Abstract
Autoreactive B cells are key drivers of pathogenic processes in autoimmune diseases by the production of autoantibodies, secretion of cytokines, and presentation of autoantigens to T cells. However, the mechanisms that underlie the development of autoreactive B cells are not well understood. Here, we review recent studies leveraging novel techniques to identify and characterize (auto)antigen-specific B cells. The insights gained from such studies pertaining to the mechanisms involved in the escape of tolerance checkpoints and the activation of autoreactive B cells are discussed. In addition, we briefly highlight potential therapeutic strategies to target and eliminate autoreactive B cells in autoimmune diseases.
Highlights
Rivero VaccariAutoimmune diseases are mostly chronic, complex, immune disorders that vary in severity from mild to lethal
We summarize our current knowledge pertaining to the development of autoreactive B cells with a main focus on the autoimmune diseases rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), granulomatosis with polyangiitis (GPA), and pemphigus (Table 1)
Cells are subjected to central tolerance mechanisms in order to eliminate these cells from the B cell pool (Figure 1). These mechanisms include: (i) clonal deletion, i.e., removal of autoreactive B cells by the induction of apoptosis; (ii) anergy, i.e., a state of B cells characterized by unresponsiveness to antigens, downregulation of B cell receptors (BCRs) expression, and a short life-span; and (iii) receptor editing, i.e., a mechanism that replaces the light chain of the BCR with a newly recombined light chain, resulting in a BCR with a different antigen specificity [28,29,30,31]
Summary
Autoimmune diseases are mostly chronic, complex, immune disorders that vary in severity from mild to lethal. Multiple factors are thought to be involved in the development of autoimmune diseases including genetic and environmental factors [3]. Autoimmune diseases are characterized by a loss of self-tolerance leading to an immune response against self-antigens. The autoimmune response can cause inflammation and damage to specific or multiple tissues and organs, depending on the target autoantigen. Bcells play a key role in the pathogenesis of many autoimmune diseases (Table 1). The presence of autoantibodies, and their described contribution to the pathogenesis of these B cell-mediated autoimmune diseases, is proof of B cell dependency. The most conclusive evidence that B cells act as key players in B cell-mediated autoimmune diseases is derived from the successful treatment of patients with therapies that deplete B cells, mainly rituximab, a chimeric anti-CD20 monoclonal antibody that targets.
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