The Expanding Roles of B Cells in Systemic Sclerosis: From Autoantibody Production to Antibody-Independent Functions and Therapeutic Targeting

Abstract

Systemic sclerosis (SSc) is a rare, clinically heterogeneous connective tissue disease defined by the triad of autoimmunity, microvasculopathy, and fibrosis of the skin and internal organs. Among the immune effectors implicated in SSc, B cells have moved from being regarded mainly as the source of disease-defining autoantibodies to being recognized as multifunctional drivers of disease through antibody-independent mechanisms. This review summarizes current understanding of B-cell biology in SSc across three domains. First, we consider the classical role of B cells as antibody-producing cells, including the diagnostic and prognostic value of SSc-specific autoantibodies, the evidence for polyclonal B-cell activation and altered B-cell homeostasis, and the contested question of autoantibody pathogenicity. Second, we examine antibody-independent functions, focusing on cytokine production by effector and regulatory B-cell subsets, the B-cell-activating factor (BAFF) axis, antigen presentation, and T-cell co-stimulation, together with the imbalance between pro-inflammatory effector B cells and interleukin (IL)-10-producing regulatory B cells that characterizes active disease. Third, we review B cells as therapeutic targets, from the rituximab experience—including the randomized DESIRES trial and its open-label extension—through anti-BAFF strategies to the emerging use of CD19-directed chimeric antigen receptor (CAR) T-cell and CAR-natural killer (NK) cell therapies that achieve deep, durable B-cell depletion. We conclude by highlighting unresolved questions, including patient selection, the balance between depleting pathogenic and protective B-cell subsets, biomarker development, and the long-term safety of deep B-cell depletion. A B-cell-centered view of SSc pathogenesis provides a coherent framework that links autoimmunity to fibrosis and is increasingly translatable into the clinic.