Role of Individual T-Cell Epitopes of Theiler’s Virus in the Pathogenesis of Demyelination Correlates with the Ability To Induce a Th1 Response

Abstract

Intracerebral inoculation of susceptible strains of mice with Theiler’s murine encephalomyelitis virus (TMEV) results in immune-mediated demyelination. Three major T-cell epitopes have previously been identified within the VP1 (VP1233–250), VP2 (VP274–86), and VP3 (VP324–37) capsid proteins in virus-infected SJL/J mice. These epitopes appear to account for the majority (∼90%) of major histocompatibility complex class II-restricted T-cell responses to TMEV. Interestingly, the effect of immunization with synthetic peptides bearing the predominant T-cell epitopes on the course of TMEV-induced demyelination indicates that T cells reactive to the VP1 and VP2 epitopes, but not VP3, accelerate the pathogenesis of demyelination. The predominant pathogenic role of the T cells is verified by similar immunization with the fusion proteins containing the entire individual capsid proteins. The order of appearance and level of T cells specific for the individual epitopes during the course of demyelination are similar to each other. However, cytokine profiles of T cells from virus-infected mice indicate that T cells specific for the VP1 (and perhaps the VP2) epitope are Th1, whereas T cells reactive to VP3 are primarily Th2. These results suggest that Th1-type cells specific for VP1 and VP2 are involved in the pathogenesis of viral demyelination induced by TMEV. Thus, a predominance of Th1-inducing viral epitopes is likely critical for the pathogenesis of demyelination.

Pathogenesis of Virus-Induced Immune-Mediated Demyelination

“…Six predominant linear antibody epitope areas, ranging from 13-26 amino acid residues were identified with antibodies from virus-infected mice (17; Fig. 1): A1A (VP1 [12][13][14][15][16][17][18][19][20][21][22][23][24][25] ),A1B (VP1 146-160 ),A1C (VP1 262-276 ), A2A (VP2 2-16 ), A2B (VP2 165-179 ), and A3A (VP3 [24][25][26][27][28][29][30][31][32][33][34][35][36][37]. A time course study indicated that susceptible SJL mice intracerebrally infected with TMEV strongly and selectively recognize the A1C epitope of VP1 as compared to resistant BALB/c or C57BL/6 mice.…”

“…The development and progression of demyelinating disease correlate well with the level of Th1 responses specific for viral epitopes (30)(31)(32). Administration of bacterial lipopolysaccharide (LPS) or IL-1β potentiating inflammatory Th1 responses into genetically resistant C57BL/6 mice infected with TMEV resulted in clinical symptoms (33).…”

“…In addition, the majority of T cells from virus-infected SJL mice recognize one of three predominant epitopes (VP1 233-250 , VP2 74-86 and VP3 24-37 ) (44). Viral infection results in primarily Th1 responses to VP1 and VP2, in contrast to a Th2 response to the VP3 epitope peptide (30,32). Further immunization with VP1 233-250 or VP2 74-86 peptide exacerbates the disease whereas VP3 24-37 epitope does not, suggesting that T cells reactive to these VP1 and VP2 epitopes are likely to be involved in the patho- Kim et al genesis of demyelination.…”

CD8-deficient SJL mice display enhanced susceptibility to Theiler's virus infection and increased demyelinating pathology

“…A large body of research has attempted to ascertain whether CD4 C or CD8 C T cells are involved in the initiation, progression and/or regulation of TMEV-IDD. The evidence for CD4 C T cells as mediators of TMEV pathology in susceptible SJL mice is signicant in that: 1) monoclonal antibodies against CD4, MHC Class II, or IL-12 either prevented or diminished clinical signs (Friedmann et al, 1987;Welsh et al, 1987;Inoue et al, 1998); 2) ow cytometric and histological data from infected SJL/J mice revealed an increased level of CD4 C T cells and their proin ammatory cytokines during clinical disease progression, and transfer of a CD4 C VP2-speci c T cell line leads to increased incidence and accelerated onset of disease (Gerety et al, 1994;Pope et al, 1996;Begolka et al, 1998); 3) the development of virus and myelin antigen-speci c DTH corresponds with onset and chronicity of demyelination (Clatch et al, 1986;Miller et al, 1997); 4) epitopes of TMEV that elicit a Th1 response and DTH can accelerate the pathogenesis of TMEV upon active immunization (Yauch et al, 1998); and 5) tolerance via ECDI-coupled cells with TMEV, known to reduce IL-2 and IFN-°from Th1 cells, reduces the severity of disease (Peterson et al, 1993;Karpus et al, 1995).…”

Innate Immune Response Induced by Theiler's Murine Encephalomyelitis Virus Infection

“…The treatment of host with either anti-thymocyte, anti-Ia (MHC class II), or anti-CD4 antibodies delays the onset of disease (15)(16)(17), suggesting the involvement of CD4 + T cells. T helper type 1 (Th1) cells preferentially producing interferon-γ (IFN-γ) are found within demyelinating lesions of the CNS and appear to be involved in the pathogenesis of demyelination (18)(19)(20)(21). Furthermore, the genetic association between susceptibility to TMEV-IDD and the major histocompatibility complex (MHC) (22,23), as well as the T-cell receptor (TCR) βchain (24,25), further supports the involvement of such immune responses in pathogenesis.…”