cleared. Specific tolerization of SJL CD8(+) T cells specific for the immunodominant TMEV VP3(159)(-)(166) epitope has no effect on viral load or development of clinical TMEV-IDD, but adoptive transfer of activated CD8(+) VP3(159)(-)(166)-specific T cell blasts shortly after TMEV infection to boost the early anti-viral response leads to clearance of CNS virus and protection from subsequent TMEV-IDD. These studies have important implications for vaccine strategies and treatment of chronic infections in humans.

Machine learning approach identifies new pathways associated with demyelination in a viral model of multiple sclerosis

Theiler’s murine encephalomyelitis is an experimentally virus-induced inflammatory demyelinating disease of the spinal cord, displaying clinical and pathological similarities to chronic progressive multiple sclerosis. The aim of this study was to identify pathways associated with chronic demyelination using an assumption-free combined microarray and immunohistology approach. Movement control as determined by rotarod assay significantly worsened in Theiler’s murine encephalomyelitis -virus-infected SJL/J mice from 42 to 196 days after infection (dpi). In the spinal cords, inflammatory changes were detected 14 to 196 dpi, and demyelination progressively increased from 42 to 196 dpi. Microarray analysis revealed 1001 differentially expressed genes over the study period. The dominating changes as revealed by k-means and functional annotation clustering included up-regulations related to intrathecal antibody production and antigen processing and presentation via major histocompatibility class II molecules. A random forest machine learning algorithm revealed that down-regulated lipid and cholesterol biosynthesis, differentially expressed neurite morphogenesis and up-regulated toll-like receptor-4-induced pathways were intimately associated with demyelination as measured by immunohistology. Conclusively, although transcriptional changes were dominated by the adaptive immune response, the main pathways associated with demyelination included up-regulation of toll-like receptor 4 and down-regulation of cholesterol biosynthesis. Cholesterol biosynthesis is a rate limiting step of myelination and its down-regulation is suggested to be involved in chronic demyelination by an inhibition of remyelination.

A Mechanism of Virus-Induced Demyelination

Myelin forms an insulating sheath surrounding axons in the central and peripheral nervous systems and is essential for rapid propagation of neuronal action potentials. Demyelination is an acquired disorder in which normally formed myelin degenerates, exposing axons to the extracellular environment. The result is dysfunction of normal neuron-to-neuron communication and in many cases, varying degrees of axonal degeneration. Numerous central nervous system demyelinating disorders exist, including multiple sclerosis. Although demyelination is the major manifestation of most of the demyelinating diseases, recent studies have clearly documented concomitant axonal loss to varying degrees resulting in long-term disability. Axonal injury may occur secondary to myelin damage (outside-in model) or myelin damage may occur secondary to axonal injury (inside-out model). Viral induced demyelination models, has provided unique imminent into the cellular mechanisms of myelin destruction. They illustrate mechanisms of viral persistence, including latent infections, virus reactivation and viral-induced tissue damage. These studies have also provided excellent paradigms to study the interactions between the immune system and the central nervous system (CNS). In this review we will discuss potential cellular and molecular mechanism of central nervous system axonal loss and demyelination in a viral induced mouse model of multiple sclerosis.

Allelic variation in the Tyk2 and EGF genes as potential genetic determinants of CNS repair

The potential for endogenous remyelination and axonal protection can be an important factor in determining disease outcome in demyelinating diseases like multiple sclerosis. In many multiple sclerosis (MS) patients CNS repair fails or is incomplete whereas in others the disease is accompanied by extensive repair of demyelinated lesions. We have described significant differences in the ability of two strains of mice to repair CNS damage following Theiler's virus-induced demyelination: FVB/NJ (FVB) mice repair damaged myelin spontaneously and completely, whereas B10.D1-H2(q)/SgJ (B10.Q) mice are deficient in the repair process. A QTL analysis was performed to identify genetic loci that differentially regulate CNS repair following chronic demyelination in these strains and two QTL were detected: one on chromosome 3 with a LOD score of 9.3 and a second on chromosome 9 with a LOD score of 14.0. The mouse genes for epidermal growth factor (EGF) and Tyk2 are encoded within the QTL on chromosomes 3 and 9, respectively. Sequence polymorphisms between the FVB and B10.Q strains at both the EGF and Tyk2 loci define functional variations consistent with roles for these genes in regulating myelin repair. EGF is a key regulator of cell growth and development and we show a sevenfold increase in EGF expression in FVB compared to B10.Q mice. Tyk2 is a Janus kinase that plays a central role in controlling the T(H)1 immune response and we show that attenuation of Tyk2 function correlates with enhanced CNS repair.

Theiler's Murine Encephalomyelitis Virus L* Amino Acid Position 93 Is Important for Virus Persistence and Virus-Induced Demyelination

The DA strain and other members of the TO subgroup of Theiler's murine encephalomyelitis virus (TMEV) induce a persistent central nervous system infection associated with an inflammatory white matter demyelinating disease. TO subgroup strains synthesize an 18-kDa protein, L*, out of frame with the polyprotein from an initiation codon 13 nucleotides downstream from the polyprotein's AUG codon. We previously generated a mutant virus from our infectious DA full-length clone that has a change of the L* AUG codon to ACG (with no change in the polyprotein's amino acid sequence). Studies of this mutant virus showed that L* was key to the TO subgroup phenotype because the mutant had a decreased ability to persist and demyelinate. This work was initially called into question because a similar mutant derived from a different full-length DA infectious clone persisted and demyelinated similarly to wild-type DA virus (O. van Eyll and T. Michiels, J. Virol. 74:9071-9077, 2000). We now report that (i) the sequence of the L* coding region differs in the two infectious clones, resulting in a Ser or Leu as the predicted amino acid at position 93 of L* (with no change in the polyprotein's amino acid sequence), (ii) the difference in this amino acid is key to the phenotypic differences between the two mutants, and (iii) the change in amino acid 93 may affect L* phosphorylation. It is of interest that this amino acid only appears critical in determining the virus phenotype when L* is present in a significantly reduced amount (i.e., following translation from an ACG initiating codon).

Restraint Stress Fails to Render C57BL/6 Mice Susceptible to Theiler’s Virus-Induced Demyelination

Objectives: Multiple sclerosis is a degenerative disease of the CNS with a pathology consistent with immunological mediation. Although its cause is unknown, multiple factors are thought to influence both the onset and exacerbation of the disease, including both genetic background as well as environmental factors. Methods: We are interested in the effect of psychological stress on the onset and exacerbation of Theiler’s virus-induced demyelinating disease (TVID), a murine model of MS in which viral persistence facilitates demyelination. In the current study, we determined whether chronic restraint stress (RS)-induced immunosuppression could result in the establishment of a persistent CNS infection in the normally TVID-resistant C57BL/6 mouse strain, resulting in demyelination. Results: Our data indicated that RS repeated over the course of 7 days was not sufficient to cause decreases in virus-specific adaptive immunity, and did not significantly alter CNS viral levels. Furthermore, chronic repeated RS lasting until 4 weeks after infection altered neither the development of virus-specific IgG nor motor function determined by Rotarod analysis. In addition, histological analysis of the CNS of stressed mice indicated no inflammation or demyelination on day 193 after infection. Conclusion: These results suggest that stress alone is not sufficient to overcome genetic resistance to TVID in the C57BL/6 mouse strain.

The Biology of Persistent Infection: Inflammation and Demyelination Following Murine Coronavirus Infection of the Central Nervous System

Multiple Sclerosis (MS) is an immune-mediated demyelinating disease of humans. Although causes of MS are enigmatic, underlying elements contributing to disease development include both genetic and environmental factors. Recent epidemiological evidence has pointed to viral infection as a trigger to initiating white matter damage in humans. Mouse hepatitis virus (MHV) is a positive strand RNA virus that, following intracranial infection of susceptible mice, induces an acute encephalomyelitis that later resolves into a chronic fulminating demyelinating disease. Immune cell infiltration into the central nervous system is critical both to quell viral replication and instigate demyelination. Recent efforts by our laboratory and others have focused upon strategies capable of enhancing remyelination in response to viral-induced demyelination, both by dampening chronic inflammation and by surgical engraftment of remyelination - competent neural precursor cells.

Brainstem 1H nuclear magnetic resonance (NMR) spectroscopy: Marker of demyelination and repair in spinal cord

Measuring in vivo spinal cord injury and repair remains elusive. Using magnetic resonance spectroscopy (MRS) we examined brainstem N-acetyl-aspartate (NAA) as a surrogate for spinal cord injury in two mouse strains with different reparative phenotypes following virus-induced demyelination. Swiss Jim Lambert (SJL) and Friend Virus B (FVB) mice progressively demyelinate with axonal loss. FVB mice demyelinate similarly but eventually remyelinate coincident with functional recovery. Brainstem NAA levels drop in both but recover in FVB mice. Chronically infected SJL mice lost 30.5% of spinal cord axons compared to FVB mice (7.3%). In remyelination-enhancing or axon-preserving clinical trials, brainstem MRS may be a viable endpoint to represent overall spinal cord dysfunction.

Neuroimmune interactions in a model of multiple sclerosis.

Psychological stress has been implicated in both the onset and exacerbation of multiple sclerosis (MS). Our research has focused on the role of stress at the onset of MS, using the mouse model Theiler's murine encephalomyelitis virus-induced demyelination. Theiler's virus is a natural pathogen of mice that causes a persistent infection of the central nervous system (CNS) and inflammatory immune-mediated demyelination that is very similar to MS. Our research has shown that restraint stress sufficiently increases corticosterone secretion to cause immunosuppression. Stressed mice develop decreased innate and adaptive immune responses, including decreased chemokine and cytokine responses, to virus, which leads to increased viral replication within the CNS. Higher levels of virus then cause increased later demyelinating disease. These findings may have important implications in our understanding of the interactions between stress and the development of autoimmune diseases induced by infectious agents.

Implication of macrophages in blood brain barrier disruption during central nervous system infection

Infection of the central nervous system (CNS) with the neurotropic JHM strain of mouse hepatitis virus (JHMV) induces extensive cell infiltration and provides a useful model to study both virus-induced encephalitis and demyelination. Cells recruited into the CNS include components of the innate response, namely neutrophils, NK cells and macrophages, followed by CD4, CD8 T cells and B cells. CD8 T cells are the primary effectors which control virus replication. The exact contribution of macrophages in JHMV pathogenesis remains unclear. Pathogenesis studies in CCR5 deficient mice (a chemokine receptor involved in macrophage and T cell recruitment) suggested a role of macrophages in demyelination. In addition, depletion of both neutrophils and monocytes by the antiGr1 antibody (RB6-8C5) significantly reduced blood brain barrier (BBB) permeability and correlated with an absence of matrix metalloproteinase-9 (MMP9) activity. These data suggested a potential role of neutrophils and macrophages in BBB disruption by MMP9 release.

Generation of a Protective T-Cell Response Following Coronavirus Infection of the Central Nervous System Is Not Dependent on IL-12/23 Signaling

The functional role of IL-12 and IL-23 in host defense and disease following viral infection of the CNS was determined. Instillation of mouse hepatitis virus (MHV, a positive-strand RNA virus) into the CNS of mice results in acute encephalitis followed by a chronic immune-mediated demyelinating disease. Antibody-mediated blocking of either IL-23 (anti-IL-23p19) or IL-12 and IL-23 (anti-IL-12/23p40) signaling did not mute T-cell trafficking into the CNS or antiviral effector responses and mice were able to control viral replication within the brain. Therapeutic administration of either anti-IL-23p19 or anti-IL-12/23p40 to mice with viral-induced demyelination did not attenuate T-cell or macrophage infiltration into the CNS nor improve clinical disease or diminish white matter damage. In contrast, treatment of mice with anti-IL-12/23p40 or anti-IL-23p19 resulted in inhibition of the autoimmune model of demyelination, experimental autoimmune encephalomyelitis (EAE). These data indicate that (1) IL-12 and IL-23 signaling are dispensable in generating a protective T-cell response following CNS infection with MHV, and (2) IL-12 and IL-23 do not contribute to demyelination in a model independent of autoimmune T-cell-mediated pathology. Therefore, therapeutic targeting of IL-12 and/or IL-23 for the treatment of autoimmune diseases may offer unique advantages by reducing disease severity without muting protective responses following viral infection.

Central nervous system Toll-like receptor expression in response to Theiler's murine encephalomyelitis virus-induced demyelination disease in resistant and susceptible mouse strains

BackgroundIn immunopathological diseases, such as multiple sclerosis (MS), genetic and environmental factors that contribute to the initiation and progression of the disease are often discussed. The Theiler murine encephalomyelitis virus-induced demyelination disease (TMEV-IDD) model used to study MS reflects this: genetically susceptible mice infected intra-cerebrally with TMEV develop a chronic demyelination disease. TMEV-IDD can be induced in resistant mouse strains by inducing innate immunity with lipopolysaccharide (LPS). Interestingly, Toll-like receptor 4 (TLR4) is the cognate receptor for LPS and its activation can induces up-regulation of other TLRs, such as TLR7 (the receptor for TMEV) and 9, known to be involved in autoimmunity. Up-regulation of TLRs could be involved in precipitating an autoimmune susceptible state. Consequently, we looked at TLR expression in the susceptible (SJL/J) and resistant (C57BL/6) strains of mice infected with TMEV. The resistant mice were induced to develop TMEV-IDD by two LPS injections following TMEV infection.ResultsBoth strains were found to up-regulate multiple TLRs (TLR2, 7 and 9) following the TMEV infection. Expression of these TLRs and of viral mRNA was significantly greater in infected SJL/J mice. The susceptible SJL/J mice showed up-regulation of TLR3, 6 and 8, which was not seen in C57BL/6 mice.ConclusionExpression of TLRs by susceptible mice and the up-regulation of the TLRs in resistant mice could participate in priming the mice toward an autoimmune state and develop TMEV-IDD. This could have implications on therapies that target TLRs to prevent the emergence of conditions such as MS in patients at risk for the disease.

Being a mouse in a man's world: what TMEV has taught us about human disease

Choosing an appropriate animal model to study a disease is guided by a variety of factors including but not limited to the questions being asked, availability of reagents, knowledge of the animal species, personal biases of the researcher, and in some cases, cost and availability of facilities to effectively investigate the model. The validity of an animal model can be further complicated when the etiology of the disease is incompletely defined. Examples of these diseases include multiple sclerosis (MS) and type 1 diabetes (T1D). In addition to host genetics, epidemiological studies have implicated infectious agents, in particular viruses as triggers of these diseases. Thus many studies of these diseases have focused on modeling the interactions of viruses and the host immune response in vivo in small animals. Theiler's murine encephalomyelitis virus (TMEV) infection of mice has been used for over 30 years as a model of virus-induced demyelination. TMEV induces a MS-like disease in susceptible strains of mice but does not cause pathology in humans. While some researchers may question the rationale for using a non-human pathogen to model human disease, the TMEV model of central nervous system (CNS) demyelination has permitted study of some aspects of human MS which would have been difficult to address in other models of the disease. Despite being 'merely a disease of mice,' many of the findings in the Theiler's virus model are directly applicable to the human condition, and studies from the model are responsible for our current understanding of mechanisms of pathology and clinical disability in human MS. In this review we will present some of the key findings from the TMEV model in the context of human disease.

NKG2D receptor signaling enhances cytolytic activity by virus-specific CD8+ T cells: evidence for a protective role in virus-induced encephalitis.

Inoculation with the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of mice results in an acute encephalitis associated with an immune-mediated demyelinating disease. During acute disease, infiltrating CD8(+) T cells secrete gamma interferon (IFN-gamma) that controls replication in oligodendrocytes, while infected astrocytes and microglia are susceptible to perforin-mediated lysis. The present study was undertaken to reveal the functional contributions of the activating NKG2D receptor in host defense and disease following JHMV infection. NKG2D ligands RAE-1, MULT1, and H60 were expressed within the CNS following JHMV infection. The immunophenotyping of infiltrating cells revealed that NKG2D was expressed on approximately 90% of infiltrating CD8(+) T cells during acute and chronic disease. Blocking NKG2D following JHMV infection resulted in increased mortality that correlated with increased viral titers within the CNS. Anti-NKG2D treatment did not alter T-cell infiltration into the CNS or the generation of virus-specific CD8(+) T cells, and the expression of IFN-gamma was not affected. However, cytotoxic T-lymphocyte (CTL) activity was dependent on NKG2D expression, because anti-NKG2D treatment resulted in a dramatic reduction in lytic activity by virus-specific CD8(+) T cells. Blocking NKG2D during chronic disease did not affect either T-cell or macrophage infiltration or the severity of demyelination, indicating that NKG2D does not contribute to virus-induced demyelination. These findings demonstrate a functional role for NKG2D in host defense during acute viral encephalitis by selectively enhancing CTL activity by infiltrating virus-specific CD8(+) T cells.

Establishment of a Model to Examine the Early Events Involved in the Development of Virus‐Induced Demyelinating Lesions

The ability to study the immediate, early events in the demyelinating process has been difficult on account of the lack of model systems that address this phase of lesion development. The vast majority of animal models used to study multiple sclerosis (MS) focuses on the later events of myelin destruction. To address this deficiency, we have modified the currently used Theiler's murine encephalomyelitis virus (TMEV)-induced model of demyelination to precisely identify the area where virus-induced demyelination first occurs. Following surgical exposure of the spinal cord, we directly injected TMEV into the spinal cord of female SJL/J mice. Characterization of the events in the spinal cord in the days following injection of virus support the use of this model to dissect the pathways triggered in the host in the early phases of demyelination. A complete understanding of the genesis of the sclerotic plaque may provide insights into enhanced treatment for patients with central nervous system (CNS) demyelination.

Generation of a protective T cell response following viral infection of the CNS is independent of either IL-12 or IL-23 (B141)

Abstract The functional role of IL-12 and IL-23 in generating effector T cells following viral infection of the central nervous system (CNS) was determined. Instillation of mouse hepatitis virus (MHV) into the CNS of C57BL/6 mice results in an acute encephalitis followed by a chronic demyelinating disease. MHV-infected mice express mRNA transcripts specific for IL-12p35 and IL-23p19 subunits within the brains. Antibody-mediated blocking of IL-23 (anti-IL-23p19) or IL-12 and IL-23 (anti-IL-12/23p40) did not reduce numbers of virus-specific T cells and treated mice cleared virus from the CNS demonstrating that blocking IL-23 does not affect the generation of a Th1 response. Therapeutic administration of anti-IL-23p19 to infected mice with established demyelination did not attenuate disease indicating IL-23 does not contribute to viral-induced demyelination. Treatment with anti-IL-12/23p40 or anti-IL-23p19 resulted in inhibition of EAE, an autoimmune model of demyelination highlighting the importance of IL-23 in CNS autoimmune inflammation and disease. These data indicate that i) IL-12 and IL-23 signaling are dispensable in generating a protective response following CNS infection with MHV and ii) IL-23 amplifies disease in a model of autoimmune demyelination. Therefore, targeting of IL-23 for the treatment of autoimmune diseases may offer unique advantages by reducing disease severity without muting protective responses following viral infection.

A recombinant human IgM promotes myelin repair after a single, very low dose

A recombinant human monoclonal IgM, rHIgM22, promotes the synthesis of new myelin when used to treat several animal models of demyelination. rHIgM22 binds to myelin and the surface of oligodendrocytes and accumulates at central nervous system lesions in vivo. The minimal dose of monoclonal IgM required to promote remyelination has a direct bearing on the proposed mechanism of action. A dose ranging study using rHIgM22 was performed in mice with chronic virus-induced demyelination, a model of chronic progressive multiple sclerosis. The lowest tested dose of rHIgM22 effective at promoting spinal cord remyelination was a single 500-ng intraperitoneal bolus injection. A time course study of spinal cord repair performed in chronically demyelinated mice revealed that remyelination plateaued by 5 weeks following treatment with rHIgM22. Two doses of rHIgM22 spaced 5 weeks apart did not increase the extent of remyelination over a single dose. The half-life of rHIgM22 in the mouse systemic circulation was determined to be 15 hr; the human IgM serum concentration was close to zero by 48 hr following antibody administration. We propose that the specificity of rHIgM22 for myelin on living tissue targets the antibody to demyelinated lesions, initiating a long-term reparative effect on the central nervous system.

Exacerbated Pathology of Viral Encephalitis in Mice with Central Nervous System-Specific Autoantibodies

We examine here the outcome of viral encephalomyelitis [mouse hepatitis virus (MHV) A59, Theiler’s encephalomyelitis virus, and Coxsackievirus B3] in mice with autoantibodies to a central nervous system (CNS)-specific antigen, myelin oligodendrocyte glycoprotein, that usually develop no clinical disease. Morbidity and mortality of the acute viral CNS disease was augmented by the presence of the autoantibodies in all three viral infections. Transfer of serum containing the autoantibodies at the time of infection with MHV was sufficient to reproduce the exacerbated disease. The presence of the autoantibodies was found to result in increased infiltration of mononuclear cells into the brain. Early demyelination was severely augmented in brains and spinal cords of MHV-infected mice with CNS-specific autoantibodies. The antibody-mediated exacerbation was shown to be independent of the complement system but to require expression of Fc receptors, because it was observed in C′-3-deficient but not in Fc receptor-deficient mice. Our study illustrates the possibility that infections can lead to much more profound immunopathology in the presence of an otherwise latent autoimmune condition.