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.

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

“…[23][24][25] The humoral immune response and propensity to develop autoimmune diseases are enhanced not only in BTLA-deficient mice 23,35 but also in HVEM-deficient mice. 48 The latter strengthens the predominant in vivo function of HVEM as an inhibitory ligand rather than a costimulatory ligand.…”

“…20,22 The experimental evidence of the role of the BTLA/ HVEM pathway in humoral immunity comes from the analysis of the phenotype of BTLA-deficient mice, which revealed defects in the regulation of this branch of immunity with implications in the development of autoimmune diseases. [23][24][25] As the HVEM receptor is the unique known partner of BTLA and both molecules are expressed on T and B cells, we postulated that the HVEM/BTLA signalling pathway may participate in providing CD4 help to B cells for the production of donorspecific antibodies. 20 With this notion in mind, we set up an experimental approach to elucidate the role of this interaction in the context of the humoral immune response during the acute phase of graft rejection.…”

B and T Lymphocyte Attenuator Suppresses IL-21 Production from Follicular Th Cells and Subsequent Humoral Immune Responses

“…The excessive production of IL-21 is also associated with the development of high titers of autoantibodies and a lupus-like pathology in sanroque mice (43). In contrast, we previously showed that BTLA 2/2 mice gradually develop hyper-g-globulinemia and autoantibodies (21). The analyses of mice lacking both BTLA and IL-21R will determine whether the autoimmune phenotype of BTLA 2/2 mice is caused by the enhanced IL-21 production.…”

Cutting Edge: B and T Lymphocyte Attenuator Signaling on NKT Cells Inhibits Cytokine Release and Tissue Injury in Early Immune Responses

“…HVEM engagement by BTLA induces tyrosine phosphorylation and the association of BTLA with the SHP-2 tyrosine phosphatase to repress Ag-driven T cell proliferation (7). We and others have shown that the absence of BTLA-HVEM inhibitory interactions leads to increased experimental autoimmune encephalomyelitis severity (9,11), enhanced rejection of partially mismatched allografts (12), an increased CD8 ϩ memory T cell population (13), increased severity of colitis (14), reduced effectiveness of T regulatory cells (15), and the development of autoimmunity over time (16). These studies suggest that the BTLA signaling therefore functions to protect the host from immunopathology arising from the overstimulation of T cells over time.…”