Expanding the spectrum of autoimmunity induced with myelin oligodendrocyte glycoprotein.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Experimental autoimmune encephalomyelitis (EAE) is an autoimmune model of MS, induced by sensitization with myelin proteins of their encephalitogenic peptides. Sensitization with amino acids 92-106 of myelin oligodendrocyte glycoprotein (MOG) induces different disease courses and neuropathology in A.SW and SJL/J mice. SJL/J mice develop a relapsing-remitting (RR-EAE) disease course characterized by mild demyelinating disease with perivascular T cell infiltration. In contrast, A.SW mice develop a progressive (P-EAE) disease course characterized by large areas of plaque-like demyelination with Ig deposition, polymorphonuclear (PMN) cell infiltration and minimal T cell infiltration and high MOG antibody titers in the serum. This thesis describes, as part of the elucidation of the role of antibody in determining disease course and neuropathology, the generation and characterization of hybridomas producing antibody reactive with MOG92-106. Two MOG92-106 hybridomas produced polyreactive IgM antibodies encoded by immunoglobulin genes in their germline configuration, indicating that the antibodies are natural autoantibodies (NAA). These MOG92-106 reactive NNA bind myelin and cause demyelination in vivo, suggesting that they could contribute to the pathogenesis of P-EAE. In addition, sensitization of A.S.W. mice with MOG92-106 or intraperitoneal injection of the MOG92-106 reactive hybridomas resulted in antibody deposition in glomeruli of kidneys and proteinuria, demonstrating that MOG92-106 reacative NAA can induce systemic autoimmunity. However, depletion of B-1 cells, the main produces of NAA, had minimal effects on the development of demyelination, antibody deposition or disease progression in mice sensitized with MOG92-106. These results indicate that while MOG92-106 reacative NAA are capable of inducing pathology in the CNS and kidneys, they play a minor role in the pathogenesis of MOG92-106-infduced EAE. In addition, this thesis describes induction of another combination of disease course and neuropathology in B10.S mice. B10.S mice have previously been considered resistant to EAE, but sensitization with MOG92-106 resulted in neuropathology in 93% of the mice and monophasic or relapsing-remitting disease course in 30% of the mice. Taken together, this work expands the spectrum of autoimmune disease that can be induced and investigated using MOG92-106.