Complementation between specific HLA-DR and HLA-DQ genes in transgenic mice determines susceptibility to experimental autoimmune encephalomyelitis

To investigate the contribution of human leukocyte antigen (HLA) class II m olecules in susceptibility to inflammatory demyelination, we induced experi mental autoimmune encephalomyelitis (EAE) in transgenic leg) mice expressin g the HLA-DR3, HLA-DQ8 and HLA-DQB molecules in the absence of endogenous c lass II (Ab degrees). Following immunization with mouse myelin, HLA-DR3 tg mice mounted strong T-cell proliferative responses, and developed inflammat ory lesions and demyelination in the central nervous system with mild to mo derate clinical symptoms of EAE. HLA-DQ8 and HLA-DQ6 tg mice elicited weak T-cell proliferative responses and did not develop clinical symptoms of EAE . HLA-DR3/DQ6 double tg mice immunized with mouse myelin experienced clinic al disease similar to the single tg HLA-DR3 tg mice, indicating that expres sion of DQ6 in this line had no effect on disease. In contrast, HLA-DR3/DQ8 double cg mice developed severe inflammatory lesions and clinical disease in response to immunization with mouse myelin. Our data suggest that in the presence of two susceptible class II alleles, namely HLA-DR3 and DQ8, ther e is additional selection and expansion of potential autoreactive T cells, resulting in enhanced severity of disease. (C) American Society for Histoco mpatibility and Immunogenetics, 2000. Published by Elsevier Science Inc.