Possible Mechanisms of Pathogenesis of MS. There are two schools of thought about the etiology of MS. Most people believe that there is a loss of immune regulation, leading to an autoimmune response against neural antigens. This theory is modeled by the murine EAE model described above. However, many epidemiological studies suggest that there is an infectious or environmental component, possibly a virus, that triggers this response. The model for this theory is Tyler’s murine encephalomyelitis (TMEV).
If the putative virus is directly cytopathic to oligodendrocytes in the myelin, there would be a primary demyelination, but this doesn’t appear to be happening in either MS or TMEV. On the other hand, the virus might induce demyelination—directly or indirectly—as a result of the immune response against the putative infection. One possible mechanism for this process might be called “bystander demyelination”: provided the infection persists in the target organ, it can induce Th-1 responses and activate macrophages that somehow, through a process of “molecular mimicry,” begin to crossreact with the self-antigenic determinant, leading to a cascade of inflammatory events.
In an alternative mechanism that might be called “epitope spreading,” the virus causes the initial damage—either directly by targeting the oligodendrocytes, or indirectly by inducing a chronic inflammatory response in the target organ—and exposes self-antigenic proteins to the immune system, but the chronic stage of the disease is mediated at least in part by responses against the autoantigens that were released by the virus infection.
Murine Models of Virus-Induced MS. Researchers use different mouse models for the two forms of human MS. Both employ the SJL strain of mouse. Experimental allergic encephalomyelitis (EAE) can be induced with myelin basic protein (MBP) or proteolipid protein MOG (another myelin antigen), or by transferring T-cells specific for those epitopes; it develops into a relapsing-remitting form of autoimmune disease. In contrast, TMEV expresses a chronic progressive disease pattern that mimics the other, more serious form of human MS.
The progression of induction in these diseases at the Th-1 level is described below. A particular peptide is recognized in conjunction with MHC Class II and—provided the appropriate costimulatory signals are sent through the CD28 molecule—it induces the proliferation and activation of potential immunopathogenic T-cells. These primed T-cells leave the peripheral lymphoid tissue and penetrate the blood-brain barrier. When they again encounter the same epitope on APCs, they release chemokines and cytokines that activate and recruit mononu-