EXACERBATED AUTOIMMUNITY ASSOCIATED WITH A T-HELPER-1 CYTOKINE PROFILE SHIFT IN H-2E-TRANSGENIC MICE

Major histocompatibility complex (MHC) class II genes are the stronges t susceptibility markers for many human autoimmune diseases. A perplex ing aspect of this is that HLA alleles can confer either susceptibilit y or dominant protection. In nonobese diabetic (NOD) mice, the stronge st known diabetes susceptibility locus is within the MHC and is presum ed to be the H-2A(g7) product. When NOD mice carry a transgenic E alph a(d) molecule allowing expression of an H-2E heterodimer, diabetes is prevented. We investigated whether, as in human autoimmunity, a single class II heterodimer might protect from some autoimmune diseases whil e predisposing to others. NOD mice are susceptible to experimental aut oimmune encephalomyelitis (EAE) induced by the proteolipoprotein (PLP) epitope 56-70. Susceptibility to EAE was analyzed in NOD mice which e ither have or lack transgenic H-2E expression. We found that H-2E expr ession in NOD mice has converse effects on diabetes and EAE: while dia betes is prevented, EAE is greatly exacerbated and leads to demyelinat ion. Although PLP 56-70 could be presented both in the context of H-2A and H-2E, increased disease severity in H-2E transgenic mice could no t be attributed either to an enhanced T cell proliferative response to PLP or to differences in determinant spread. However, cytokine analys is of the response revealed important differences between NOD mice and their H-2E transgenic counterparts: H-2E expression was associated wi th reduced interleukin-4 secretion and enhanced interferon-gamma (IFN- gamma) secretion by lymph node cells, while the response of central ne rvous system infiltrating T cells displayed a markedly enhanced IFN-ga mma response. Thus, whether a particular class II molecule confers res istance or susceptibility to an autoimmune disease may depend on diffe rential cytokine profiles elicited by particular class II/autoantigen complexes.