REVIEWS B cell checkpoints in autoimmune rheumatic diseases Samuel J. S. Rubin1,2,3, Michelle S. Bloom1,2,3 and William H. Robinson1,2,3* Abstract | B cells have important functions in the pathogenesis of autoimmune diseases, including autoimmune rheumatic diseases. In addition to producing autoantibodies, B cells contribute to autoimmunity by serving as professional antigen- presenting cells (APCs), producing cytokines, and through additional mechanisms. B cell activation and effector functions are regulated by immune checkpoints, including both activating and inhibitory checkpoint receptors that contribute to the regulation of B cell tolerance, activation, antigen presentation, T cell help, class switching, antibody production and cytokine production. The various activating checkpoint receptors include B cell activating receptors that engage with cognate receptors on T cells or other cells, as well as Toll-like receptors that can provide dual stimulation to B cells via co- engagement with the B cell receptor. Furthermore, various inhibitory checkpoint receptors, including B cell inhibitory receptors, have important functions in regulating B cell development, activation and effector functions. Therapeutically targeting B cell checkpoints represents a promising strategy for the treatment of a variety of autoimmune rheumatic diseases. Antibody- dependent B cells are multifunctional lymphocytes that contribute that serve as precursors to and thereby give rise to acti- cell- mediated cytotoxicity to the pathogenesis of autoimmune diseases via B cell- vated B cells that serve as professional APCs to promote (ADCC). A mechanism by intrinsic, antibody-mediated and T cell-dependent mecha- autoimmune responses12. which antibodies direct nisms. Although antibody production by B cells pro- Although B cell- depleting therapies that target CD19 immune cells via Fc receptor antibody- dependent cell- mediated cytotoxicity (FcR) engagement to lyse a motes both or CD20 are effective in treating multiple autoimmune target cell bound by specific (ADCC) and complement- dependent cytotoxicity (CDC), diseases, these therapies also result in immune deficits. antibodies. B cells can also present antigen and provide T cell Specifically, anti- CD20 B cell- depleting therapies con- help1–3. B cell activation and effector functions are regu- fer increased susceptibility to infections13–15 and in a Complement- dependent lated by immune checkpoints, including activating and subset of patients result in chronically low serum anti- cytotoxicity 6,16 (CDC). A mechanism by which inhibitory checkpoints. B cell functions are critical for body titres that further increase the risk of infection . the complement system kills orchestrating pathogenic immune responses (Fig. 1), and Furthermore, B cell- depleted patients have reduced pathogens or cells bound by thereby, B cells and B cell immune checkpoints repre- responses to vaccination17–19. specific antibodies by insertion sent promising therapeutic targets for autoimmune As a result of the limitations and complications of anti- of the membrane attack 1–3 complex (MAC) to form pores rheumatic disease . CD20 B cell- depleting antibody therapeutics, new types that mediate lysis. Interest in understanding the mechanisms by which of treatments that either deplete specific subsets of patho- B cells contribute to autoimmunity and autoimmune tis- genic B cells or modulate B cell activation and function sue destruction was sparked in part by the unanticipated in more precise manners are needed for the treatment efficacy of B cell- depleting anti- CD20 monoclonal of autoimmunity. Thus, targeting B cells through other 1Immunology Program, Stanford University School of antibodies in treating autoimmune diseases including mechanisms has become a major focus in the development Medicine, Stanford, CA, USA. rheumatoid arthritis (RA), anti- neutrophil cytoplas- of next- generation therapeutics to treat auto immune 2Division of Immunology and mic antibody (ANCA)-associated vasculitis and multi- disease. Some of these next- generation approaches Rheumatology, Department ple sclerosis4–8. Nevertheless, B cell depletion reduces involve small molecules as well as new therapeutic anti- of Medicine, Stanford autoantibody levels by only approximately 30–70%9,10, bodies and antibody- based constructs, which can modu- University School of Medicine, Stanford, CA, USA. suggesting that other B cell functions are also critical late B cell activation or deplete subsets of B cells. Several in the pathogenesis of autoimmunity6,11. B cells, in therapeutics that modulate B cell activation and function 3VA Palo Alto Health Care System, Palo Alto, CA, USA. addition to dendritic cells and macrophages, are pro- are currently approved, while numerous others are being (Table 1) *e- mail: wrobins@ fessional antigen- presenting cells (APCs). The efficacy developed and/or evaluated in clinical trials . stanford.edu of anti-CD20-mediated B cell depletion in treating auto- In this Review, we discuss the multiple mechanisms https://doi.org/10.1038/ immune diseases might, in part, be explained by the by which B cells contribute to autoimmunity. These B cell s41584-019-0211-0 depletion of immature and mature B cell populations functions include autoantibody production, antigen NATURE REVIEWS | RHEUMATOLOGY REVIEWS Key points and other effector cell types. For example, lupus- prone mice with mutations in the IgG FcR that abrogate effec- • B cells have important pathogenic functions in autoimmune rheumatic diseases; tor cell engagement had reduced glomerulonephritis they can produce antibodies, serve as professional antigen- presenting cells (APCs) and improved renal outcomes24. Third, autoantibody- and produce cytokines. containing immune complexes can also activate immune • B cells express activating receptors and inhibitory receptors, which serve as immune cells through dual engagement of FcRs and Toll- like checkpoints that regulate their activation and function. receptors (TLRs) (on macrophages and dendritic cells) or • Activating receptors include the B cell receptor, Toll- like receptors, cytokine dual engagement of the B cell receptor (BCR) and TLRs receptors, CD19, CD40 and other co- stimulatory receptors. (on B cells; as discussed in a later section). For example, • Inhibitory receptors include the low- affinity immunoglobulin-γ Fc region receptor IIb ACPAs, a hallmark of RA, form immune complexes with (Fc RIIb), CD22, programmed cell death 1 (PD1) and other receptors, which transmit γ citrullinated proteins that can stimulate macrophages inhibitory signals to B cells. via dual engagement of the FcR and TLR4 to produce • Various B cell- targeting strategies could be used for the treatment of autoimmune pro- inflammatory cytokines25. IgG rheumatoid factor rheumatic diseases, such as B cell depletion, blockade of activation checkpoints, inhibition of pro- inflammatory cytokines, triggering of B cell inhibitory checkpoints can crosslink immune complexes to potentiate citrulli- and trafficking blockade. nated antigen–immune complex-mediated macrophage activation and cytokine production26,27. Finally, immune complexes facilitate antigen loading onto dendritic cells presentation, T cell help, cytokine secretion and poten- via immune complexes, enabling these cells to efficiently tially other processes. Further, we discuss the mecha- activate T cells28–30. Together, these examples illustrate nisms of B cell activation by antigen and co- receptor the diverse mechanisms through which autoantibodies ligands, as well as B cell regulatory networks governed contribute to pathologies seen in autoimmune disease. by inhibitory receptors. Finally, we present an overview of current and next-generation therapeutic strategies for T cell–B cell interactions targeting B cells and B cell checkpoints for the treatment Although autoantibody production is widely implicated of autoimmune rheumatic diseases. in the pathogenesis of autoimmune diseases, patho- logical interactions between B cells and T cells can also Mechanisms of B cell autoimmunity contribute to autoimmunity. B cells are one of a few cell B cell functions including autoantibody production, types that can function as professional APCs through antigen presentation, T cell help and cytokine produc- constitutive expression of MHC class II molecules. tion all contribute to the pathogenesis of autoimmune Although dendritic cells are thought to be the primary diseases (Fig. 1). As a result of the growing appreciation of initiators of naive CD4+ T cell responses, B cells can also these functions in self-tolerance and the mechanisms by interact with and activate CD4+ T cells via MHC class II- which they contribute to autoimmunity, next-generation mediated antigen presentation, and CD4+ T cells, in therapeutic approaches are focusing on specifically turn, provide help to cognate B cells. During an immune modu lating B cell activation and effector mechanisms response, naive CD4+ T cells are primed by antigen- rather than globally depleting B cells. presenting dendritic cells and subsequently differentiate Fc region into T helper cell subsets including T follicular helper The tail region of an antibody, Autoantibodies (TFH) cells. In the germinal centre, TFH cells interact containing two heavy chain The classic paradigm of B cell- mediated autoimmune with cognate B cells to promote isotype switching and constant domains, that disease centres around production of autoantibodies20. somatic hypermutation, as well as B