Development of autoimmune hepatitis–like disease and production of autoantibodies to nuclear antigens in mice lacking B and T lymphocyte attenuator

Abstract

OBJECTIVE: B and T lymphocyte attenuator (BTLA), a coreceptor expressed on lymphocytes, was recently described as an inhibitory coreceptor that negatively regulates lymphocyte activation. The purpose of this study was to investigate the role of BTLA in the regulation of immune homeostasis and the pathogenesis of autoimmunity. METHODS: We examined the levels of immunoglobulins and autoantibodies to nuclear antigens and the activation status of T cells in BTLA(-/-) mice. We also examined histopathologic changes in the organs of BTLA(-/-) mice. RESULTS: We observed that BTLA(-/-) mice gradually developed hypergammaglobulinemia, antinuclear antibodies, anti-SSA antibodies, anti-double-stranded DNA antibodies, and an increased number of activated CD4+ T cells in the periphery with age. Lack of BTLA led to spontaneous development of autoimmune hepatitis-like disease characterized by an elevation in the level of transaminases, interface hepatitis, and spotty necrosis of the liver. BTLA(-/-) mice also showed inflammatory cell infiltration of multiple organs, including the salivary glands, lungs, and pancreas; these features are similar to those of Sjögren's syndrome, which is a frequent complication of autoimmune hepatitis. Furthermore, the survival rate of BTLA(-/-) mice was significantly reduced after the age of 7 months. CONCLUSION: Our results indicate that BTLA plays an important role in the maintenance of immune tolerance and the prevention of autoimmune diseases.