Semliki Forest virus-induced demyelination and remyelination—involvement of B cells and anti-myelin antibodies
Introduction
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system (CNS), in which epidemiologic studies have implicated an initiating viral infection, although a persistent virus has never been isolated. Certain CNS viruses [e.g. Theiler's virus, JHM strain of mouse hepatitis virus (MHV), corona, measles and herpes viruses] are known to induce demyelinating diseases through different mechanisms, including viral persistence Lampert et al., 1973, Cristallo et al., 1997, Lane and Buchmeier, 1997, Zhoa et al., 1998, Marten et al., 2000, Stohlman and Hinton, 2001 and/or activation of myelin-reactive T cells Mokhtarian and Swoveland, 1987, Liebert et al., 1988, and some have been proposed to play a role in the pathogenesis of MS (Cristallo et al., 1997). These mechanisms also include a bystander effect related to the release of sequestered myelin proteins (peptides), either by budding a virus or by the cytopathic effect of an acute virus infection Simas et al., 1995, Brahic et al., 1991, Fazakerley et al., 1992, which leads to an autoimmune response. Another, more defined, mechanism is molecular mimicry, a mechanism postulated to be important in the activation of autoreactive T cells Gautam et al., 1998, Oldstone, 1987 and possibly antibodies. Viral peptides with sufficient sequence homology or similarity to self-peptides are believed to be able to induce autoimmune responses that lead to demyelinating disease Oldstone, 1987, Wucherpfennig and Strominger, 1995, Jahnke et al., 1985, Fujinami and Oldstone, 1985, Mokhtarian et al., 1999.
Remyelination has also been found following demyelination in MS lesions Suzuki et al., 1969, Prineas and Connell, 1979. This process, however, is limited and incomplete in MS, and in animal models may be enhanced by certain monoclonal antibodies or suppression of the immune response (Warrington et al., 2000).
Semliki Forest virus (SFV) infection of the CNS has been used for many years as a model to study the pathogenesis of demyelinating diseases like MS (Fazakerley et al., 1997). Mice infected intraperitoneally (ip) with SFV, an alpha-togavirus, develop an acute encephalomyelitis that clears the virus by day 8 post-infection (pi) from both blood and brain. Immune-mediated demyelination is observed between 14 and 21 days in the absence of viral persistence Fazakerley et al., 1983, Subak-Sharpe et al., 1993, followed by remyelination by day 35 pi. We have previously shown that SFV infection triggered susceptibility to experimental autoimmune encephalomyelitis (EAE) induced with myelin basic protein (MBP) in the usually EAE-resistant C57BL/6 (B6) strain of mouse (Mokhtarian and Swoveland, 1987). Furthermore, SFV-infected mice produced cross-reactive T cell responses and antibodies to mimicked peptides of myelin oligodendrocyte glycoprotein (MOG), MBP and proteolipid protein (PLP). Mice immunized with either E2 115–129 or MOG 18–32 (mimicked peptides) developed a mild, late-onset CNS disease with spongiform white matter lesions that correlated more closely with onset and incidence of serum antibody response than the T cell response to the mimicked peptides (Mokhtarian et al., 1999). We have further demonstrated that SFV-infected B cell-deficient mice do not exhibit the late-onset primary demyelination that normally follows acute encephalomyelitis in the CNS of wild-type mice (Smith-Norowitz et al., 2000).
The present study has focused on the types of immune responses in the CNS of SFV-infected mice at the time of demyelination and remyelination. We have found that while peak percentage of CD8+ T cells was associated with initial myelin injury, the peaks of the antibody response and microglial cell proliferation more closely correlated with a late-onset primary demyelination and subsequent remyelination in recovered mice.
Section snippets
Infection of mice
The avirulent A774 strain of SFV with a titer of 3×108 plaque-forming units (PFU) per milliliter on BHK-21 cell [American Type Culture Collection (ATCC), Rockville, MD] was used as stock virus (Mokhtarian and Swoveland, 1987). Female, 5- to 6-week-old normal B6 mice (Jackson Laboratory, Bar Harbor, ME) were inoculated intraperitoneally with SFV (104 PFU) in Dulbecco's phosphate-buffered saline (D-PBS) (GIBCO/BRL). Mice were observed daily for clinical manifestations of SFV and were scored on a
Clinical disease and viral titration in SFV-infected B6 mice
Following intraperitoneal (ip) infection of B6 mice with SFV, mice were observed daily for clinical manifestations of disease and were scored on a scale of 0–VI as described above. From 24 SFV-infected mice, 5 had clinical score of I and 6 had clinical score of II. Ten mice were paralyzed, of which five had clinical score of III, three had clinical score of IV and two had clinical score of V. No mice with a clinical score of VI was observed, and three mice died. In SFV-infected B6 mice, viral
Discussion
In this study, we investigated the initial phase of SFV infection in mice and subsequent immune-mediated demyelination and remyelination to gain insight into the pathogenesis of demyelination occurring secondarily to a viral infection, information perhaps of relevance to MS. SFV crossed the blood–brain barrier after peripheral inoculation, grew mostly in neurons and induced virus-associated pathology, including neuronophagia and Wallerian degeneration which led to collapse of some myelin
Acknowledgements
We thank Abdul W. Elahi, Jason Feliberti, Miriam Pakingan and Everett Swanson for expert technical assistance, and Patricia Cobban-Bond for administrative assistance with the manuscript. We also thank Dr. Anne H. Cross and Dr. Jerri-Anne Lyons who kindly provided the MOG protein for this study. This work was supported by a grant from Maimonides Research and Development Foundation and by NIH grants NS 40157 (FM), NS 08952 and NS 11920 (CSR) and NMSS 1001-J-10 (CSR).
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