Open AccessDevelopment of autoimmune hepatitis–like disease and production of autoantibodies to nuclear antigens in mice lacking B and T lymphocyte attenuator
Author(s) -
Oya Yoshihiro,
Watanabe Norihiko,
Owada Takayoshi,
Oki Mie,
Hirose Koichi,
Suto Akira,
Kagami ShinIchiro,
Nakajima Hiroshi,
Kishimoto Takashi,
Iwamoto Itsuo,
Murphy Theresa L.,
Murphy Kenneth M.,
Saito Yasushi
Publication year - 2008
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.23674
Subject(s) - btla , immunology , autoantibody , autoimmune hepatitis , autoimmunity , anti nuclear antibody , immune system , antibody , medicine , hepatitis , antigen , lymphocyte , t lymphocyte , autoimmune disease
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.