If, indeed, some obscure infection is the initial event in the genesis of MS, then a secondary factor must be operative in later life to reactivate the disease and cause exacerbations. One view is that this secondary mechanism is an autoimmune reaction attacking some component of myelin and, in its most intense form, destroying all tissue elements, including axons. Several lines of argument have been advanced in support of this view. One is inclined to draw an analogy between the lesions of MS and those of acute disseminated encephalomyelitis (ADEM), which is almost certainly an autoimmune disease of delayed hypersensitivity type (see further on). Also in support of this possibility is the finding of antibodies to specific myelin proteins—for example, myelin basic protein (MBP)—in both the serum and cerebrospinal fluid (CSF) of MS patients, and these antibodies, along with T cells that are reactive to MBP and to other myelin proteolipids, increase with disease activity; moreover, MBP cross-reacts to some extent with measles virus antibodies. The arguments that a chronic viral infection reactivates and perpetuates the disease are, however, less convincing than those proposing a role for viruses in the initiation of the process in susceptible individuals.
The relative roles of humoral and cellular factors in the production of MS plaques are not fully understood. The deposition of immunoglobulin in the plaques of patients with acute and relapsing–remitting disease, but not in the plaques of those with progressive MS, was alluded to earlier. That the humoral immune system is involved is evident from the presence in the CSF of most patients of oligoclonal immune protein antibodies (called “bands”), which are produced by B lymphocytes within the CNS. Sera from patients with MS (and some normal controls), when added to cultures of nervous system tissue from newborn mice in the presence of complement, can damage myelin, inhibit remyelination, and block axonal conduction. Antibodies to oligodendrocytes are present in the serum of up to 90 percent of patients in some studies, but far less frequently in others.
Autoantibodies have been found inconsistently that are directed against myelin oligodendrocyte glycoprotein (MOG) and MBP. It has also been demonstrated that subsets of T cells (CD41 Th2 cells) are activated by MBP and MOG to activate B cells, the production of oligoclonal bands and membrane attack complexes, and the release of cytokines (tumor necrosis factor-alpha [TNF-α], interleukins, interferon-gamma [IFN-γ]). The inflammatory process erodes the blood–brain barrier and ultimately destroys both oligodendroglia and axons. The eventual functional outcome reflects both the activity of this inflammatory cascade and the degree of axonal damage. In other cases, there may be a compromise of oligodendroglial function and axonal degeneration in the absence of prominent inflammation. Many times, one or another putative antigenic target has been found by immunologic techniques in one laboratory, only to fail to be replicated by another group. None of these provide a unifying etiology for the disease but the humoral aspects may provide insights particularly into the pauci-inflammatory type of oligodendrocyte degeneration that characterizes some lesions, as discussed in the section on pathology.