Myelin oligodendrocyte glycoprotein induces experimental autoimmune encephalomyelitis in the "resistant" brown Norway rat: Disease susceptibility is determined by MHC and MHC-linked effects on the B cell response

Experimental autoimmune encephalomyelitis (EAE) induced by active immunizat ion with the myelin oligodendrocyte glycoprotein (MOG) is an Ab-mediated, T cell-dependent autoimmune disease that replicates the inflammatory demyeli nating pathology of multiple sclerosis. We report that disease susceptibili ty and severity are determined by MHC and MHC-linked effects on the MOG-spe cific B cell response that mediate severe clinical EAE in the EAE-resistant Brown Norway (BN) rat. Immunization with the extracellular domain of MOG i n CPA induced fulminant clinical disease associated with widespread demyeli nation and with an inflammatory infiltrate containing large numbers of poly morphonuclear cells and eosinophils within 10 days of immunization. To anal yze the effects of the MHC (RT1 system) we compared BN (RT1 (n)) rats with Lewis (LEW) (RT1 (l)) and two reciprocal MHC congenic strains, LEW.1N (RT1( n)) and BN.1L (RT1 (l)), This comparison revealed that disease severity and clinical course were strongly influenced by the MHC haplotype that modulat ed the pathogenic MOG-specific autoantibody response, The intra-MHC recombi nant congenic strain LEW.1R38 demonstrated that gene loci located both with in the centromeric segment of the MHC containing classical class I and clas s II genes and within the telomeric RT1.M region containing the MOG gene ar e involved in determining Ab production and disease susceptibility, This st udy indicates that the current T cell-centered interpretation of MHC-mediat ed effects on disease susceptibility must be reassessed in multiple scleros is and other autoimmune diseases in which autoantibody is involved in disea se pathogenesis.