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Abnormal B Lymphocyte Activation and Function in Systemic Sclerosis

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초록

Systemic sclerosis (SSc) is characterized by tissue fibrosis andautoimmunity. Although the pathogenic relationship betweenautoimmunity and clinical manifestations of SSc remainsunknown, SSc patients display abnormal immune responsesincluding the production of disease-specificautoantibodies. Previous studies have demonstrated that Bcells play a critical role in systemic autoimmunity and diseaseexpression through various functions such as inductionof the activation of other immune cells in addition to autoantibodyproduction. CD19 is a crucial regulator of B cellactivation. Recent studies demonstrated that B cells from SScpatients showed an up-regulated CD19 signaling pathwaythat induced SSc-specific autoantibody production in SScmouse models. CD19 transgenic mice lost tolerance for autoantigenand generated autoantibodies spontaneously. Bcells from SSc patients exhibited an overexpression of CD19that induced SSc-specific autoantibody production in transgenicmice. Moreover, SSc patients displayed intrinsic B cellabnormalities characterized by chronic hyper-reactivity ofmemory B cells, which was possibly due to CD19overexpression. Similarly, B cells from a tight-skin mouse, agenetic model of SSc, showed augmented CD19 signaling. Inbleomycin-induced SSc mouse models, endogenous ligandsfor toll-like receptor 4 induced by bleomycin stimulated Bcells to produce various fibrogenic cytokines and autoantibodies. Remarkably, the loss of CD19 resulted in the inhibitionof B cell hyper-reactivity and autoantibody production,which are associated with improvements in fibrosisand a parallel decrease in fibrogenic cytokine production byB cells. Taken together, the findings suggest that altered B cellfunction may result in tissue fibrosis as well as autoimmunityin SSc.

Abstract

Systemic sclerosis (SSc) is characterized by tissue fibrosis andautoimmunity. Although the pathogenic relationship betweenautoimmunity and clinical manifestations of SSc remainsunknown, SSc patients display abnormal immune responsesincluding the production of disease-specificautoantibodies. Previous studies have demonstrated that Bcells play a critical role in systemic autoimmunity and diseaseexpression through various functions such as inductionof the activation of other immune cells in addition to autoantibodyproduction. CD19 is a crucial regulator of B cellactivation. Recent studies demonstrated that B cells from SScpatients showed an up-regulated CD19 signaling pathwaythat induced SSc-specific autoantibody production in SScmouse models. CD19 transgenic mice lost tolerance for autoantigenand generated autoantibodies spontaneously. Bcells from SSc patients exhibited an overexpression of CD19that induced SSc-specific autoantibody production in transgenicmice. Moreover, SSc patients displayed intrinsic B cellabnormalities characterized by chronic hyper-reactivity ofmemory B cells, which was possibly due to CD19overexpression. Similarly, B cells from a tight-skin mouse, agenetic model of SSc, showed augmented CD19 signaling. Inbleomycin-induced SSc mouse models, endogenous ligandsfor toll-like receptor 4 induced by bleomycin stimulated Bcells to produce various fibrogenic cytokines and autoantibodies. Remarkably, the loss of CD19 resulted in the inhibitionof B cell hyper-reactivity and autoantibody production,which are associated with improvements in fibrosisand a parallel decrease in fibrogenic cytokine production byB cells. Taken together, the findings suggest that altered B cellfunction may result in tissue fibrosis as well as autoimmunityin SSc.

참고문헌 (65)

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