Pathogenesis of Multiple Sclerosis

There is abundant evidence that in mice, EAE is caused by activated, CD4+ TH1 and TH17 cells specific for protein antigens in myelin. By analogy with the experimental disease, MS is also thought to be caused by myelin-specific TH1 and TH17 cells, and these cells have been detected in patients and isolated from the blood and CNS. How these cells are activated in patients remains an enigma. It has been suggested that an infection, most likely a viral infection, activates self myelin-reactive T cells by the phenomenon of molecular mimicry (see Chapter 14). Self-tolerance may fail because of the inheritance of susceptibility genes. Identical twins have a 25% to 40% concordance rate for development of MS, whereas nonidentical twins have a 1% concordance rate, implicating genetic factors in the development of the disease. Genetic polymorphisms associated with MS include the HLA locus, with HLA-DR2 being the strongest linkage. Genome-wide association studies have revealed an association with a polymorphism in the noncoding region of the gene encoding the IL-2 receptor a chain, CD25. Expression of CD25 on effector and memory T cells may be different in patients compared with healthy individuals, but how this results in disease is unclear. Some studies have suggested that regulatory T cells are defective in MS patients, but how this contributes to a failure of self-tolerance is also not known. Once myelin-specific T cells are activated, they migrate into the CNS, where they encounter myelin proteins and release cytokines that recruit and activate macrophages and more T cells, leading to myelin destruction. Studies of EAE suggest that the disease is propagated by the process known as epitope spreading (see Chapter 14). The tissue breakdown results in release of new protein antigens and expression of new, previously sequestered epitopes that activate more autoreactive T cells.

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