Can virus infections trigger autoimmune disease?
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Biomedical subjects
R S Fujinami
Publications and source records attributed to R S Fujinami.
DNA immunization and central nervous system viral infection.
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Viruses and autoimmune disease--two sides of the same coin?
Some viruses have the ability to modulate the development of autoimmune diseases. Virus infections have long been associated with the exacerbation of autoimmune disease, however, there is also evidence that viruses can actually protect against autoimmune disease. Several experimental models have been developed to investigate how some virus infections can prime for and trigger autoimmunity whereas others ameliorate the pathway leading to clinical disease. It is possible that the type I interferons, via interleukin 12, provide the link between viruses and autoimmunity.
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Peripheral nerve protein, P0, as a potential receptor for Theiler's murine encephalomyelitis virus.
Theiler's murine encephalomyelitis virus (TMEV) belongs the family Picornaviridae. TMEV not only replicates in the gastrointestinal tract but also spreads to the central nervous system (CNS) either by a hematogenous or a neural pathway during natural infection. The DA strain of TMEV infects neurons during the acute phase, and glial cells and macrophages during the chronic phase, leading to a demyelinating disease similar to multiple sclerosis. Different virus-host receptor interactions in the peripheral and the neuronal cells could explain the pathways of viral spread from the peripheral to the CNS and neurons to glial cells. However, the receptor for TMEV remains unknown. P0 protein, a 28-31 kD glycoprotein, belongs to the immunoglobulin superfamily and constitutes 50% of the total myelin protein in the peripheral nerve. Other picornaviruses use members of the immunoglobulin superfamily as receptors. Thus we hypothesized P0 protein could act as a receptor for TMEV. In a virus overlay assay, radiolabeled TMEV bound to a 28-30 kD protein from the peripheral nerve of wild-type C57BL/6, but no binding was found in the peripheral nerve from P0-knockout mice. TMEV replicated fourfold higher in P0-transfected BW5147.G.1.4 cells than in mock-transfected cells. The increase in virus replication in the P0-transfected cell line was blocked by preincubation of the cells with anti-P0 antibody. A virus binding study showed that TMEV bound to P0-transfected cells but not to mock-transfected cells. The use of the P0 protein in Schwann cells as a receptor may be one mechanism by which TMEV spreads from the gastrointestinal tract to the CNS.
Amino Acid Sequence↗
Viruses can silently prime for and trigger central nervous system autoimmune disease.
Although many viruses have been isolated from patients with multiple sclerosis (MS), as yet, no one agent has been demonstrated to cause MS. In contrast, epidemiological data indicate that viral infections are associated with exacerbations of MS. Here, we present data showing that virus infections can subclinically prime animals for central nervous system (CNS) autoimmune disease; long after the original infection has been eradicated, a nonspecific challenge/infection can trigger an exacerbation. The priming infectious agent must show molecular mimicry with self-CNS antigens such as glial fibrillary acidic protein (GFAP), myelin associated glycoprotein (MAG) or myelin proteolipid protein (PLP). The subsequent challenge, however, may be nonspecific; complete Freund's adjuvant (CFA), or infection with a recombinant vaccinia virus encoding an irrelevant protein, could trigger CNS disease. In the CNS, we could detect a mononuclear cell infiltration, but no demyelination was found. However, if the pathogenesis of MS is similar to that of this novel animal model for CNS autoimmune disease, our findings could help explain why exacerbations of MS are often associated with a variety of different viral infections.
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Prolonged gray matter disease without demyelination caused by Theiler's murine encephalomyelitis virus with a mutation in VP2 puff B.
Theiler's murine encephalomyelitis virus (TMEV) is divided into two subgroups based on neurovirulence. During the acute phase, DA virus infects cells in the gray matter of the central nervous system (CNS). Throughout the chronic phase, DA virus infects glial cells in the white matter, causing demyelinating disease. Although GDVII virus also infects neurons in the gray matter, infected mice developed a severe polioencephalomyelitis, and no virus is detected in the white matter or other areas in the CNS in rare survivors. Several sequence differences between the two viruses are located in VP2 puff B and VP1 loop II, which are located near each other, close to the proposed receptor binding site. We constructed a DA virus mutant, DApBL2M, which has the VP1 loop II of GDVII virus and a mutation at position 171 in VP2 puff B. While DApBL2M virus replicated less efficiently than DA virus during the acute phase, DApBL2M-induced acute polioencephalitis was comparable to that in DA virus infection. Interestingly, during the chronic phase, DApBL2M caused prolonged gray matter disease in the brain without white matter involvement in the spinal cord. This is opposite what is observed during wild-type DA virus infection. Our study is the first to demonstrate that conformational differences via interaction of VP2 puff B and VP1 loop II between GDVII and DA viruses can play an important role in making the transition of infection from the gray matter in the brain to the spinal cord white matter during TMEV infection.
Amino Acid Sequence↗
Alterations in cytokine but not chemokine mRNA expression during three distinct Theiler's virus infections.
DA, GDVII and H101 are neurovirulent strains of Theiler's murine encephalomyelitis virus that cause very different neuropathology and CNS disease when inoculated into SJL/J mice. DA virus causes a chronic demyelinating disease, GDVII virus causes an acute fatal polioencephalomyelitis, and H101 virus causes an acute pachymeningitis with hydrocephalus. Performing RNase protection assays, we detected the same pattern of chemokine (RANTES, MCP-1, IP-10, MIP-1beta, MIP-1alpha and MIP-2) mRNA expression in brain and spinal cord during all three infections. In contrast, IFN-beta and IL-6 mRNA were highly expressed only in GDVII virus infection, whereas high levels of LT-alpha mRNA were only found during DA virus infection. Our study demonstrates that proinflammatory cytokines are involved in the neuropathogenesis of CNS disease and modulate the acute and chronic process underlying different pathologic features of disease.
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Antibody association with a novel model for primary progressive multiple sclerosis: induction of relapsing-remitting and progressive forms of EAE in H2s mouse strains.
Multiple sclerosis (MS) can be divided into 4 clinical forms: relapsing-remitting (RR), primary progressive (PP), secondary progressive (SP), and progressive relapsing (PR). Since PP-MS is notably different from the other forms of MS, both clinically and pathologically, the question arises whether PP-MS is immunologically similar to the other forms. The pathogenesis of the PP-MS remains unclear, partly due to a lack of highly relevant animal models. Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)92-106, we have established animal models that mimic different forms of MS in 2 strains of H-2s mice, SJL/J and A.SW. We induced experimental allergic encephalomyelitis (EAE) using MOG92-106 in the presence or absence of supplemental Bordetella pertussis (BP). Although, SJL/J mice developed RR-EAE whether BP was given or not, A.SW mice developed PP-EAE without BP and SP-EAE with BP. Histologically, SJL/J mice developed mild demyelinating disease with T cell infiltration, while A.SW mice developed large areas of plaque-like demyelination with immunoglobulin deposition and neutrophil infiltration, but with minimal T cell infiltration. In A.SW mice without BP, high titer serum anti-MOG antibody was detected and the anti-MOG IgG2a/IgG1 ratio correlated with survival times of mice. We hypothesized that, in A.SW mice, a Th2 response favors production of myelinotoxic antibodies, leading to progressive forms with early death. Our new models indicate that a single encephalitogen could induce either RR-, PP-, or SP- forms of demyelinating disease in hosts with immunologically different humoral immune responses.
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Contrasting effects of anti-adhesion molecule therapy in experimental allergic encephalomyelitis and Theiler's murine encephalomyelitis.
An augmentation of experimental allergic encephalomyelitis (EAE) was observed when monoclonal antibody (mAb) to intercellular adhesion molecule 1 (ICAM-1) was administered after adoptive transfer. Clinical disease was more severe in the ICAM-1 specific mAb-treated EAE mice and included prominent ataxia compared to the PBS-treated controls or Theiler's murine encephalomyelitis virus (TMEV) infected mice treated with ICAM-1 specific mAb. Neuropathologic evaluation demonstrated a distinctly different distribution of lesions in the anti-ICAM-1-treated EAE mice which featured prominent demyelination and inflammation in the cerebellum, brainstem and cerebrum. These structures were minimally involved in the control mice and mAb treatment did not alter the neuropathology in TMEV-infected mice. These results indicate that anti-ICAM-1 can alter trafficking of lymphocytes and mononuclear cells in EAE but not TMEV-induced demyelinating disease.
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Infection with a recombinant vaccinia virus encoding myelin proteolipid protein causes suppression of chronic relapsing-remitting experimental allergic encephalomyelitis.
Mice infected with a recombinant vaccinia virus (VVplp) encoding the myelin proteolipid protein (PLP) and then challenged with the encephalitogenic peptide, PLP139-151, developed a more severe acute attack vs. control mice. Following this initial acute attack, vaccinated mice had significantly less clinical disease (relapses) than control vaccinated or mock vaccinated mice. Control mice developed a relapsing-remitting disease with severe clinical relapses. During the remission state in VVplp vaccinated mice, histopathologic changes were markedly reduced in the central nervous system (CNS) vs. control vaccinated or unvaccinated mice. Inflammation was mainly limited to the meninges with a reduction of mononuclear cells in the parenchyma of the spinal cord in VVplp vaccinated and PLP139-151 challenged mice vs. control mice where inflammatory changes with demyelination was observed. During the remission period an increase in IL-4 was seen. In addition, there was significantly less T cell proliferation to PLP139-151 that was confirmed by an in vivo measurement of T cell reactivity, DTH responses. This suggests that the almost permanent remission state was dictated by a decreased responsiveness to PLP139-151 in VVplp vaccinated mice.
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Lipopeptide particles as the immunologically active component of CTL inducing vaccines.
Using a bipalmitoylated lipopeptide consisting of an ovalbumin helper T-cell epitope covalently linked to an influenza virus cytotoxic T-lymphocyte (CTL) epitope, we addressed possible factors that may be critical for CTL induction. Antigen processing of lipopeptide appears to be required for T-cell induction since there was virtually no in vitro binding of lipopeptide to purified MHC molecules. A major portion of lipopeptide immunogenicity was due to its particulate nature inasmuch as CTL induction in mice correlated with insoluble lipopeptide constructs, whereas more soluble analogs were significantly less immunogenic. Immunohistological analysis of tissue from immunized animals revealed that lipopeptide migration from the s.c. injection site to the spleen could be detected as early as 1 h after immunization and cell-associated lipopeptide was observed on macrophages and dendritic cells, implicating both cell populations in the processing and presentation of lipopeptide particles to CTLs.
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Endogenous retroviruses: are they the cause of multiple sclerosis?
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Viruses as triggers of autoimmunity: facts and fantasies.
Autoimmunity has been proposed as the cause of several human chronic inflammatory diseases, and recent animal studies show that viruses can induce autoimmune disease. These studies demonstrate how viruses might misdirect the immune system, and here we discuss critically the evidence that similar phenomena may lead to human disease.
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Exacerbation of viral and autoimmune animal models for multiple sclerosis by bacterial DNA.
Theiler's murine encephalomyelitis virus (TMEV) infection and relapsing-remitting experimental allergic encephalomyelitis (R-EAE) have been used to investigate the viral and autoimmune etiology of multiple sclerosis (MS), a possible Th1-type mediated disease. DNA immunization is a novel vaccination strategy in which few harmful effects have been reported. Bacterial DNA and oligodeoxynucleotides, which contain CpG motifs, have been reported to enhance immunostimulation. Our objectives were two-fold: first, to ascertain whether plasmid DNA, pCMV, which is widely used as a vector in DNA immunization studies, could exert immunostimulation in vitro; and second, to test if pCMV injection could modulate animal models for MS in vivo. We demonstrated that this bacterially derived DNA could induce interleukin (IL)-12, interferon (IFN)gamma, (Th1-promoting cytokines), and IL-6 production as well as activate NK cells. Following pCMV injections, SJL/J mice were infected with TMEV or challenged with encephalitogenic myelin proteolipid protein (PLP) peptides. pCMV injection exacerbated TMEV-induced demyelinating disease in a dose-dependent manner. Exacerbation of the disease did not correlate with the number of TMEV-antigen positive cells but did with an increase in anti-TMEV antibody. pCMV injection also enhanced R-EAE with increased IFNgamma and IL-6 responses. These results caution the use of DNA vaccination in MS patients and other possible Th1-mediated diseases.
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DNA vaccination against Theiler's murine encephalomyelitis virus leads to alterations in demyelinating disease.
Although the etiology of multiple sclerosis (MS) is not known, several factors play a role in this disease: genetic contributions, immunologic elements, and environmental factors. Viruses and virus infections have been associated with the initiation and/or enhancement of exacerbations in MS. Theiler's murine encephalomyelitis virus (TMEV) infection of mice is one of the animal models used to mimic MS. In other animal model systems, DNA vaccination has been used to protect animals against a variety of virus infections. To explore the utility of DNA vaccination, we have constructed eukaryotic expression vectors encoding the TMEV capsid proteins VP1, VP2, and VP3. SJL/J mice were vaccinated intramuscularly once, twice, or three times with the different capsid protein cDNAs. This was followed by intracerebral TMEV infection to determine the effects of DNA vaccination on the course of TMEV-induced central nervous system (CNS) demyelinating disease. We found that vaccination of mice three times with cDNA encoding VP2 led to partial protection of mice from CNS demyelinating disease as determined by a decrease in clinical symptoms and histopathology. Vaccination of mice with cDNA encoding VP3 also led to a decrease in clinical symptoms. In contrast, mice vaccinated with cDNA encoding VP1 experienced a more severe disease with an earlier onset of clinical signs and enhanced histopathology compared with control mice. There was no correlation between anti-TMEV antibody titers and disease course. These results indicate that DNA immunization can modify chronic virus-induced demyelinating disease and may eventually lead to potential treatments for illnesses such as MS.
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Theiler's viruses with mutations in loop I of VP1 lead to altered tropism and pathogenesis.
Theiler's murine encephalomyelitis viruses are picornaviruses that can infect the central nervous system. The DA strain produces an acute polioencephalomyelitis followed by a chronic demyelinating disease in its natural host, the mouse. The ability of DA virus to induce a demyelinating disease renders this virus infection a model for human demyelinating diseases such as multiple sclerosis. Here we describe the generation and characterization of DA virus mutants that contain specific mutations in the viral capsid protein VP1 at sites believed to be important contact regions for the cellular receptor(s). A mutant virus with a threonine-to-aspartate (T81D) substitution in VP1 loop I adjacent to the putative virus receptor binding site exhibited a large-plaque phenotype but had a slower replication cycle in vitro. When this mutant virus was injected into susceptible mice, an altered tropism was seen during the acute stage of the disease and the chronic demyelinating disease was not produced. A virus with a threonine-to-valine substitution (T81V) did not cause any changes in the pattern or extent of disease seen in mice, whereas a virus with a tryptophan substitution at this position (T81W) produced a similar acute disease but was attenuated for the development of the chronic disease. A change in amino acids in a hydrophobic patch located in the wall of the pit, VP1 position 91, to a hydrophilic threonine (V91T) resulted in a profound attenuation of the acute and chronic disease without persistence of virus. This report illustrates the importance of the loop I of VP1 and a site in the wall of the pit in pathogenesis and that amino acid substitutions at these sites result in altered virus-host interactions.
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Suppression of antigen-specific T cell proliferation by measles virus infection: role of a soluble factor in suppression.
Measles virus infection causes a profound immunosuppression. The basis for this immunosuppression is not known. This immunosuppression could be due to virus acting directly on lymphoid cells, the production of an immunosuppressive viral product, or a lymphoid product. We have developed an antigen-specific T cell system to study measles virus-T-cell interactions. We demonstrate that as few as five infectious viral particles added to 1000 T cells results in profound inhibition of antigen-specific T cell proliferation. Supernates taken from measles virus-infected T cells suppress the proliferation of uninfected T cells. Measles-virus-infected HeLa or Vero cells do not produce the factor. The antiproliferative effects of the supernates cannot be attributed to infectious virus, IL-10 or TGF-beta. The soluble factor appears to be larger than 100 kDa, yet retains antiproliferative activity following trypsin digestion with a size less than 10 kDa. Loss of activity is seen following heat treatment at 56 degrees C. The factor is lymphoid cell specific and exhibits cytokine-like behavior yet appears not to be a known cytokine. This soluble factor may be responsible for the overt clinical immunosuppression seen in man and a previously undescribed cytokine induced by measles virus infection of human lymphocytes.
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Gender variations in early Theiler's virus induced demyelinating disease: differential susceptibility and effects of IL-4, IL-10 and combined IL-4 with IL-10.
Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease, is an animal model of multiple sclerosis (MS). The viral-induced encephalitis is followed by an inflammatory and demyelinating disease. We quantitated the response of female and male mice during the transition from encephalitis to early demyelination. CNS neuropathology and antiviral antibody production were evaluated. Parallel studies were done with anti-inflammatory cytokines IL-4, IL-10 or a combination of IL-4 with IL-10. Results show female mice demonstrate an augmented susceptibility to the virus and a greater response to the cytokine therapies. Significant variation was noted during early demyelinating disease. The combination therapy of IL-4 with IL-10 produced striking decreases in antiviral antibody levels and virus-induced neuropathologic disease. Male mice are less susceptible to viral-induced disease and are less responsive to the cytokine treatments. Gender bias in TMEV-induced demyelinating disease appears to parallel the differences noted with other experimental immune diseases.
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