Impaired B‐cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies

Abstract

A role for B cells in autoimmune diseases is now clearly established both in mouse models and humans by successful treatment of multiple sclerosis and rheumatoid arthritis with anti-CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells promote the development of autoimmune diseases remain poorly understood. Here, we review evidence that patients with autoimmune disease suffer from defects in early B-cell tolerance checkpoints and therefore fail to counterselect developing autoreactive B cells. These B-cell tolerance defects are primary to autoimmune diseases and may result from altered Bcell receptor signaling and dysregulated T-cell/regulatory T-cell compartment. As a consequence, large numbers of autoreactive naive B cells accumulate in the blood of patients with autoimmune diseases and may promote autoimmunity through the presentation of self-antigen to T cells. In addition, new evidence suggests that this reservoir of autoreactive naive B cells contains clones that may develop into CD27 − CD21 −/lo B cells associated with increased disease severity and plasma cells secreting potentially pathogenic autoantibodies after the acquisition of somatic hypermutations that improve affinity for self-antigens. K E Y W O R D Sautoantibodies, autoimmune disease, B-cell development, immune tolerance checkpoint

“Age Related Differences in the Biology of Chronic Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation”

“…In the area of autoimmunity, increased circulating NF-B cells are found in SLE, type 1 diabetes, and juvenile dermatomyositis (28,29) possibly as an important source of pathogenic autoantibodies. It is suggested that autoreactive NF-B cells contains clones that may develop into CD27 − CD21 −/lo B cells after the acquisition of somatic hypermutations that improve affinity for self-antigens (27). In adults, we observed an inverse relationship between increased CD21 lo B cells and decreased T1 B regs, suggesting a possible inhibitory impact of B reg cells on CD21 lo B cells at the early B cell checkpoint.…”

“…The tissue distribution of cGvHD in the two cohorts was different, in that skin and lung cGvHD was more common in the adult population compared to the pediatric cohort. Atypical cGvHD presentations not associated with the diagnostic criteria 1411 (25) 12 (27) We have previously analyzed these two cohorts separately and published the results (4,8,18). While the pediatric analysis is only focused on immune profiles at day 100 post HSTC (8) and measured before the onset of cGvHD, and published adult results (4) were measured at the onset of cGvHD, we felt we could identify age-related patterns to guide additional comparisons of the two cohorts.…”

“…The different B cell patterns seen in NF-B cells between children and adults suggests there are significant differences in the role that B cell regulation may play in pediatric versus adult cGvHD. There is evidence that patients with autoimmune disease suffer from defects in early B-cell tolerance checkpoints in the T1 transitional NF-B cell populations, resulting in selection of autoreactive NF-B cells (26,27) that potentially present selfantigen to T cells, similar to early murine models of cGvHD (23). In the area of autoimmunity, increased circulating NF-B cells are found in SLE, type 1 diabetes, and juvenile dermatomyositis (28,29) possibly as an important source of pathogenic autoantibodies.…”

Phenotypes, Functions, and Clinical Relevance of Regulatory B Cells in Cancer

“…In immune system, B cells are classically recognized as positive modulators to regulate inflammation and immune responses by releasing antibodies and activating T cells through antigen presentation (1)(2)(3). Generally, B cells produce antibodies which are a critical part of the host immunity against infection, that can neutralize pathogens, opsonize pathogens for subsequent phagocytosis and mediate antibody-dependent cellular cytotoxicity (4)(5)(6).…”

Peripheral B Cell Subsets in Autoimmune Diseases: Clinical Implications and Effects of B Cell-Targeted Therapies

“…This highly activated process of differentiation to ASCs is believed to be induced by the disruption of tolerance checkpoints, which promotes survival of autoreactive ASCs with increasing quantities of autoantibodies [7][8][9]. Through the detection of B cells that recognize nuclear antigens (ANA + B cells) using flow cytometry, the checkpoints between transitional/naïve and naïve/memory cells have been identified in SLE and healthy individuals but naïve ANA + compartments are defective in SLE [10].…”