Abnormal B lymphocyte activation and function in systemic sclerosis

Abstract

Systemic sclerosis (SSc) is characterized by tissue fibrosis and autoimmunity. Although the pathogenic relationship between autoimmunity and clinical manifestations of SSc remains unknown, SSc patients display abnormal immune responses including the production of disease-specific autoantibodies. Previous studies have demonstrated that B cells play a critical role in systemic autoimmunity and disease expression through various functions such as induction of the activation of other immune cells in addition to autoantibody production. CD19 is a crucial regulator of B cell activation. Recent studies demonstrated that B cells from SSc patients showed an up-regulated CD19 signaling pathway that induced SSc-specific autoantibody production in SSc mouse models. CD19 transgenic mice lost tolerance for autoantigen and generated autoantibodies spontaneously. B cells from SSc patients exhibited an overexpression of CD19 that induced SSc-specific autoantibody production in transgenic mice. Moreover, SSc patients displayed intrinsic B cell abnormalities characterized by chronic hyper-reactivity of memory B cells, which was possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a genetic model of SSc, showed augmented CD19 signaling. In bleomycin-induced SSc mouse models, endogenous ligands for toll-like receptor 4 induced by bleomycin stimulated B cells to produce various fibrogenic cytokines and autoantibodies. Remarkably, the loss of CD19 resulted in the inhibition of B cell hyper-reactivity and autoantibody production, which are associated with improvements in fibrosis and a parallel decrease in fibrogenic cytokine production by B cells. Taken together, the findings suggest that altered B cell function may result in tissue fibrosis as well as autoimmunity in SSc.

Keywords: Autoimmunity; B lymphocyte; Bleomycin-induced systemic sclerosis model mouse; CD19; Systemic sclerosis; Tight-skin mouse.

Fig. 1

B cells play multiple roles in the immune system. B cells regulate immune responses and immune system development. B cells are not only involved in natural, adaptive, and autoantibody production, but also interact with T cells and other antigen presenting cells including macrophages and dendritic cells, produce multiple regulatory cytokines, and are critical for lymphoid tissue development.

Fig. 2

Surface molecules regulate positively or negatively the activation of B cells. On B cells, several molecules have been identified as response regulators. These molecules are categorized as either positive or negative response regulators of B cell function. CD19 and CD21 are positive response regulators that augment B cell antigen receptor (BCR) signaling, while CD22, CD72, and FcγRIIB are negative response regulators that reduce BCR signals. Abnormal regulation of the response regulator function and expression may result in hyper-activation of B cells and autoantibody production.

Fig. 3

A model linking systemic autoimmunity and tissue fibrosis in systemic sclerosis (SSc) patients and bleomycin (BLM)-induced SSc mouse models. BLM induced the production of reactive oxygen species (ROS). SSc patients exhibited enhanced ROS production, which was due to ischemia and reperfusion injury following Raynaud's phenomenon. Consequently, ROS increased the production of hyaluronan fragments, which induced B cell activation through toll-like receptor 4 (TLR4) signaling. Simultaneously, in BLM-induced SSc mouse models, apoptosis was prominently detected in the skin. In addition, apoptosis was detected in the skin of patients with early stage SSc. In the surface blebs of apoptotic cells, autoantigens including topo I were concentrated, which may result in the antigen presentation of the cryptic epitopes. Remarkably, CD19 loss inhibited B cell activation and autoantibody production. We hypothesize that BLM and Raynaud's phenomenon induce fibrosis by enhancing hyaluronan production, which activates B cells to produce fibrogenic cytokines mainly via CD19 and TLR4 signaling and to induce autoantibody production.