B cell abnormalities and therapeutic strategies in systemic sclerosis

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Abstract
One of the major roles of B cells is to generate antibodies to specific antigens. Secreted antibodies are the principal molecules involved in humoral immunity, with the capacity not only to neutralize pathogens, but also to enhance their elimination by activating phagocytosis or complement proteins. Recently, it has been highlighted that B cells exert important regulatory roles independent of their antibody producing function. These roles include efficiently presenting antigens to the T cells, secreting cytokines, and inducing immune cell differentiation. Thus, B cells have emerged as cells that play crucial roles in immune systems in addition to producing antibodies. Systemic sclerosis (SSc) is characterized by autoimmunity and tissue fibrosis of several organs. Although the pathogenic relationship between systemic autoimmunity and the clinical manifestations of SSc remains unknown, SSc patients display a variety of abnormal immune activation including the production of disease-specific autoantibodies. Previous studies have demonstrated that immune cells, mainly including B cells, play a critical role in systemic autoimmunity and disease expression, though the role of autoimmunity in generating the clinical and pathologic phenotype in SSc remains uncertain. SSc patients have B cell abnormalities characterized by chronic hyper-reactivity of memory B cells. Although distinct subsets of autoantibodies do not have a proven pathogenic role, they are selectively associated with unique disease manifestations. To date, the treatment of SSc has largely relied on cytotoxic immunosuppressants and corticosteroids. Although this has resulted in improved disease survival, these patients may still suffer severe adverse events and refractory disease to conventional immunosuppressive therapies. Recently, clinical trials involving the chimeric monoclonal antibody rituximab have raised high expectations. B cell depleting therapy with rituximab offers a promising treatment for the rheumatic autoimmune diseases including SSc. This article reviews the current knowledge of B cell biology and pathogenesis in SSc as well as the therapeutic approaches focusing on the targeting of B cell specific surface molecules and on the blocking of B cell activation and survival.

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