AN AUTOIMMUNE-DISEASE WITH MULTIPLE MOLECULAR TARGETS ABROGATED BY THE TRANSGENIC EXPRESSION OF A SINGLE AUTOANTIGEN IN THE THYMUS

Many autoimmune diseases are characterized by autoantibody reactivitie s to multiple cellular antigens. Autoantigens are commonly defined as targets of the autoimmune B cell response, but the role, if any, of th ese autoantigens in T cell-mediated autoimmune diseases is generally u nknown. Murine experimental autoimmune gastritis is a CD4+ T cell-medi ated organ-specific autoimmune disease induced by neonatal thymectomy of BALB/c mice. The murine disease is similar to human autoimmune gast ritis and pernicious anemia, and is characterized by parietal and chie f cell loss, submucosal mononuclear cell infiltrates, and autoantibodi es to the alpha and beta subunits of the gastric H/K ATPase. However, the specificity of T cells that cause the disease is not known. To exa mine the role of the H/K ATPase in this T cell-mediated disease, trans genic mice were generated that express the beta subunit of the H/K ATP ase under the control of the major histocompatibility complex class II I-E(alpha)k promoter. We show that transgenic expression of the gastr ic H/K ATPase beta subunit specifically prevents the onset of autoimmu ne gastritis after neonatal thymectomy. In addition, thymocyte transfe r experiments suggest that tolerance of pathogenic autoreactive T cell s is induced within the thymus of the transgenic mice. We conclude tha t the beta subunit of the gastric H/K ATPase is a major T cell target in autoimmune gastritis and that thymic expression of a single autoant igen can abrogate an autoimmune response to multiple autoantigens.