Revisiting B cell tolerance and autoantibodies in seropositive and seronegative autoimmune rheumatic disease (AIRD)

Abstract

Autoimmune rheumatic diseases (AIRD) are categorized seropositive or seronegative, dependent upon the presence or absence of specific autoreactive antibodies, including rheumatoid factor and anti-citrullinated protein antibodies. Autoantibody-based diagnostics have proved helpful in patient care, not only for diagnosis but also for monitoring of disease activity and prediction of therapy responsiveness. Recent work demonstrates that AIRD patients develop autoantibodies beyond those contained in the original categorization. In this study we discuss key mechanisms that underlie autoantibody development in AIRD: defects in early B cell development, genetic variants involved in regulating B cell and T cell tolerance, environmental triggers and antigen modification. We describe how autoantibodies can directly contribute to AIRD pathogenesis through innate and adaptive immune mechanisms, eventually culminating in systemic inflammation and localized tissue damage. We conclude by discussing recent insights that suggest distinct AIRD have incorrectly been denominated seronegative.

Keywords: B cell; arthritis (including rheumatoid arthritis); autoantibodies; autoimmunity; autoinflammatory disease.

Fig. 1

Breaches in B cell tolerance that contribute to autoantibody production in autoantibodies in autoimmune rheumatic diseases (AIRD) are generated if the immune system fails to eliminate and control (proto)autoreactive B cells. Involved in this multi‐factorial process are deficient B cell development checkpoints (a,b) and additional mechanisms that breach B cell tolerance (1c). (a) Central checkpoints of B cell development in bone marrow include positive selection of cells with a functional pre‐B cell receptor (BCR) (checkpoint 1), negative selection of immature B cells with an autoreactive pre‐BCR (checkpoint 2) and immunoglobulin (Ig) receptor ligand‐mediated apoptosis of immature B cells with an autoreactive BCR (checkpoint 3). (b) Peripheral checkpoints include apoptosis of immature proto‐autoreactive B cells in the spleen (checkpoint 4), anergy and follicular exclusion of mature proto‐autoreactive B cells upon autoantigen encounter (checkpoint 5) and prevention of recirculation of autoreactive B cells that emerged after somatic hypermutation in secondary lymphoid organs (checkpoint 6). (c) Additional mechanisms that contribute to a breach in B cell tolerance are the genetic predisposition, environmental factors and immunological triggers. Figure created using images fromhttp://smart.servier.com.HLA = human leukocyte antigen.

Fig. 2

Key pathogenic effects of autoantibodies in autoantibody production in autoantibodies in autoimmune rheumatic diseases (AIRD). Autoantibodies can induce tissue damage and create a proinflammatory microenvironment through multiple components of the innate and adaptive immune system. Localized tissue damage mediated by autoantibodies involves three mechanisms. First, antibody‐dependent cellular cytotoxicity (top right): killing of antibody coated target cells by binding of the Fc domain of IgG autoantibody by Fcγ receptor (FcγR)‐expressing effector cells, most notably natural killer (NK) cells, granulocytes and macrophages. Secondly, through antibody‐induced activation of the complement pathway (lower right). Complement activation can cause cell lysis through assembly of the membrane‐attack complex, can induce phagocytosis of complement C3 proteolytic fragment‐coated (opsonized) damaged cells, and can recruit innate inflammatory cells through release of small complement fragments C3a and C5a (anaphylatoxins). Thirdly, immunpoglobulin (Ig)G autoantibodies can activate various FcγR‐expressing innate immune cells (lower left). For example, plasmacytoid dendritic cells (DC) that produce type I interferon (IFN), macrophages that produce tumor necrosis factor (TNF)‐α and mast cells that release granules with degrading enzymes and produce proinflammatory cytokines. Systemic inflammation is primarily mediated through deposition of circulating immune complexes (IC) (top left). These ICs contain autoantibodies bound to self‐antigens (such as DNA), Toll‐like receptor (TLR) ligands and post‐translationally modified proteins. IC deposition induces the systemic and synergistic activation of cells of the innate immune system via FcγR and TLR ligation. As a result, T helper cell responses are amplified and trigger the release of degrading enzymes and production of proinflammatory cytokines such as TNF‐α, interleukin (IL)‐1β and IL‐6. Together, these mechanisms contribute to a proinflammatory microenvironment with cytokines that further enhance inflammation and damage, through activation of parenchymal and immune cells, production of matrix‐degrading and proteolytic enzymes and release of reactive oxygen species. Figure created using images fromhttp://smart.servier.com. References listed in Supporting information, Table C.