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 auto­immune 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

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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 modu­lating 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 cell differentiation interacts with Fc receptors There are multiple mechanisms by which autoantibodies into memory B cells and plasma cells31,32. (FcRs) to mediate immune cell effector functions. contribute to the pathogenesis of autoimmune disease. Dysregulated antigen presentation is implicated in First, immune complexes can form or deposit in tissues the pathogenesis of autoimmunity. For example, some Ectopic lymphoid structures where they can activate complement and induce CDC HLA-​DRB1 alleles can bind citrullinated peptides33 Also known as tertiary to cause tissue damage. For example, in a mouse model and are associated with the development of RA34. lymphoid structures; organized aggregates of lymphocytes and of lupus nephritis, blockade of B cell co-​stimulation in Furthermore, other HLA class I and class II alleles have other cells that possess some combination with cyclophosphamide treatment reduced been associated with susceptibility to systemic lupus features of germinal centres. immune complex deposition and glomerulonephritis erythematosus (SLE)35,36 and ankylosing spondylitis37,38. These structures can develop and preserved renal function21. RA is associated with Pathological T cell–B cell interactions are also impli- in chronically inflamed the production of rheumatoid factor, autoantibodies that cated by the presence of ectopic lymphoid structures in nonlymphoid tissues such Fc region 39 as the synovium in rheumatoid bind the of IgG, and anti-​citrullinated protein inflamed tissues (for example, in the synovium in RA ), arthritis. antibodies (ACPAs). In RA, both rheumatoid factor-​ as well as by evidence of autoantibody affinity maturation. containing and ACPA-​containing immune complexes For example, in mouse models of SLE, antinuclear anti- Affinity maturation activate complement pathways in joints, leading to the bodies (ANAs) undergo somatic hypermutation to A process in the germinal centre by which B cells, production of C5a and the generation of the membrane become high-​affinity (and hence, highly pathogenic) 40 following interaction and attack complex (MAC), which both contribute to joint autoantibodies . Additionally, ACPAs and rheumatoid activation by follicular damage22; IgM rheumatoid factor can also increase factor from patients with RA show signs of somatic helper T cells, undergo complement activation mediated by ACPA-​containing hypermutation, implicating the involvement of affinity immunoglobulin gene mutation immune complexes23. Second, autoantibodies can pro- maturation in RA pathogenesis41,42. and subsequent selection to generate B cells that express mote tissue damage via ADCC by co-​engagement of In addition to B cell–TFH cell interactions, interactions antibodies with increased antigens on the target tissue and Fc receptors (FcRs) between B cells and other cells can be dysregulated in affinity for the target antigen. on macrophages, neutrophils, natural killer (NK) cells autoimmunity. For example, a distinct T cell population

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Autoantibody models of autoimmunity and in multiple sclerosis, production 51 SLE and RA . TGFβ is produced by some Breg cells and can also modu­late T cell activity52. Additionally, in 2014, researchers described a population of IL-35- expressing B cells that can suppress autoimmunity53–55. Co-stimulation reg Autoantibodies BCR Autoantigen How Breg cells mediate their suppressive functions is not CD28 fully understood, and additional work is needed to fully CD80 or define their developmental paths and regulatory func- CD86 tions in immune responses as well as the mechanisms by which they can suppress autoimmunity (reviewed elsewhere56). Understanding these mechanisms could facilitate development of B cell-modulating​ therapies for MHC the treatment of autoimmune rheumatic disease. Cytokine class II production Autoreactive TCR Autoreactive B cell T cell B cell activation B cell activation is important for adaptive immune Antigen presentation responses and is regulated by key stimulatory and Cytokines inhibitory checkpoints. B cell inhibitory checkpoints serve to both inhibit activation of autoreactive B cells | Fig. 1 the functions of B cells in autoimmune disease. Central B cell functions, and dampen overstimulated responses (Fig. 2). For non-​ including antibody production, antigen presentation and T cell help via co-stimulation​ polyvalent antigens, two signals are required for the and/or cytokine secretion, can all contribute to the pathogenesis of autoimmune diseases. BCR , B cell receptor; TCR , T cell receptor. activation of B cells: the engagement of the BCR and a co-​stimulatory signal. Antigen binding to the BCR defines the specificity of the B cell response, whereas that can augment B cell responses in nonlymphoid tis- co-​stimulatory functions are important for overcoming sue (referred to as peripheral T helper cells) is expanded inhibitory checkpoints. in the synovium of patients with RA42. In addition, in Throughout the development of B cells, both posi- RA, fibroblast-​like synoviocytes can interact with and tive and negative selection via the BCR shape the mature provide pro-survival​ factors to B cells43. B cell repertoire and reduce reactivity to autoantigens. Together, these findings suggest the important Early in the development of B cells, autoreactive B cells involvement of B cell–T cell interactions in autoimmun- in the bone marrow undergo the process of negative ity. Thus, targeting these interactions could be effective selection that involves receptor editing and/or cell dele- for preventing the development and progression of tion57. The detection of extraneous autoreactive naive autoimmune diseases. B cells in both SLE and RA indicates that dysregulation of these central tolerance mechanisms contributes to Cytokine production autoimmunity57. Once B cells migrate to the periphery, In addition to autoantibody production and antigen additional inhibitory checkpoint pathways ensure that presentation, B cells can regulate immune responses residual autoreactive B cells are eliminated or silenced, through the production of cytokines. B cells can produce whereas co-​stimulatory signals ensure that only B cells pro-inflammatory​ cytokines such as IFNγ, IL-6 and IL-2 with non-autoreactive​ BCRs are activated. Many of these as well as anti-inflammatory​ cytokines such as IL-10 and stimulatory and inhibitory checkpoint pathways func- IL-4 (Refs.44,45). Multiple sclerosis, in particular, involves tion indirectly to control the survival, proliferation and perturbations in cytokine production by B cells46, but activation of B cells. Ongoing studies by multiple groups B cell-​mediated cytokine secretion is also perturbed in aim to further define and characterize the effect of indi- other autoimmune diseases such as SLE and RA47,48. vidual stimulatory and inhibitory checkpoints on anti- The production of IL-6 and IFNγ by B cells is required gen presentation, antibody production, co-​stimulation,

for spontaneous germinal centre formation and TFH cell Breg cell activity and other B cell functions. differentiation in a mouse model of SLE49, and this pro- In addition to extrinsic regulatory signals, confor- cess probably also occurs in other autoimmune diseases mational changes in the BCR are also required to acti- (for example, IFNγ-​expressing B cells are expanded in vate B cells. There are two predominant models for how multiple sclerosis46). B cell-​derived IL-6 can promote antigen binding and BCR oligomerization mediate the B cell proliferation as well as exert pleiotropic effects activation of B cells. The conformation-​induced model on T cells and other cell types (reviewed elsewhere50). posits that activation occurs via crosslinking of multi- Thus, therapeutically targeting B cells could prevent loss ple BCRs on the B cell membrane, which then triggers of tolerance in both B cells and T cells as well as reduce downstream signalling58. The dissociation activation inflammatory responses that can promote autoimmunity. model alternatively suggests that unstimulated BCRs In contrast to pro-​inflammatory B cell responses, reside in auto-​inhibited oligomers on the B cell mem-

regu­latory B (Breg) cells are characterized by the pro- brane and that these structures are inaccessible to the duction of anti-​inflammatory cytokines such as IL-10, kinases involved in B cell activation. Antigen binding

TGFβ and IL-35. IL-10-producing Breg cells (so-​called promotes the opening of clustered BCR oligomers, ena- B10 cells) have important protective functions against bling access to these kinases and downstream signalling the development of autoimmunity, including in mouse (reviewed elsewhere59). Regardless of these models, B cell

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activation by either model is dependent on non-covalent​ CD40. Cognate T cells promote B cell and plasma cell interactions between the BCR and the invariant Igα and differentiation by providing co-​stimulatory signals Igβ chains (also known as CD79A and CD79B). These in the form of CD40 ligand (CD40L; also known as chains contain immunoreceptor tyrosine-​based acti- CD154). These cognate T cells are reciprocally activated vation motifs (ITAMs) that, upon antigen engagement by engagement of CD40L with CD40 on the surface of of the BCR, are phosphorylated by the tyrosine kinase B cells (reviewed elsewhere62,63). CD40, a member of the LYN60. Downstream activation signals are then ampli- TNF receptor (TNFR) family, is expressed by a variety fied and relayed by the SYK and BTK kinases (reviewed of immune cells, including B cells, but also by other cells elsewhere60,61). Thus, BCR activation is mediated by acti- such as platelets. Without co-​stimulation via CD40 or vating co-receptors​ and their associated kinases, which other receptors, BCR triggering can lead to apoptosis requires overcoming constitutive inhibitory signals from of the B cell instead of B cell activation64. The inability of inhibitory co-receptors.​ B cells to be activated without CD40-mediated co-​ stimulation serves as a checkpoint to prevent the matu- B cell stimulatory pathways ration of autoreactive B cells. However, the breakdown B cell stimulatory checkpoints are important in the of tolerance to self-antigens​ in autoimmune diseases can regu­lation of B cell activation. These stimulatory check- be mediated by B cell–T cell interactions, as exemplified points consist of numerous cytokines, cytokine receptors, in one study that found that CD40 signalling in B cells other cell surface receptors and downstream signalling is required for the development of SLE-​like disease in pathways. mice and is also probably an important contributor to

Table 1 | approved and advanced development therapeutics that could be used to target B cells in autoimmunity target molecule Format Ra Sle multiple malignancy Refs sclerosis B cell depletion CD20 Rituximab Monoclonal antibody Approved Off-​label use Off-​label use Approved 6,7,111 CD20 Ocrelizumab Monoclonal antibody – – Approved – 112,113 CD19 Inebilizumab Monoclonal antibody – – Investigational Phase II 121,182 CD52 Alemtuzumab Monoclonal antibody – – Approved Approved 123,133 CD38 Daratumumab Monoclonal antibody – – – Approved 126 CD138 Indatuximab ravtansine Chimeric monoclonal – – – Approved 183 antibody B cell activation or activity modulation CD19 and XmAb5871 Fc-​engineered Phase I and Phase II – – 136,137,139 FcγRIIb monoclonal antibody phase II Igβ and FcγRIIb MGD010 DART Phase I – – – 104 CD40 CFZ533 Monoclonal antibody Phase I Phase II – – 184–187 CD40L Dapirolizumab pegol Pegylated Fab fragment – Phase II – – 188 ICOS MEDI-570 Monoclonal antibody – Phase I – Phase I 189,190 ICOSL AMG557 Monoclonal antibody – Phase I – – 191–194 CD22 Epratuzumab Monoclonal antibody – Investigational – Phase III 133,134 PI3Kδ Idelalisib Small molecule – – – Approved 148 BTK Ibrutinib Small molecule – – – Approved 146,195 Inhibition of cytokines or cytokine signalling BAFF Belimumab Monoclonal antibody Investigational Approved – Investigational 196–198 BAFF and APRIL Atacicept TACI and human IgG Fc Investigational Phase III Phase II – 199–203 fusion protein IL-6R Tocilizumab Monoclonal antibody Approved – – Phase II 89,204,205 IL-21 NNC114-0005 Monoclonal antibody Phase I – – – 206 JAK1 and JAK3 Tofacitinib Small molecule Approved Phase I and – – 207–210 phase II JAK1 and JAK2 Baricitinib Small molecule Approved Phase III – – 211–215 Trafficking blockade α4 Integrin Natalizumab Monoclonal antibody Phase II – Approved – 216–219 Shown are autoimmune indications for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and/or multiple sclerosis, although some of these interventions have been approved for other diseases as well. Approved and investigational statuses refer to the US and FDA-registered​ clinical trials. APRIL , a proliferation-​ inducing ligand; BAFF, B cell activating factor ; CD40L , CD40 ligand; DART, dual-affinity​ retargeting molecule; FcγRIIb, low-affinity​ immunoglobulin-γ​ Fc region receptor IIb; IL-6R , IL-6 receptor ; JAK , Janus kinase; PI3Kδ, phosphoinositide 3-kinase-δ​ ; TACI, transmembrane activator and calcium modulator.

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a Stimulatory checkpoints b Inhibitory checkpoints Other cell PDL1 or BAFF CD40L PDL2 CD5 MHC TIM3 Sialic acid class I

Antigen DAMP or IL-6 IgG BCR C3d PAMP CD19 IL-21 Collagen

IL-6R IL-21R BAFFR CD40 FcγRIIb PD1 CD72 TLR CEACAM1 LAIR1 CD21 gp130 LIR1 Igα Igβ CD22

B cell

Fig. 2 | examples of B cell stimulatory and inhibitory checkpoints. B cells express a repertoire of stimulatory and inhibitory receptors, the relative levels of which change through the course of B cell development. B cell functions are modulated by the balance of expression and colocalization of stimulatory checkpoint receptors (part a) and inhibitory checkpoint receptors (part b). Some Toll-like​ receptors (TLRs) are also expressed in the endosome. BAFF, B cell activating factor ; BAFFR , B cell activating factor receptor; BCR , B cell receptor; CD40L , CD40 ligand; CEACAM1, carcinoembryonic antigen-related​ cell adhesion molecule 1; DAMP, damage-associated​ molecular pattern; FcγRIIb, low-affinity​ immunoglobulin-γ​ Fc region receptor IIb; IL-21R, IL-21 receptor ; IL-6R , IL-6 receptor ; L AIR1, leukocyte-associated​ immunoglobulin-like​ receptor 1; LIR1, leukocyte immunoglobulin-like​ receptor 1; PAMP, pathogen-associated​ molecular pattern; PD1, programmed cell death 1.

autoimmunity in humans65. Consistent with this finding, can simultaneously activate TLRs and BCRs, lower- CD40L is upregulated on T cells in multiple auto­immune ing the receptor engagement threshold needed for diseases including SLE, RA and multiple sclerosis, and B cell activation69,70. soluble CD40L levels correlate with autoantibody titres In 2002, TLRs were noted to contribute to autoim- and disease activity66,67. mune B cell activation in an in vitro system, in which dual stimulation of TLR9 and the BCR by self-DNA-containing​ Toll-​like receptors. As an alternative to CD40-mediated immune complexes led to autoimmune B cell activation co-​stimulation of BCRs, B cells can be activated inde- (in this case, the activation of rheumatoid factor-​positive pendently of T cells via dual stimulation of the BCR and B cells)68,71. This observation provided a mechanistic TLRs. TLRs recognize pathogen-​associated molecu- model to explain the production of rheumatoid factor; lar patterns (PAMPs) and damage-associated​ molecular in this model, engagement of the BCR on rheumatoid patterns (DAMPs) that are important for host defence factor-​positive B cells with the Fc domain of an anti- and wound healing (Fig. 3). Bacterial or viral PAMPs, body also bound to a TLR ligand (such as DNA, RNA such as lipopolysaccharide (LPS), double-stranded​ RNA or fibrinogen) leads to dual stimulation and activation of or virus-like​ particles, can be detected by both the BCR the B cell68,71. In addition, TLR9, TLR7 and TLR8, which (on antigen-specific​ B cells) and TLRs. Cell surface TLRs bind viral single-​stranded RNA (ssRNA), have also been can engage ligands residing on the surface of the patho­ implicated in the development of autoimmunity60. For gen simultaneously with the BCR, whereas lysosomal instance, immune complexes containing ssRNA or RNA-​ TLRs can interact with RNA, DNA and other intracellu- binding proteins (such as small nuclear ribonucleopro- lar ligands upon internalization and digestion of patho­ teins (snRNPs), Sm, Ro, La and transfer RNA synthetases) gens or pathogen debris following interaction with the can stimulate rheumatoid factor-positive​ B cells upon dual BCR. Thus, engagement of BCRs by bacterial or viral engagement of TLR7 and the BCR72. B cells that directly structures in an antigen-​specific manner and simulta- bind TLR ligands, or RNA-binding​ proteins that bind TLR neous engagement of TLRs in a PAMP-​specific manner ligands (Fig. 3) via their BCR, might also be activated in leads to activation of B cells68. a similar fashion72. Dual stimulation of TLRs and BCRs TLRs are also capable of binding self-​ligands or probably contributes to autoantibody production in, and DAMPs, which can promote protective and reparative to the pathogenesis of SLE, myositis, Sjögren syndrome responses as well as pathogenic autoimmune responses and other autoimmune rheumatic diseases in which under certain conditions (Fig. 3). Intracellular compo- autoreactive B cells and autoantibodies target proteins nents, such as DNA and RNA, can be exposed during or molecular complexes containing DNA or RNA69. cell death and tissue damage and can then interact with TLRs on B cells. Although these components are nor- CD19. In addition to co-​stimulation by CD40 or dual mally cleared by macrophages, interactions with anti- stimulation by TLRs, B cell activation can be facilitated bodies can lead to the accumulation and stabilization by the activation of the co-​receptor CD19. CD19 is an of these self-​antigens. The resultant immune complexes immunoglobulin superfamily glycoprotein associated

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a Host defence b Autoimmunity the predominant BAFF receptor on germinal centre RNA B cells; and BAFF receptor (BAFFR), the predominant RBP BAFF receptor on peripheral B cells77. DAMP or Similar to some other cytokines, BAFF facilitates PAMP T cell co-​stimulation of B cells by functioning as a pro-​ Internalized Internalized BCR survival factor rather than by providing a traditional co-​stimulatory signal. Instead of providing a secondary B cell activating signal, BAFF promotes B cell survival and increases the probability that a B cell will encounter Endosome Igα sufficient signals to become activated. Thus, in auto- Igβ immunity, BAFF can increase the overall numbers of TLR7 autoreactive B cells and/or outweigh peripheral tol­ MYD88 MYD88 e­rance mechanisms by predisposing B cells to receive activation signals78. BAFF concentrations are often increased in the serum NF-κB NF-κB of patients with SLE or other autoimmune conditions79. For example, serum concentrations of BAFF correlate with anti-​double-stranded DNA (dsDNA) antibody titres in patients with SLE80. Furthermore, a variant in the B cell BAFF-​encoding gene, TNFSF13B, is strongly associated with multiple sclerosis and SLE. This variant encodes a Fig. 3 | B cell activation via dual stimulation by antigens. a | During an immune truncated mRNA, which escapes microRNA-​mediated response to an infection, the simultaneous engagement of the B cell receptor (BCR) and inhibition, leading to increased production of the BAFF Toll-​like receptors (TLRs) on B cells by bacterial or viral structures (pathogen-associated​ protein81. Belimumab, a human IgG1 monoclonal anti- molecular patterns (PAMPs)) or by damage-associated​ molecular patterns (DAMPs) body that targets BAFF, is an effective treatment for can lead to B cell activation. b | In some autoimmune diseases, autoantigens can dual patients with SLE who are autoantibody positive82,83. stimulate B cells through TLRs and the BCR. The example provided is for systemic lupus erythematosus (SLE), in which B cells that recognize RNA-binding​ proteins (RBPs) through their membrane-bound​ BCR bind and co-internalize​ RBPs along with their associated IL-6. The cytokine IL-6 was originally identified as a ribonucleic acids, and the ribonucleic acids then bind TLR7 in the endosomes. Similar B cell growth factor and plasma cell differentiation fac- 84 examples are found in other autoimmune diseases. tor , but IL-6 can also have pleiotropic effects on other immune cell types. IL-6 is produced both intrinsically by B cells and by other cells such as macrophages49,84; with the BCR and is expressed on B cells from the pre-​ macrophages increase their IL-6 production as a result of B cell stage through to the plasma cell differentiation feedforward processes in response to FcR engagement by stage. CD19 signals though the tyrosine kinases LYN IgG antibodies85. In RA, increased IL-6 serum concen- and phosphoinositide 3-kinase (PI3K), which amplify trations correlate with joint damage, probably because of signals from the BCR, decreasing the threshold for BCR the involvement of IL-6 in promoting osteoclastogene- activation60. CD19 is an integral feature of the BCR sig- sis86,87. Blockade of IL-6 with tocilizumab, a humanized nalling complex and is important for B cell activation. monoclonal antibody against the IL-6 receptor (IL-6R), Both CD19 and the BCR are needed for B cell activa- leads to improved radiographic outcomes in patients tion, whereas stimulation of either receptor alone leads with RA88,89. In SLE, B cell-​derived IL-6 can drive auto- to B cell apoptosis73. immune GC formation by promoting T helper cell dif- Interestingly, investigators have identified a unique ferentiation and IL-21 production49,84, which in turn can population of CD19hi B cells in patients with SLE or pem- lead to B cell growth and differentiation. Preliminary phigus, although the function of these cells in disease studies of IL-6 blockade in patients with SLE, however, requires further investigation74. Thus, CD19 is a poten- have shown minimal beneficial effects90,91. tial immunomodulatory therapeutic target, in addition to CD20 and other B cell antigens, for the treatment of IL-21. The cytokine IL-21 is produced by multiple autoimmune diseases75,76. T helper cell subsets and has critical functions in B cell activation, proliferation, differentiation, affinity matu­ BAFF. B cell activating factor (BAFF; also known as ration and antibody production. IL-21 drives pro-​ TNFSF13B) is a cytokine that belongs to the TNF inflammatory responses by promoting B cell activation family and can facilitate B cell activation indirectly by and expansion, and patients with SLE, type 1 diabetes promoting B cell survival, proliferation and/or differen- or inflammatory bowel diseases have increased serum tiation77. BAFF is produced by various types of immune concentrations of IL-21 compared with healthy indi- 92 cells including follicular dendritic cells and monocytes viduals . In germinal centres, TFH cell-​derived IL-21 and can influence B cell populations through interac- regulates class switching to IgG, IgA and IgE in B cells tions with three different receptors: transmembrane through the activation of activation-​induced cytidine activator and calcium modulator (TACI; also known as deaminase (AID) and promotes differentiation of acti- TNFRSF13B), the predominant BAFF receptor on splenic vated B cells into memory B cells and plasma cells93. transitional type 2 and marginal zone B cells; B cell Blockade of IL-21 consequently results in decreased matu­ration antigen (BCMA; also known as TNFRSF17), T cell-​induced B cell proliferation, differentiation and

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antibody secretion94. Interestingly, IL-21 also prevents B cell-​modulating therapeutics as our understanding of nonspecific B cell activation by promoting apoptosis in their mechanism(s) continues to improve. B cells that receive signals through the BCR and/or TLRs but that do not receive T cell co-​stimulatory signals95. Therapeutic approaches Thus, as IL-21 contributes to B cell function through B cell depletion with the B cell-depleting​ anti-CD20​ anti­ multiple mechanisms, targeting IL-21 might be valuable body, rituximab, is currently the therapeutic approach as a broad treatment for autoimmune diseases that stem most widely used to target B cells. The finding that B cell from dysregulated B cell function at various stages of dysregulation contributes to auto­immune diseases has development and/or activation. inspired the development of novel, mecha­nistically informed treatments. A number of both B cell-​ B cell inhibitory pathways depleting antibodies, such as anti-​CD138 and anti-​ During B cell development and maturation, inhibitory CD38, and small-​molecule kinase inhibitors, such checkpoints balance activating signals to ensure central as Janus kinase (JAK), SYK and BTK inhibitors, hold tolerance96 (Fig. 2). promise for the treatment of autoimmune disease (Table 1). However, these nonspecific strategies result in CD22. CD22 is important for regulating B cell acti- broad immune suppression, which increases the risk of vation in response to self-​antigens. This molecule is infectious complications and other adverse events. The a transmembrane receptor and member of the sialic shortcomings of these therapies have led to new efforts acid-binding​ immunoglobulin-like​ lectin family. CD22 focused on the development of approaches that engage binds α2,6-linked sialic acids found on the surfaces of B cell inhibitory or other checkpoint pathways in a spe- eukaryotic but not bacterial cells97,98. The receptor is con- cific manner (Fig. 4). Ongoing strategies for the devel- stitutively associated with the BCR and contains three opment of therapeutics to treat autoimmunity include cytoplasmic immunoreceptor tyrosine-based​ inhibition antibody-​based B cell depletion, small-molecule​ kinase motifs (ITIMs), which are phosphorylated upon ligand inhibition, antibody-​based blockade of B cell activat- binding in conjunction with BCR-​antigen binding99. ing receptors and antibody-​based induction of B cell Subsequently, recruitment of the phosphatases SHIP1 inhibitory signals104–110. and SHP1 inhibits signalling downstream of the BCR. This inhibition is thought to modulate the BCR activa- B cell-depleting​ therapies tion threshold to prevent B cell activation in response Cell depletion was an initial approach used to target to self-antigens​ 60. B cells for the treatment of autoimmune disease. The B cell-​depleting anti-​CD20 antibody rituximab is FcγRIIb. The low-affinity​ immunoglobulin-​γ Fc region FDA-​approved for the treatment of RA. Although not receptor IIb (FcγRIIb) is the only inhibitory FcR and the approved for multiple sclerosis and having failed trials in only FcR expressed by B cells; this molecule is crucial SLE, rituximab is also used off-label​ for the treatment of for restricting antibody-mediated​ immune responses100. these diseases on the basis of clinician experience111. In After binding of the IgG Fc region to the extracellular addition, ocrelizumab, a humanized anti-​CD20 mono­ domain of FcγRIIb, its single intracellular ITIM domain clonal antibody, was approved in 2017 for the treat- is phosphorylated by BCR-​associated kinases; subse- ment of multi­ple sclerosis112,113. Clinical studies have quent recruitment of the SHIP1 phosphatase inhibits shown some efficacy of ocrelizumab in treating SLE114, signalling downstream of the BCR and destabilizes although concerns over adverse events have halted the BCR complex101. This process is thought to modu­ clinical trials for SLE and RA11, and future studies will late immune responses when antigens saturated with probably demonstrate its utility in other B cell-​mediated IgG antibodies in immune complexes trigger FcγRIIb diseases. Despite depleting only B cells that express in conjunction with the BCR60. As a result, FcγRIIb is CD20, which is downregulated by antibody-​secreting thought to help prevent autoimmunity, and mutations at cells115, these antibody therapies are thought to func- its genetic locus have been associated with RA, SLE and tion by targeting precursors to these antibody-​secreting multiple sclerosis in human genome-​wide association B cells and/or B cells with antigen-​presenting or other studies and mouse studies96,102. pathogenic functions. Given that many antibody-​secreting B cells, includ- Other inhibitory receptors. Polymorphisms in genes ing plasmablasts and plasma cells, lack CD20 (refs116,117) encoding other inhibitory receptors expressed by B cells, but retain CD19 expression, CD19-targeting therapies including CD5, CD72, leukocyte immunoglobulin-​ that are being developed for B cell malignancies are also like receptor 1 (LIR1; also known as CD85j) and pro- being explored as therapeutics for autoimmune diseases. grammed cell death 1 (PD1), have also been associated Inebilizumab, a humanized monoclonal anti-​CD19 with autoimmunity96,102. B cells express additional inhib- antibody that is afucosylated for increased ADCC118, itory receptors, including carcinoembryonic antigen-​ has shown promising results in multiple mouse models related cell adhesion molecule 1 (CEACAM1) and of autoimmunity119,120 and early-​phase clinical trials121. leukocyte-​associated immunoglobulin-​like receptor 1 Furthermore, in clinical trials in multiple sclerosis (LAIR1)96,103. These receptors, along with other, less-​well and other diseases, inebilizumab treatment resulted understood molecules, contribute to the maintenance of in considerable depletion of plasma cells121. However, B cell tolerance­ during development and in the periph- CD19 expression is absent on a subset of plasma cells ery96. These receptors provide additional targets for future in the bone marrow that are known to contribute to

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autoantibody production122. Thus, these CD19-targeting indatuximab ravtansine are currently being investi- therapies might miss subsets of cells that produce gated for their efficacy in treating patients with multi- autoantibodies and contribute to the pathogenesis of ple myeloma125,126 but could have potential in treating autoimmune diseases. Further studies regarding the autoimmune disease. efficacy of CD19-targeting therapies are ongoing117. Alemtuzumab is an anti-​CD52 monoclonal anti- Targeting B cell checkpoints body that depletes T cells, B cells and macrophages123. The risks associated with systemic depletion of B cells The efficacy of alemtuzumab, which is FDA-​approved have led to the development of therapies that modulate, for the treatment of multiple sclerosis, is potentially rather than deplete, B cells. high because of its B cell-depleting​ properties. However, One approach for therapeutically modulating B cell alemtuzumab is also associated with a high rate of seri- activation is the disruption of CD40–CD40L interactions. ous adverse events, probably because the treatment Despite initial promising results from clinical trials of results in depletion of such broad leukocyte populations. the anti-​CD40L antibodies toralizumab, BG9588 and Antibodies that target other molecules expressed by ABI793 (Ref.127) in SLE, thromboembolic events, caused B cells including CD38 (daratumumab124), CD138 (inda- by engagement of CD40L expressed on platelets, tuximab ravtansine125), and other surface receptors are have hampered this approach66,67. Nevertheless, next-​ undergoing clinical development. Daratumumab and generation antagonists for CD40–CD40L are now in the

a Disruption of B cell activation or activity

Epratuzumab CFZ533 MGD010a Dapirolizumab pegolb

a BCR FcγRIIb XmAb5871 CD19 d Trafficking AMG557 and blockade MEDI-570b FcγRIIb Igα B cell Natalizumab Igβ b depletion CD40 CD22 ICOSL α4 Integrin BTK Ibrutinib Inebilizumab PI3Kδ Idelalisib BAFFR CD19 Belimumab Tofacitinib and Rituximab baricitinib B cell

Atacicept CD52 CD20 JAKs CD38 TACI Alemtuzumab IL-21R CD138 IL-6R Cytokine receptor Daratumumab NNC114-0005 Indatuximab ravtansine Tocilizumab gp130

c Inhibition of pro-inflammatory cytokines

Fig. 4 | therapeutic approaches for modulating B cells in autoimmunity. Disruption of B cell activation or engagement of inhibitory checkpoint receptors (part a), B cell depletion (part b), inhibition of pro-inflammatory​ soluble factors (part c) and trafficking blockade (part d) are being used to target B cells in autoimmunity. aXmAb5871 and MGD010 function by binding both the low-affinity​ immunoglobulin-γ​ Fc region receptor IIb (FcγRIIb) and components that are positioned near the B cell receptor (BCR), bringing this inhibitory receptor in close proximity to the BCR to inhibit BCR signalling. bDapirolizumab pegol and MEDI-570 target CD40 ligand (CD40L) and ICOS, respectively; although these receptors are not normally expressed on B cells, they are expressed on T cells and bind to receptors on B cells (CD40 and ICOSL) to mediate B cell–T cell interactions. BAFFR, B cell activating factor receptor; IL-21R , IL-21 receptor ; IL-6R , IL-6 receptor ; JAK , Janus kinase; PI3Kδ, phosphoinositide 3-kinase-δ​ ; TACI, transmembrane activator and calcium modulator.

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clinic, with promising results for multiple autoimmune SLE, RA and other autoimmune rheumatic diseases143–145 diseases128,129 (Table 1). In addition, CD40 agonizing (Table 1). In addition, several companies are pursuing antibodies are being pursued for antitumour therapy130,131. the development of BTK inhibitors in combination with Similarly, inhibition of interactions between ICOS other small-molecule​ kinase inhibitors for the treatment and ICOSL (also known as ICOSLG) (expressed on of B cell malignancy and autoimmunity146,147. Similar

T cells and B cells, respectively) to disrupt TFH cell– efforts are directed towards developing inhibitors B cell interactions is being pursued for the treatment of PI3K, another important molecule in the signalling of autoimmune diseases. Antibodies that block ICOSL cascade downstream of the BCR148,149. (AMG557 (Ref.132)) or ICOS (MEDI-570 (ref.133)) are being developed. Both MEDI-570 and AMG557 can Targeting cytokines

block TFH cell–B cell interactions and the production of An alternative approach to targeting autoimmune B cells autoantibodies and have shown promise in clinical trials themselves is inhibiting the soluble factors that activate for SLE treatment132,133. B cells. Examples of these strategies include inhibiting There is also considerable interest in targeting CD22 the BAFF signalling pathway and cytokines such as IL-6. for the treatment of autoimmune disease. As CD22 has Several therapeutic strategies that target soluble B cell three ITIMs, promoting the inhibitory function of this activating factors are either FDA-approved​ or are under receptor could have potent inhibitory effects on B cells. development. For example, belimumab, a monoclonal However, treatment with the anti-​CD22 antibody antibody that targets BAFF (and prevents BAFF from epratuzumab (an antibody that is thought to promote binding to its three receptors) is approved for the treat- the function of CD22 and thereby inhibit BCR acti- ment of SLE150,151. In patients with SLE, treatment with vation134) did not result in improved response rates in belimumab reduces the number of CD20-positive B cells patients with SLE in a phase II clinical trial134. and plasma cells in the blood and lowers the titres of Another approach being pursued is the co-engagement​ anti-​dsDNA antibodies80. Alternatively, atacicept152, of a B cell inhibitory receptor with a surface receptor on a fusion protein of the extracellular domain of TACI the same B cells. For example, the anti-​CD19 antibody and a human IgG1 Fc, is currently in clinical trials for XmAb5871 contains an Fc region that is engineered to the treatment of SLE60,77,79,153,154. Treatment with atacicept have an increased affinity and selectivity for the inhib- leads to a reduction in the total number of B cells and a itory FcγRIIb receptor. XmAb5871, hence, co-​engages dose-dependent​ reduction in antibody titres. In contrast CD19 and FcγRIIb on B cells, bringing the inhibitory to the ability of belimumab to bind BAFF, atacicept binds receptor in close proximity to the BCR to inhibit down- and blocks both BAFF and a proliferation-​inducing stream signalling135. In clinical trials for the treatment ligand (APRIL, or TNFSF13, another B cell stimulatory of SLE136 and IgG4-related disease137, this dual-targeting​ molecule), preventing their signalling via BAFFR and antibody decreased the production of ACPAs and TACI, respectively, on B cells, which could potentially rheumatoid factor by B cells from patients with RA138,139. lead to greater potency152 (Table 1). A similar approach for simultaneously targeting a Targeting IL-6 has shown efficacy in the treatment of B cell inhibitory receptor and a B cell surface receptor several autoimmune diseases. This cytokine is produced to modulate B cell function makes use of a bispecific by a variety of leukocytes and promotes the differentiation antibody platform termed dual-​affinity retargeting of CD40-activated B cells into plasma cells155. The concen- mole­cules (DARTs). DARTs target two molecules by tration of IL-6 is increased in the serum and syno­vial tis- linking together single-​chain variable fragments derived sue of patients with RA as well as in the serum of patients from two different monoclonal antibodies. One DART with other inflammatory diseases including Crohn’s therapy that is currently being developed (MGD010) disease, SLE and multiple sclerosis156. The downstream targets FcγRIIb and Igβ on B cells in an effort to disrupt inflammatory effects of IL-6 can be offset by treatment BCR signalling140. This molecule is in early-phase​ clini- with conventional therapies including corticosteroids cal trials141 and might be developed for RA or other dis- and NSAIDs. However, antibodies that directly block ease indications for which B cells and/or autoantibodies the actions of IL-6 are also available. Both tocilizumab, contribute to disease pathogenesis. Overall, antibody-​ a humanized anti-​IL-6R monoclonal antibody, and based constructs are an attractive approach for target- sarilumab, a fully human anti-​IL-6R monoclonal anti- ing B cell activity, as they can be highly engineered and body, are approved for the treatment of RA, whereas customized for bioactivity and biocompatibility using additional IL-6-targeting therapies are showing promise the growing antibody knowledge base. in clinical trials for various other autoimmune diseases156. Finally, the inhibition of signalling molecules JAKs mediate signalling by the IL-6R and many involved in B cell activation is being pursued as a strat- other cytokine receptors. Small-​molecule inhibitors egy to abrogate B cell activation in autoimmune disease. of JAKs are available, such as tofacitinib and baric- Following BCR engagement, the tyrosine kinase BTK itinib157, that block the effects of these pro-inflammatory​ initiates intracellular signalling networks that result in cytokines158,159. JAK inhibition is an effective strategy in Single-chain​ variable B cell activation. Ibrutinib is a small-molecule​ drug that the treatment of RA and other autoimmune diseases160, fragments covalently binds BTK to inhibit its function, resulting which is possibly in part dependent on the inhibition of Single polypeptide fusion in B cell apoptosis. This inhibitor is FDA-​approved for IL-6-mediated B cell survival, maturation and activation. proteins of the variable regions 109,142 of the heavy and light chains of the treatment of B cell malignancies , and next-​ Indeed, blockade of JAK1-mediated and JAK3-mediated 161,162 an antibody connected by a generation BTK inhibitors are being developed for the signalling with tofacitinib inhibits B cell activation . peptide linker. treatment of multiple autoimmune diseases, including Additional JAK inhibitors are being developed to treat

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malignancy and/or autoimmunity, many of which are both T cells and B cells172–174, and although anti-​PD1 being engineered to have a greater specificity for specific therapy is known to promote antitumour T cell responses JAK family members. in patients with cancer175, this strategy could potentially Molecules that target IL-21 are under development also promote antitumour B cell responses. As blockade for the treatment of autoimmunity owing to its function of these inhibitory receptors has proved revolu­tionary in driving T cell-dependent​ B cell maturation. NNC114- for the treatment of cancer, activating the same targets 0005 (also known as NNC0114-0006)163–165 is an anti-​ might be useful for inducing tolerance in the context of IL-21 neutralizing monoclonal antibody in phase II autoimmunity. Many of the proteins targeted by check- clinical trials for the treatment of RA. Moreover, JAK point immunotherapy on T cells and NK cells are also inhibitors such as tofacitinib also interfere with IL-21 sig- expressed on B cells, where they regulate B cell func- nalling, as JAKs mediate signalling events downstream tions that contribute to autoimmunity. Therefore, tar- of IL-21–IL-21 receptor binding. geting these inhibitory checkpoints could enable a more Other FDA-​approved therapeutics for autoimmune fine-​tuned approach to modulating B cell responses disease might also exert their beneficial effects by inhib- and reducing their pathogenic cellular activities104,176–178. iting B cells or their effector functions. For example, The field is also working to develop molecules that natalizumab, a humanized monoclonal antibody against target specific pathogenic B cell subsets or functions, α4 integrin (CD49d), inhibits leukocyte trafficking and such as antigen presentation or antibody production, to is FDA-​approved for the treatment of multiple sclero- minimize unnecessary immunosuppressive effects and sis and Crohn’s disease166–168. Although the beneficial to maximize their potency in restricting autoimmun- effects of natalizumab treatment are widely thought to ity. In the future, autoantigen-​specific B cell-​tolerizing be caused by blockade of T cell trafficking, this anti- therapies might also be developed to precisely target body also inhibits B cell trafficking, which might also pathogenic B cells. contribute to its efficacy169,170. Conclusions Future therapeutic prospects Multiple B cell effector functions contribute to the Although several targeted therapies for autoimmune dis- pathogenesis of autoimmune disease, and target- eases currently exist, therapies that target more special- ing the checkpoints that control B cell activation has ized subsets of B cells such as activated or autoreactive therapeutic potential. Compared with anti-​CD20 B B cells could have improved efficacy and a lower risk of cell-​depleting therapeutics, emerging efforts are using adverse effects. Several monoclonal antibody therapies mechanistically informed strategies to target B cells to that target subsets of B cells, such as targeting of CD138+ combat disease in a more precise manner. Targeting B cells by indatuximab ravtansine, and factors that pro- B cell activation and effector functions, rather than mote B cell activation, such as IL-21, are in develop­ broadly depleting B cells, has the potential to control ment124. Dual-​targeting strategies with engineered autoimmunity without broad immunosuppression. bispecific proteins also hold promise. Such approaches might leverage newly developed Therapies that block inhibitory checkpoint proteins tools including bispecific or trispecific antibody engi- on T cells, such as PD1 and CTLA4, to promote immune neering179, cell-​targeting therapies180,181 or other next-​ responses are being used to treat patients with cancer. generation biologic therapeutics. In the future, these The use of these treatments can result in secondary auto- strategies could be used to target specific pathogenic immune complications, suggesting that these inhibitory B cell subpopulations or B cell responses. checkpoints could potentially be targeted with agonists to treat autoimmunity171. Notably, PD1 is expressed on Published online xx xx xxxx

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