The mechanism(s) responsible for generating the different forms of
multiple sclerosis, primary progressive (PP) and secondary progressive (SP) versus relapsing-remitting (RR), is not well understood. Using
myelin oligodendrocyte glycoprotein (MOG)(92-106), we have established animal models that mimic the different types of
multiple sclerosis. A.SW mice develop PP or SP-
experimental allergic encephalomyelitis (EAE) with large areas of
demyelination and high titers of MOG antibody whereas SJL/J mice develop RR-EAE with perivascular T cells and mild
demyelination. In A.SW progressive EAE, we found
atrophy of the thymus, spleen, and lymph nodes with depletion of T and B cells and massive apoptosis, as demonstrated by immunohistochemistry, terminal dUTP nick-end labeling, and
DNA agarose gel electrophoresis. To test whether lymphoid apoptosis itself contributes to
disease progression, we injected SJL/J mice with apoptotic thymocytes. Injection of apoptotic cells resulted in greater than 20% of mice developing SP-EAE with
ataxia. SJL/J mice with SP-EAE had large areas of
demyelination, high MOG antibody titers and atrophic lymphoid organs. Spleen cells from mice with progressive EAE produced less
interferon-gamma than those from RR-EAE when stimulated with
mitogen. We suggest that induction of lymphoid apoptosis alters the balance of Th1 versus Th2 immune responses and increases MOG antibody production, leading to exacerbation of
demyelination and subsequent
disease progression.