response to viral antigens arises within 2 or 3 weeks after infection, before the initial expression of disease.
Conclusions. T-cell responses in MS and other Th1-mediated autoimmune diseases appear to evolve dynamically during the course of both relapsing-remitting and chronic-progressive types of disease. Autoimmune reactivity in MS may in part be a secondary consequence of chronic CNS damage initiated by some putative persisting virus. Over the past 15 to 20 years, perhaps 15 or 20 different viruses have been associated with MS, but none has stood the test of time. One of the most recent is herpes virus type 6, which has been reported to be associated with oligodendrocytes in some cases of MS.
The dynamic nature of the T-cell repertoire has important implications for treatment modalities that employ antigen-specific strategies. Because the target changes as the disease progresses, for example, researchers hope to target the B7.1 molecule and costimulation generally, in order to inhibit disease progression without prior knowledge of the epitopes or T-cell receptors that are involved.
The model that emerges. The inducing epitope may be either a self-antigen or a viral antigen, provided the virus persists in the target organ. A Th1-type response leads to inflammation and tissue destruction that produces myelin debris, which stimulates T-cells expressed against endogenous myelin epitopes. Examples of such viruses in humans include Theiler’s virus, encephalomyocarditis virus (EMCV), and Coxsackie virus, all of which have been shown to persist in tissues and to be associated with autoimmune sequelae. With EMCV and Coxsackie the sequelae depends on the strain of virus, and the latter may be involved with human diabetes.
In response to questions from the audience, Dr. Miller added the following:
Researchers still know relatively little about what induces the remissions that follow the acute phase: a Th1-to-Th2 switch, antigen-induced programmed cell death, or some combination of processes. However, the persistence of some of the primed T-cells argues against propriocidal cell death as the sole explanation.
In Coxsackie B3-induced myocarditis, the inflammation produced by viral infection releases myosin, which is the antigen in the autoimmune phase. However, researchers have blocked the secondary autoimmune response by giving susceptible mice IL-1 receptor antagonist. They have also induced autoimmune myocarditis in normally nonsusceptible mice by administering IL-1. Hence it would appear that inflammation, and especially the cytokines induced by the viral infection, are critical in activating the true autoimmune process.
TMEV can be a lytic virus. It lives in some APCs, but primarily in F480 macrophages, where it undergoes defective replication, producing more viral antigen than infectious viral particles. The virus can persist in mice up to 18 months after infection. Because it lives in APCs, it may interfere with endoge-