Autoimmune Disease and Viral Infection

Immunology ofNervous System Infections, Progress in Brain Research, Vol. 59, edited by P . O . Behan, V . ter Meulen and F . Clirord Rose 0I983 Elsevier Science Publishers B.V.

Autoimmune Disease and Viral Infection J.O. FLEMING and L.P. WEINER University of Southern California, School of Medicine, 2025 Zonal Ave, Los Angeles, CA 90033 (U.S.A.)

INTRODUCTION The relationship between host responses to self-antigens and viral infection continues to be a perplexing problem in the understanding of “autoimmune” diseases of man. In diseases such as multiple sclerosis, post-infectious encephalomyelitis, Guillain-Barre Syndrome and polymyositis the target antigen has not been defined. In each case, viruses have been implicated in the pathogenesis of the disease. In myasthenia gravis, the target antigen has been identified, but the chain of events leading to the disease process has not been deciphered. In this chapter we will attempt to define the mechanism by which viruses could induce “autoimmune’’ diseases, discuss models of viral-induced immunopathology , and review possible host antigens which could and do serve as targets in nervous system disease. MECHANISMS Johnson and Weiner (1972) reviewed possible mechanisms by which viruses could induce an immune mediated demyelinating process. The most obvious mechanism is that a virus might share an antigenic determinant with normal host cell membrane constituents. Panitch et al. (1979) have perhaps given credence to this mechanism, having demonstrated cross-reactivity between measles virus and myelin basic protein. Wroblewska et al. (personal communication) have recently shown that an anti-herpes hybridoma antibody exhibits a cross-reactivity between viral and cellular components. A second mechanism by which autoimmune responsiveness may be associated with virus infection involves viral infection leading to the release of host cell antigens with which immunocytes have never previously interacted. These may be internal antigens which are released following viral-induced cell lysis or “neo-antigens” which, because of the viral infection, have become “unmasked” and are expressed on the cell surface. Such antigens have probably not been expressed since an early stage of development, and hence are not recognized as self. Paterson (1980) described additional mechanisms of virus-augmented neuroimmunologic disease. These include viral activation of neuro-reactive lymphoid cells, increased vulnerability of CNS target tissue through enhanced vascular permeability, and finally, the induction of the “bystander effect”. The so-called “bystander effect” has been applied to the possibility that myelin may be destroyed incidental to an immune reaction to nearby, but unrelated antigens. The theoretical

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basis for this phenomenon derives from the observations of Ruddle and Waksman (1968) who showed non-specific cytolysis of cells in the presence of heterologous antigen and sensitized lymphoid cells. Wisniewski and Bloom produced CNS demyelination in previously sensitized guinea pigs following local injection of tuberculin-purified protein derivative (Wisniewski and Bloom, 1975). Such a mechanism has been suggested in the Theiler’s virus-induced demyelination (Lipton and Dal Canto, 1976) and in the peripheral demyelination induced by the herpes infection of chickens (Marek’s disease) (Stevens et al., 1981). The virus serves as the target antigen and myelin is non-specifically destroyed by the antiviral immune response. The mechanism for the “bystander effect” has been attributed to the liberation of proteolytic enzymes. Cammer et al. (1978) have shown myelin fragmentation in the presence of neutral proteases secreted by activated macrophages. Dal Canto et al. (1975) have further suggested that the vesicular disruption of myelin seen by electron microscopy in demyelinating models may be due to lysosomal enzymes. Dal Canto and Rabinowitz (1982) have recently commented on the attractiveness of this theory, suggesting a mechanism by which similar pathological patterns in white matter could be produced by different and often unrelated viruses. VIRAL MODELS AND IMMUNOPATHOLOGY The relationship between viral models and “autoimmune” disease remains tenuous. The immunopathology may be due to direct infection of immune cells producing probable disruption of immune cell regulation, or to the interaction of viral antigen with specific host cell antigens (Weiner and Stohlman, 1978). There are a number of models in which virus, host cell antigens and the immune response combine to produce an immunopathologic process. Lactic dehydrogenase virus Lactic dehydrogenase virus (LDV) is an RNA-enveloped virus which produces interesting immunologic abnormalities in NZB mice. The NZB strain of mice is known to have immune complex nephritis. During LDV infection, there is an exaggerated humoral response to some antigens and depression to other antigens (Oldstone et al., 1974). The graft-host reaction, induction of tolerance, and phagocytosis are depressed (Notkins et al., 1978). A number of immune derangements seem to be taking place. The exaggerated humoral response results in incomplete neutralizing activity which could be due to blocking factors such as antigen-antibody complexes, or inhibitory immunoglobulin. It might also be due to a failure of macrophage function or viral destruction of suppressor T-cells. Certainly T-cells are destroyed by LDV. The T-cell destruction in LDV-infected animals, coupled with an increase in the number of germinal centers and plasma cells in thymus-dependent areas of spleen and lymph nodes, may account for the Ig enhancement and for the defects in cell-mediated immunity. The findings in LDV are not unlike those seen in autoimmune processes in which IgG levels are increased in conjunction with defects in cell-mediated immunity (Rowson and Mahy, 1975). Aleutian disease Aleutian disease (AD) of mink is due to a naturally occurring, temperature-sensitive, parvovirus infection. The virus contains a single-stranded DNA. Aleutian disease virus (ADV) replicates in macrophages of mink and lesions are not noted immediately. When lesions first

93 appear, they coincide with an exaggerated antiviral antibody response and hypergmaglobulinemia. The IgG levels can reach 11 gil00 ml. Late in the disease, ADV circulates as infectious antigen-antibody complexes and smaller complexes are deposited in glomeruli and arteries causing severe inflammatory lesions. Both host and viral genotype influence the severity of the arteritis (Porter et al., 1980). Thus, non-aleutian mink have persistent infection without lethal disease. One group of pastel mink has no viremia, but does have a transient increase in serum gamma-globulin and a relatively low ADV antibody. In the Aleutian mink there is hyperplasia of the B-lymphoid cell system. Lymphocytes and plasma cells infiltrate many organs. Both the percentage of gamma-globulin and the total serum protein is increased during AD. Thus far no immunologic differences have been shown between IgG of normal and AD mink. The IgG does show some restriction of mobility, and after one year 10% of animals developed monoclonal gammopathy (Porter et al., 1980). The relationship of antigen-antibody complexes to disease appears to depend on viral antigen, but it is not known how much of the IgG is indeed virus specific antibody. Peak ADV antibody titers are reached before the maximal increase in serum IgG is present, suggesting most of IgG is not specific antibody (Bloom et al., 1975). The question of autoimmune processes is further complicated by the occasional finding of nuclear antigens and antinuclear antibodies in the serum of AD mink.

Lymphocytic choriomeningitis Lymphocytic choriomeningitis (LCM) and other arenaviruses produce an immunopathology which has been well studied in regard to T-lymphocyte-mediated killing of vims-infected target cells (Cole and Nathanson, 1974), activation of natural killer (NK) cells in acute infection (Welsh, 1978) viral antigen-antibody complex-induced disease (Oldstone and Dixon, 1971), and associated H-2 restriction (Zinkemagel and Doherty, 1974). It is the H-2 restriction in both LCM and, more recently, in influenza virus studies (Frankel et al., 1979), that has suggested that T-cell recognition is directed against some association of viral and H-2 glycoproteins, which has led to the “altered self” concept. An antibody to a sufficiently stable association of viral or H-2 glycoproteins, or the presence of the particular antibody attachment sites sufficiently close to a neo-antigen (formed by the nexus of viral and H-2 molecules) to sterically block the function of cytotoxic T-cells, might be involved. Theiler’s virus Theiler’s virus (TV), a murine picomavirus, has been associated with immunopathology . TV produces a chronic CNS infection in which viral antigen can be localized to neuronal terminals, astrocytes, and inflammatory cells, particularly macrophages, around white matter lesions (Dal Canto and Lipton, 1982). The pathology consists of primary demyelination with disruption of myelin and stripping of myelin sheaths by mononuclear cell processes. These changes are similar to EAE (Dal Canto and Lipton, 1975). Oligodendrocytes in and around the myelin breakdown are free of viral antigen, suggesting that the myelin degeneration is not a direct viral-induced oligodendrocytolysis. Immunosuppression with cyclophosphamide results in a marked decrease in the white matter lesions, suggesting that demyelination is dependent on the host immune response (Lipton and Dal Canto, 1976). Of interest are the large amounts of viral antigen in macrophages, but a role for these cells has not yet been defined. The mechanisms underlying host-mediated virus-induced demyelination in the Theiler’s model is still unknown, but a “bystander effect” has been postulated.

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Herpes viruses Herpes viruses have also been implicated in autoimmune disease. Both cytomegalovims (Schmitz and Enders, 1977) and Epstein-Barr virus (EBV) have been associated with Guillain-Barre syndrome (Bimbaum, 1973). Marek’s disease, an avian herpes Virus, has been suggested as an experimental model for GBS (Stevens et al., 1981). The virus consistently induces lymphocytic infiltration and subsequent demyelination of peripheral nerves in domestic chickens. Latent infection can be established in satellite cells, non-myelinating Schwann cells and lymphocytes of spinal ganglia and associated nerves. In reactivation experiments, virus was not found in neurons or myelinating Schwann cells (Stevens et al., 1981). Studies in chickens show that infected birds develop specific cellular immune responses to chicken peripheral nerve (Schmahl et al., 1975). Stevens et al. (1981) have postulated that in “bystander” demyelination in which latent infection of non-myelinating Schwann cells and satellite cells are the proposed target of a cellular immune response, lymphotoxins and proteolytic enzymes actually produce the demyelination. Released myelin, possibly with viral antigens acting as adjuvants, sensitizes the host and results in an ongoing autoimmune demyelinating process. There is, however, an alternate hypothesis which needs to be explored. Most cells infected with herpes viruses express a protein which binds to the Fc region of IgG. The Fc cellular receptors have been demonstrated on lymphocyte and tumor cell membranes (Kerbel and Davies, 1974), staphylococcus aureus cell walls (Forsgren and Sjoquist, 1966), and a variety of non-lymphoid cells. The affinity for the Fc region seems to be a non-specific phenomenon, but probably has an important role in immune regulation, persistent and latent infection and, perhaps, autoimmune disease. Cowan et al. (1980) recently reviewed the role of Fc and immune complexes and indicated that MHC antigens, transfer factor and immune interferon, as immune regulatory or modulator molecules, are either associated with Fc receptors or alter Fc receptor-mediated immunity. They further suggest that Fc receptors may provide a link between antigen specific, immune complex-mediated, intercellular interactions and intracellular regulation of gene expression. These latter factors appear to be important in immune regulation, cellular differentiation, viral replication, and malignant transformation. Cells infected with herpes viruses express a protein which binds the Fc fragment. This has been shown in HSV-I, -11, zoster-varicella and cytomegalovirus and includes cultured epithelioid, fibroblasts, and neural cells (Watkins, 1964; Westmoreland and Watkins, 1974; Rahman et al., 1976; Coster et al., 1977; Adler et al., 1978). Spear and her colleagues, in a series of papers, demonstrated that the receptor for Fc in HSV-I-infected cells is a viral-specified glycosylated membrane protein (Baucke and Spear, 1979; Para et al., 1980, 1982). They have designated this protein as glycoprotein E (gE), and detected it also in virion preparations isolated from infected cells. An antiserum prepared against this glycoprotein selectively precipitated gE from a variety of cell types infected with HSV-I and neutralized HSV-I infectivity in the presence of complement. F (ab), fragments interfered with Fc binding activity. The inhibition of the Fc receptor function by the F (ab), fragments of anti-gE antibodies supports the hypothesis that g E and the Fc receptor on herpes-infected cells are the same protein (Para et al., 1982). The physiological role of the Fc binding receptor is unknown, but it has been postulated that IgG binding might interfere with cytotoxic antibodies or lymphocytes. Lehner et al. (1975) have suggested that anti-HSV antibodies which bind to both Fc receptor and HSV cell surface antigens would make the Fc portion of these antibodies unavailable for complement or cytotoxic cells. Although most investigators postulate a role for Fc-binding in the establish-

95 ment of latency, it is certainly possible that the gE expression and subsequent binding may play an important part in non-specific IgG binding and in the subsequent immune cytolysis which is complement-dependent. Rager-Zisman et al. (1976) have shown that cross-linking of effector and target cells through aggregated immunoglobulins bound to Fc receptor present on HSVinfected cells is the mechanism of selective, nonspecific killing. CONCLUSION The role of viruses in autoimmune human disease is still not defined. The epidemiology of multiple sclerosis suggests a viral etiology, and the pathology is most consistent with an immunopathologic process. Antigen or antigens have not been demonstrated, but we have set out the theoretical and experimental evidence which implicates a virus in the pathogenesis of the disease. We have discussed the interaction of virus with host cell antigens, described the presence of the Fc receptor in herpes infection, and indicated the possibility of a “bystander” effect in the pathogenesis of autoimmune disease.

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