Antibody B cell checkpoints in autoimmune SamuelJSRubin MichelleSBloom and WilliamHRobinsonAbstract B cells have important functions in the pathogenesis of autoimmune diseases including ID: 936993
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B cells are multifunctional lymphocytes that contribute to the pathogenesis of autoimmune diseases via B cell-intrinsic, antibody-mediated and T cell-dependent mechanisms. Although antibody production by B cells promotes both mediated cytotoxicity(ADCC) and dependent cytotoxicity (CDC), B cells can also present antigen and provide T cell help. B cell activation and effector functions are regulated by immune checkpoints, including activating and Antibody- B cell checkpoints in autoimmune Samuel J. S. Rubin, Michelle S. Bloom and William H. RobinsonAbstract 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 D [ | K O O W P G E J G E M R Q K P V U K P E N W F K P I D Q V J C E V K X C V K P I C P F K P J K D K V Q T [ E J G E M R Q K P V T G E G R V Q T U V J C V E Q P V T K D W V G V Q V J G T G I W N C V K Q P Q H $ E G N N V Q N G T C P E G C E V K X C V K Q P C P V K I G P R T G U G P V C V K Q P 6 | E G N N J G N R E N C U U | U Y K V E J K P I C P V K D Q F [ R T Q F W E V K Q P C P F E [ V Q M K P G R T Q F W E V K Q P 6 J G X C T K Q W U C E V K X C V K P I E J G E M R Q K P V presentation, T cell help, cytokine secretion and potentially other processes. Further, we discuss the mechanisms of B cell activation by antigen and co-receptor ligands, as well as B cell regulatory networks governed by inhibitory receptors. Finally, we present an overview of current and next-generation therapeutic strategies for targeting B cells and B cell checkpoints for the treatment of autoimmune rheumatic diseases.B cell functions including autoantibody production, antigen presentation, T cell help and cytokine production all contribute to the pathogenesis of autoimmune diseases . As a result of the growing appreciation of these functions in self-tolerance and the mechanisms by which they contribute to autoimmunity, next-generation therapeutic approaches are focusing on specifically modulating B cell activation and effector mechanisms rather than globally depleting B cells.The classic paradigm of B cell-mediated autoimmune disease centres around production of autoantibodiesThere are multiple mechanisms by which autoantibodies contribute to the pathogenesis of autoimmune disease. First, immune complexes can form or deposit in tissues where they can activate complement and induce CDC to cause tissue damage. For example, in a mouse model of lupus nephritis, blockade of B cell co-stimulation in combination with cyclophosphamide treatment reduced immune complex deposition and glomerulonephritis and preserved renal function. RA is associated with the production of rheumatoid factor, autoantibodies that bind the Fc region of IgG, and anti-citrullinated protein antibodies (ACPAs). In RA, both rheumatoid factor-containing and ACPA-containing immune complexes activate complement pathways in joints, leading to the production of C5a and the generation of the membrane attack complex (MAC), which both contribute to joint damage; IgM rheumatoid factor can also increase complement activation mediated by ACPA-containing immune complexes23. Second, autoantibodies can promote tissue damage via ADCC by co-engagement of antigens on the target tissue and Fc receptors (FcRs) on macrophages, neutrophils, natural killer (NK) cells and other effector cell types. For example, lupus-prone mice with mutations in the IgG FcR that abrogate effector cell engagement had reduced glomerulonephritis and improved renal outcomes. Third, autoantibody-containing immune complexes can also activate immune cells through dual engagement of FcRs and Toll-like receptors (TLRs) (on macrophages and dendritic cells) or dual engagement of the B cell receptor (BCR) and TLRs (on B cells; as discussed in a later section). For example, ACPAs, a hallmark of RA, form immune complexes with citrullinated proteins that can stimulate macrophages via dual engagement of the FcR and TLR4 to produce pro-inflammatory cytokines. IgG rheumatoid factor can crosslink immune complexes to potentiate citrullinated antigenimmune complex-mediated macrophage activation and cytokine production. Finally, immune complexes facilitate antigen loading onto dendritic cells via immune complexes, enabling these cells to efficiently activate T cells2830. Together, these examples illustrate the diverse mechanisms through which autoantibodies contribute to pathologies seen in autoimmune disease. 6 | E G N N s $ E G N N K P V G T C E V K Q P UAlthough autoantibody production is widely implicated in the pathogenesis of autoimmune diseases, pathological interactions between B cells and T cells can also contribute to autoimmunity. B cells are one of a few cell types that can function as professional APCs through constitutive expression of MHC class II molecules. Although dendritic cells are thought to be the primary initiators of naive CD4 T cell responses, B cells can also interact with and activate CD4 T cells via MHC class II-mediated antigen presentation, and CD4 T cells, in turn, provide help to cognate B cells. During an immune response, naive CD4 T cells are primed by antigen-presenting dendritic cells and subsequently differentiate into T helper cell subsets including T follicular helper ) cells. In the germinal centre, T cells interact with cognate B cells to promote isotype switching and somatic hypermutation, as well as B cell differentiation into memory B cells and plasma cellsDysregulated antigen presentation is implicated in the pathogenesis of autoimmunity. For example, some HLA-DRB1 alleles can bind citrullinated peptides33and are associated with the development of RAFurthermore, other HLA class I and class II alleles have been associated with susceptibility to systemic lupus erythematosus (SLE) and ankylosing spondylitisPathological T cellB cell interactions are also implicated by the presence of ectopic lymphoid structures in inflamed tissues (for example, in the synovium in RA), as well as by evidence of autoantibody affini
ty maturationFor example, in mouse models of SLE, antinuclear antibodies (ANAs) undergo somatic hypermutation to become high-affinity (and hence, highly pathogenic) autoantibodies. Additionally, ACPAs and rheumatoid factor from patients with RA show signs of somatic hypermutation, implicating the involvement of affinity maturation in RA pathogenesisIn addition to B cellT cell interactions, interactions between B cells and other cells can be dysregulated in autoimmunity. For example, a distinct T cell population Key pointsey pointsþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; E C Pþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; R T Q F W E G R T Q H G U U K Q P C N R T G U G P V K P I R T Q F W E G Q F W E G r $þÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; E G N N Uþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; G Z R T G U U T G E G R V Q T U G E G R V Q T Uþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; T G E G R V Q T U T G I W N C V G T G E G R V Q T U T G E G R V Q T 6 Q N N T G E G R V Q T U G E G R V Q T U þÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; T G E G R V Q T U G E G R V Q T U þÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; T G E G R V Q T U G E G R V Q T U þÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; T G E G R V Q T U G E G R V Q T Uþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; K O O W P Q I N Q D W N K P þÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; þÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; ( E T G I K Q P T G E G R V Q T \n ( E R T Q I T C O O G F T G E G R V Q T U V T C P U O K V C P U O K Vþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; U K I P C N Uþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; V Qþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; $þÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; E G N N U r 8 C T K Q W U V C T I G V K P I U V T C V G I K G U V T G C V O G P V R T Q Q þÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; E [ V Q M K P G U þÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; V T K I I G T K P Iþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; Q Hþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; $þÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; E G N Nþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; K P J K D K V Q T [þÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; E J G E M R Q K P V Uþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; C P Fþÿ &#x/Act;&#xualT;xt0;&#x/Act;&#xualT;xt0; V T C H H K E M K P I Fc regionThe tail region of an antibody, containing two heavy chain constant domains, that interacts with Fc receptors (FcRs) to mediate immune cell effector functions.Ectopic lymphoid structureslso known as tertiary lymphoid structures; organized aggregates of lymphocytes and other cells that possess some features of germinal centres. These structures can develop in chronically inflamed nonlymphoid tissues such as the synovium in rheumatoid arthritis.Affinity maturation process in the germinal centre by which cells, following interaction and activation by follicular helper T cells, undergo immunoglobulin gene mutation and subsequent selection to generate cells that express antibodies with increased affinity for the target antigen. that can augment B cell responses in nonlymphoid tissue (referred to as peripheral T helper cells) is expanded in the synovium of patients with RA. In addition, in RA, fibroblast-like synoviocytes can interact with and provide pro-survival factors to B cellsTogether, these findings suggest the important involvement of B cellT cell interactions in autoimmunity. Thus, targeting these interactions could be effective for preventing the development and progression of autoimmune diseases. % [ V Q M K P G R T Q F W E V K Q PIn addition to autoantibody production and antigen presentation, B cells can regulate immune responses through the production of cytokines. B cells can produce pro-inflammatory cytokines such as IFN , IL-6 and IL-2 as well as anti-inflammatory cytokines such as IL-10 and IL-4 . Multiple sclerosis, in particular, involves perturbations in cytokine production by B cells, but B cell-mediated cytokine secretion is also perturbed in other autoimmune diseases such as SLE and RAThe production of IL-6 and IFN by B cells is required for spontaneous germinal centre formation and T cell differentiation in a mouse model of SLE, and this process probably also occurs in other autoimmune diseases (for example, IFN -expressing B cells are expanded in multiple sclerosis). B cell-derived IL-6 can promote B cell proliferation as well as exert pleiotropic effects on T cells and other cell types (reviewed elsewhere). Thus, therapeutically targeting B cells could prevent loss of tolerance in both B cells and T cells as well as reduce inflammatory responses that can promote autoimmunity.In contrast to pro-inflammatory B cell responses, regulatory B (Breg) cells are characterized by the production of anti-inflammatory cytokines such as IL-10, TGF and IL-35. IL-10-producing Breg cells (so-called B10 cells) have important protective functions against the development of autoimmunity, including in mouse models of autoimmunity and in multiple sclerosis, SLE and RA. TGF is produced by some Breg cells and can also modulate T cell activity. Additionally, in 2014, researchers described a population of IL-35-expressing Breg cells that can suppress autoimmunityHow Breg cells mediate their suppressive functions is not fully understood, and additional work is needed to fully define their developmental paths and regulatory functions in immune responses as well as the mechanisms by which they can suppress autoimmunity (reviewed elsewhere). Understanding these mechanisms could facilitate development of B cell-modulating therapies for the treatment of autoimmune rheumatic disease.B cell activationB cell activation is important for adaptive immune responses and is regulated by key stimulatory and inhibitory checkpoints. B cell inhibitory checkpoints serve to both inhibit activation of autoreactive B cells and dampen overstimulated responses . For non-polyvalent antigens, two signals are required for the activation of B cells: the engagement of the BCR and stimulatory signal. Anti
gen binding to the BCR defines the specificity of the B cell response, whereas stimulatory functions are important for overcoming inhibitory checkpoints.Throughout the development of B cells, both positive and negative selection via the BCR shape the mature B cell repertoire and reduce reactivity to autoantigens. Early in the development of B cells, autoreactive B cells in the bone marrow undergo the process of negative selection that involves receptor editing and/or cell deletion. The detection of extraneous autoreactive naive B cells in both SLE and RA indicates that dysregulation of these central tolerance mechanisms contributes to autoimmunity. Once B cells migrate to the periphery, additional inhibitory checkpoint pathways ensure that residual autoreactive B cells are eliminated or silenced, whereas co-stimulatory signals ensure that only B cells with non-autoreactive BCRs are activated. Many of these stimulatory and inhibitory checkpoint pathways function indirectly to control the survival, proliferation and activation of B cells. Ongoing studies by multiple groups aim to further define and characterize the effect of individual stimulatory and inhibitory checkpoints on antigen presentation, antibody production, co-stimulation, reg cell activity and other B cell functions.In addition to extrinsic regulatory signals, conformational changes in the BCR are also required to activate B cells. There are two predominant models for how antigen binding and BCR oligomerization mediate the activation of B cells. The conformation-induced model posits that activation occurs via crosslinking of multiple BCRs on the B cell membrane, which then triggers downstream signalling. The dissociation activation model alternatively suggests that unstimulated BCRs reside in auto-inhibited oligomers on the B cell membrane and that these structures are inaccessible to the kinases involved in B cell activation. Antigen binding promotes the opening of clustered BCR oligomers, enabling access to these kinases and downstream signalling (reviewed elsewhere). Regardless of these models, B cell CD28MHCclass IITCRCD80 or AutoreactiveAutoreactive Autoantibodies Autoantigen Autoantibodyproduction Co-stimulation production Antigenpresentation ( K I The functions of B cells in autoimmune disease. Central B cell functions, K P E N W F K P I C P V K D Q F [ R T Q F W E V K Q P C P V K I G P R T G U G P V C V K Q P C P F 6 | E G N N J G N R X K C E Q U V K O W N C V K Q P and/or cytokine secretion, can all contribute to the pathogenesis of autoimmune F K U G C U G U $ % 4 $ E G N N T G E G R V Q T 6 % 4 6 | E G N N T G E G R V Q T activation by either model is dependent on non-covalent interactions between the BCR and the invariant Ig and Ig chains (also known as CD79A and CD79B). These chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) that, upon antigen engagement of the BCR, are phosphorylated by the tyrosine kinase LYN. Downstream activation signals are then amplified and relayed by the SYK and BTK kinases (reviewed elsewhere). Thus, BCR activation is mediated by activating co-receptors and their associated kinases, which requires overcoming constitutive inhibitory signals from inhibitory co-receptors. $ E G N N U V K O W N C V Q T [ R C V J Y C [ UB cell stimulatory checkpoints are important in the regulation of B cell activation. These stimulatory checkpoints consist of numerous cytokines, cytokine receptors, other cell surface receptors and downstream signalling pathways. Cognate T cells promote B cell and plasma cell differentiation by providing co-stimulatory signals in the form of CD40 ligand (CD40L; also known as CD154). These cognate T cells are reciprocally activated by engagement of CD40L with CD40 on the surface of B cells (reviewed elsewhere). CD40, a member of the TNF receptor (TNFR) family, is expressed by a variety of immune cells, including B cells, but also by other cells such as platelets. Without co-stimulation via CD40 or other receptors, BCR triggering can lead to apoptosis of the B cell instead of B cell activation. The inability of B cells to be activated without CD40-mediated co-stimulation serves as a checkpoint to prevent the maturation of autoreactive B cells. However, the breakdown of tolerance to self-antigens in autoimmune diseases can be mediated by B cellT cell interactions, as exemplified in one study that found that CD40 signalling in B cells is required for the development of SLE-like disease in mice and is also probably an important contributor to 6 C D N G Approved and advanced development therapeutics that could be used to target B cells in autoimmunity TargetFormatsclerosisB cell depletionMonoclonal antibodyApprovedlabel uselabel useApprovedOcrelizumabMonoclonal antibodyApprovedMonoclonal antibodyMonoclonal antibodyApprovedApprovedDaratumumabMonoclonal antibodyApprovedIndatuximab ravtansineChimeric monoclonal ApprovedB cell activation or activity modulation % & C P F ( E G P I K P G G T G F monoclonal antibodyPhase I and phase IIPhase II C P F ( EDARTPhase IMonoclonal antibodyPhase IPhase IIDapirolizumab pegol 2 G I [ N C V G F ( C D H T C I O G P VPhase IIMonoclonal antibodyPhase IMonoclonal antibodyPhase IEpratuzumabMonoclonal antibodySmall moleculeApprovedSmall moleculeApprovedInhibition of cytokines or cytokine signallingMonoclonal antibodyApproved $ # ( ( C P F # 2 4 + . 6 # % + C P F J W O C P + I ) ( E fusion proteinPhase IIIPhase IITocilizumabMonoclonal antibodyApprovedMonoclonal antibodyPhase I , # - C P F , # - TofacitinibSmall moleculeApprovedPhase I and phase II , # - C P F , # - Small moleculeApprovedPhase IIITrafficking blockade + P V G I T K PMonoclonal antibodyPhase IIApproved 5 J Q Y P C T G C W V Q K O O W P G K P F K E C V K Q P U H Q T T J G W O C V Q K F C T V J T K V K U \n 4 # U [ U V G O K E N W R W U G T [ V J G O C V Q U W U \n 5 . ' C P F Q T O W N V K R N G U E N G T Q U K U C N V J Q W I J U Q O G Q H V J G U G K P V G T X G P V K Q P U J C X G D G G P C R R T Q X G F H Q T Q V J G T F K U G C U G U C U Y G N N # R R T Q X G F C P F K P X G U V K I C V K Q P C N U V C V W U G U T G H G T
V Q V J G 7 5 C P F ( & # T G I K U V G T G F E N K P K E C N V T K C N U # 2 4 + . C R T Q N K H G T C V K Q P K P F W E K P I N K I C P F $ # ( ( $ E G N N C E V K X C V K P I H C E V Q T % & . % & N K I C P F & # 4 6 F W C N C H H K P K V [ T G V C T I G V K P I O Q N G E W N G ( E 4 + + D N Q Y C H H K P K V [ K O O W P Q I N Q D W N K P ( E T G I K Q P T G E G R V Q T + + D + . 4 + . T G E G R V Q T , # - , C P W U M K P C U G 2 + - R J Q U R J Q K P Q U K V K F G M K P C U G ; TACI, transmembrane activator and calcium modulator. autoimmunity in humans. Consistent with this finding, CD40L is upregulated on T cells in multiple autoimmune diseases including SLE, RA and multiple sclerosis, and soluble CD40L levels correlate with autoantibody titres and disease activityToll-like receptors. As an alternative to CD40-mediated stimulation of BCRs, B cells can be activated independently of T cells via dual stimulation of the BCR and TLRs. TLRs recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) that are important for host defence and wound healing (FIG. . Bacterial or viral PAMPs, such as lipopolysaccharide (LPS), double-stranded RNA or virus-like particles, can be detected by both the BCR (on antigen-specific B cells) and TLRs. Cell surface TLRs can engage ligands residing on the surface of the pathogen simultaneously with the BCR, whereas lysosomal TLRs can interact with RNA, DNA and other intracellular ligands upon internalization and digestion of pathogens or pathogen debris following interaction with the BCR. Thus, engagement of BCRs by bacterial or viral structures in an antigen-specific manner and simultaneous engagement of TLRs in a PAMP-specific manner leads to activation of B cellsTLRs are also capable of binding self-ligands or DAMPs, which can promote protective and reparative responses as well as pathogenic autoimmune responses under certain conditions . Intracellular components, such as DNA and RNA, can be exposed during cell death and tissue damage and can then interact with TLRs on B cells. Although these components are normally cleared by macrophages, interactions with antibodies can lead to the accumulation and stabilization of these self-antigens. The resultant immune complexes can simultaneously activate TLRs and BCRs, lowering the receptor engagement threshold needed for B cell activationIn 2002, TLRs were noted to contribute to autoimmune B cell activation in an in vitro system, in which dual stimulation of TLR9 and the BCR by self-DNA-containing immune complexes led to autoimmune B cell activation (in this case, the activation of rheumatoid factor-positive B cells). This observation provided a mechanistic model to explain the production of rheumatoid factor; in this model, engagement of the BCR on rheumatoid factor-positive B cells with the Fc domain of an antibody also bound to a TLR ligand (such as DNA, RNA or fibrinogen) leads to dual stimulation and activation of the B cell. In addition, TLR9, TLR7 and TLR8, which bind viral single-stranded RNA (ssRNA), have also been implicated in the development of autoimmunity. For instance, immune complexes containing ssRNA or RNA-binding proteins (such as small nuclear ribonucleoproteins (snRNPs), Sm, Ro, La and transfer RNA synthetases) can stimulate rheumatoid factor-positive B cells upon dual engagement of TLR7 and the BCR. B cells that directly bind TLR ligands, or RNA-binding proteins that bind TLR ligands via their BCR, might also be activated in a similar fashion. Dual stimulation of TLRs and BCRs probably contributes to autoantibody production in, and to the pathogenesis of SLE, myositis, Sjögren syndrome and other autoimmune rheumatic diseases in which autoreactive B cells and autoantibodies target proteins or molecular complexes containing DNA or RNA In addition to co-stimulation by CD40 or dual stimulation by TLRs, B cell activation can be facilitated by the activation of the co-receptor CD19. CD19 is an immunoglobulin superfamily glycoprotein associated BCR Antigen C3d Ig Ig BAFFR CD40LCD40 BAFF IL-6RIL-21IL-21R IL-6 PAMP TLR CD19CD21 MHC LAIR1 Fc RIIbIgG CD22 a Stimulatory checkpointsB cellOther cellb Inhibitory checkpoints Collagen ( K I B cells express a repertoire of stimulatory and K P J K D K V Q T [ T G E G R V Q T U V J G T G N C V K X G N G X G N U Q H Y J K E J E J C P I G V J T Q W I J V J G E Q W T U G Q H $ E G N N F G X G N Q R O G P V $ E G N N H W P E V K Q P U C T G modulated by the balance of expression and colocalization of stimulatory checkpoint receptors (part ) and inhibitory checkpoint receptors (part 5 Q O G 6 Q N N N K M G T G E G R V Q T U \n 6 . 4 U C T G C N U Q G Z R T G U U G F K P V J G G P F Q U Q O G $ # ( ( $ E G N N C E V K X C V K P I $ # ( ( 4 $ E G N N C E V K X C V K P I H C E V Q T T G E G R V Q T $ % 4 $ E G N N T G E G R V Q T % & . % & N K I C P F % ' # % # / E C T E K P Q G O D T [ Q P K E T G N C V G F E G N N C F J G U K Q P O Q N G E W N G & # / 2 F C O C I G C U U Q E K C V G F O Q N G E W N C T R C V V G T P ( E 4 + + D N Q Y C H H K P K V [ ( E T G I K Q P T G E G R V Q T + + D + . 4 + . T G E G R V Q T + . 4 + . T G E G R V Q T . # + 4 N G W M Q E [ V G C U U Q E K C V G F N K M G T G E G R V Q T . + 4 N G W M Q E [ V G K O O W P Q I N Q D W N K P N K M G T G E G R V Q T 2 # / 2 R C V J Q I G P C U U Q E K C V G F O Q N G E W N C T R C V V G T P 2 & R T Q I T C O O G F E G N N F G C V J with the BCR and is expressed on B cells from the pre-B cell stage through to the plasma cell differentiation stage. CD19 signals though the tyrosine kinases LYN and phosphoinositide 3-kinase (PI3K), which amplify signals from the BCR, decreasing the threshold for BCR activation. CD19 is an integral feature of the BCR signalling complex and is important for B cell activation. Both CD19 and the BCR are needed for B cell activa
tion, whereas stimulation of either receptor alone leads to B cell apoptosisInterestingly, investigators have identified a unique population of CD19 B cells in patients with SLE or pemphigus, although the function of these cells in disease requires further investigation. Thus, CD19 is a potential immunomodulatory therapeutic target, in addition to CD20 and other B cell antigens, for the treatment of autoimmune diseasesBAFF. B cell activating factor (BAFF; also known as TNFSF13B) is a cytokine that belongs to the TNF family and can facilitate B cell activation indirectly by promoting B cell survival, proliferation and/or differentiation. BAFF is produced by various types of immune cells including follicular dendritic cells and monocytes and can influence B cell populations through interactions with three different receptors: transmembrane activator and calcium modulator (TACI; also known as TNFRSF13B), the predominant BAFF receptor on splenic transitional type 2 and marginal zone B cells; B cell maturation antigen (BCMA; also known as TNFRSF17), the predominant BAFF receptor on germinal centre B cells; and BAFF receptor (BAFFR), the predominant BAFF receptor on peripheral B cellsSimilar to some other cytokines, BAFF facilitates T cell co-stimulation of B cells by functioning as a pro-survival factor rather than by providing a traditional 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 sufficient signals to become activated. Thus, in autoimmunity, BAFF can increase the overall numbers of autoreactive B cells and/or outweigh peripheral tolrance mechanisms by predisposing B cells to receive activation signalsBAFF concentrations are often increased in the serum of patients with SLE or other autoimmune conditionsFor example, serum concentrations of BAFF correlate with anti-double-stranded DNA (dsDNA) antibody titres in patients with SLE. Furthermore, a variant in the BAFF-encoding gene, TNFSF13B, is strongly associated with multiple sclerosis and SLE. This variant encodes a truncated mRNA, which escapes microRNA-mediated inhibition, leading to increased production of the BAFF protein. Belimumab, a human IgG1 monoclonal antibody that targets BAFF, is an effective treatment for patients with SLE who are autoantibody positiveIL-6. The cytokine IL-6 was originally identified as a B cell growth factor and plasma cell differentiation factor, 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 macrophagesmacrophages increase their IL-6 production as a result of feedforward processes in response to FcR engagement by IgG antibodies85. In RA, increased IL-6 serum concentrations correlate with joint damage, probably because of the involvement of IL-6 in promoting osteoclastogenesis. Blockade of IL-6 with tocilizumab, a humanized monoclonal antibody against the IL-6 receptor (IL-6R), leads to improved radiographic outcomes in patients with RA. In SLE, B cell-derived IL-6 can drive autoimmune GC formation by promoting T helper cell differentiation and IL-21 production, which in turn can lead to B cell growth and differentiation. Preliminary studies of IL-6 blockade in patients with SLE, however, have shown minimal beneficial effectsIL-21. The cytokine IL-21 is produced by multiple T helper cell subsets and has critical functions in B cell activation, proliferation, differentiation, affinity maturation and antibody production. IL-21 drives pro-inflammatory responses by promoting B cell activation and expansion, and patients with SLE, type 1 diabetes or inflammatory bowel diseases have increased serum concentrations of IL-21 compared with healthy individuals. In germinal centres, T cell-derived IL-21 regulates class switching to IgG, IgA and IgE in B cells through the activation of activation-induced cytidine deaminase (AID) and promotes differentiation of activated B cells into memory B cells and plasma cellsBlockade of IL-21 consequently results in decreased T cell-induced B cell proliferation, differentiation and B cellBCRIg Ig RBPRNA Internalized NF- NF- MYD88 PAMP Internalized ( K I B cell activation via dual stimulation by antigens. During an immune response to an infection, the simultaneous engagement of the B cell receptor (BCR) and 6 Q N N N K M G T G E G R V Q T U \n 6 . 4 U Q P $ E G N N U D [ D C E V G T K C N Q T X K T C N U V T W E V W T G U \n R C V J Q I G P C U U Q E K C V G F molecular patterns (PAMPs)) or by damage-associated molecular patterns (DAMPs) can lead to B cell activation. In some autoimmune diseases, autoantigens can dual U V K O W N C V G $ E G N N U V J T Q W I J 6 . 4 U C P F V J G $ % 4 6 J G G Z C O R N G R T Q X K F G F K U H Q T U [ U V G O K E N W R W U G T [ V J G O C V Q U W U \n 5 . ' K P Y J K E J $ E G N N U V J C V T G E Q I P K \ G 4 0 # D K P F K P I R T Q V G K P U \n 4 $ 2 U V J T Q W I J V J G K T O G O D T C P G D Q W P F $ % 4 D K P F C P F E Q K P V G T P C N K \ G 4 $ 2 U C N Q P I Y K V J V J G K T C U U Q E K C V G F T K D Q P W E N G K E C E K F U C P F V J G T K D Q P W E N G K E C E K F U V J G P D K P F 6 . 4 K P V J G G P F Q U Q O G U 5 K O K N C T examples are found in other autoimmune diseases. antibody secretion. Interestingly, IL-21 also prevents nonspecific B cell activation by promoting apoptosis in B cells that receive signals through the BCR and/or TLRs but that do not receive T cell co-stimulatory signalsThus, as IL-21 contributes to B cell function through multiple mechanisms, targeting IL-21 might be valuable as a broad treatment for autoimmune diseases that stem from dysregulated B cell function at various stages of development and/or activation. $ E G N N K P J K D K V Q T [ R C V J Y C [ UDuring B cell development and maturation, inhibitory checkpoints balance activating signals to ensure central tolerance CD22 is important for regulating B cell activation in response to self-antigens. This molecule is a transmembrane receptor and member of the sialic binding immunoglobulin-like lectin family. CD22 binds 2,
6-linked sialic acids found on the surfaces of eukaryotic but not bacterial cells. The receptor is constitutively associated with the BCR and contains three cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs), which are phosphorylated upon ligand binding in conjunction with BCR-antigen bindingSubsequently, recruitment of the phosphatases SHIP1 and SHP1 inhibits signalling downstream of the BCR. This inhibition is thought to modulate the BCR activation threshold to prevent B cell activation in response to self-antigensRIIb. The low-affinity immunoglobulin- Fc region receptor IIb (Fc RIIb) is the only inhibitory FcR and the only FcR expressed by B cells; this molecule is crucial for restricting antibody-mediated immune responsesAfter binding of the IgG Fc region to the extracellular domain of Fc RIIb, its single intracellular ITIM domain is phosphorylated by BCR-associated kinases; subsequent recruitment of the SHIP1 phosphatase inhibits signalling downstream of the BCR and destabilizes the BCR complex101. This process is thought to modulate immune responses when antigens saturated with IgG antibodies in immune complexes trigger Fc RIIb in conjunction with the BCR. As a result, Fc RIIb is thought to help prevent autoimmunity, and mutations at its genetic locus have been associated with RA, SLE and multiple sclerosis in human genome-wide association studies and mouse studiesOther inhibitory receptors. Polymorphisms in genes encoding other inhibitory receptors expressed by B cells, including CD5, CD72, leukocyte immunoglobulin-like receptor 1 (LIR1; also known as CD85j) and programmed cell death 1 (PD1), have also been associated with autoimmunity96102. B cells express additional inhibitory receptors, including carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and leukocyte-associated immunoglobulin-like receptor 1 (LAIR1). These receptors, along with other, less-well understood molecules, contribute to the maintenance of B cell tolerance during development and in the periphery. These receptors provide additional targets for future B cell-modulating therapeutics as our understanding of their mechanism(s) continues to improve.Therapeutic approachesB cell depletion with the B cell-depleting anti-CD20 antibody, rituximab, is currently the therapeutic approach most widely used to target B cells. The finding that B cell dysregulation contributes to autoimmune diseases has inspired the development of novel, mechanistically informed treatments. A number of both B cell-depleting antibodies, such as anti-CD138 and anti-CD38, and small-molecule kinase inhibitors, such as Janus kinase (JAK), SYK and BTK inhibitors, hold promise for the treatment of autoimmune disease (TABLE . However, these nonspecific strategies result in broad immune suppression, which increases the risk of infectious complications and other adverse events. The shortcomings of these therapies have led to new efforts focused on the development of approaches that engage B cell inhibitory or other checkpoint pathways in a specific manner . Ongoing strategies for the development of therapeutics to treat autoimmunity include antibody-based B cell depletion, small-molecule kinase inhibition, antibody-based blockade of B cell activating receptors and antibody-based induction of B cell inhibitory signals $ E G N N F G R N G V K P I V J G T C R K G UCell depletion was an initial approach used to target B cells for the treatment of autoimmune disease. The B cell-depleting anti-CD20 antibody rituximab is FDA-approved for the treatment of RA. Although not approved for multiple sclerosis and having failed trials in SLE, rituximab is also used off-label for the treatment of these diseases on the basis of clinician experience. In addition, ocrelizumab, a humanized anti-CD20 monoclonal antibody, was approved in 2017 for the treatment of multiple sclerosis. Clinical studies have shown some efficacy of ocrelizumab in treating SLE114although concerns over adverse events have halted clinical trials for SLE and RA, and future studies will probably demonstrate its utility in other B cell-mediated diseases. Despite depleting only B cells that express CD20, which is downregulated by antibody-secreting cells, these antibody therapies are thought to function by targeting precursors to these antibody-secreting B cells and/or B cells with antigen-presenting or other pathogenic functions.Given that many antibody-secreting B cells, including plasmablasts and plasma cells, lack CD20 but retain CD19 expression, CD19-targeting therapies that are being developed for B cell malignancies are also being explored as therapeutics for autoimmune diseases. Inebilizumab, a humanized monoclonal anti-CD19 antibody that is afucosylated for increased ADCChas shown promising results in multiple mouse models of autoimmunity and early-phase clinical trialsFurthermore, in clinical trials in multiple sclerosis and other diseases, inebilizumab treatment resulted in considerable depletion of plasma cells. However, CD19 expression is absent on a subset of plasma cells in the bone marrow that are known to contribute to autoantibody production. Thus, these CD19-targeting therapies might miss subsets of cells that produce autoantibodies and contribute to the pathogenesis of autoimmune diseases. Further studies regarding the efficacy of CD19-targeting therapies are ongoingAlemtuzumab is an anti-CD52 monoclonal antibody that depletes T cells, B cells and macrophagesThe efficacy of alemtuzumab, which is FDA-approved for the treatment of multiple sclerosis, is potentially high because of its B cell-depleting properties. However, alemtuzumab is also associated with a high rate of serious adverse events, probably because the treatment results in depletion of such broad leukocyte populations.Antibodies that target other molecules expressed by B cells including CD38 (daratumumab124), CD138 (indatuximab ravtansine), and other surface receptors are undergoing clinical development. Daratumumab and indatuximab ravtansine are currently being investigated for their efficacy in treating patients with multiple myeloma but could have potential in treating autoimmune disease. 6 C T I G V K P I $ E G N N E J G E M R Q K P V UThe risks associated with systemic depletion of B cells have led to the developmen
t of therapies that modulate, rather than deplete, B cells.One approach for therapeutically modulating B cell activation is the disruption of CD40CD40L interactions. Despite initial promising results from clinical trials of the anti-CD40L antibodies toralizumab, BG9588 and ABI793 in SLE, thromboembolic events, caused by engagement of CD40L expressed on platelets, have hampered this approach. Nevertheless, next-generation antagonists for CD40CD40L are now in the JAKs BTK IL-6RTACIreceptor4 Integrin Tofacitinib andbaricitinib Ibrutinib Atacicept Belimumab NNC114-0005 Tocilizumab AMG557 andb PI3K BCR Ig Ig CD20 CD22 CD52 CD38CD40 ICOSL CD138 CD19 gp130 IL-21R Disruption of B cell activation or activity + P J K D K V K Q P Q H R T Q K P1 C O O C V Q T [ E [ V Q M K P G U 6 T C H0 E M K P I Fc RIIbFc RIIb B cell Natalizumab Rituximab Alemtuzumab Daratumumab ravtansine Inebilizumab MGD010a XmAb5871a Epratuzumab CFZ533 Dapirolizumab pegol Idelalisib ( K I Therapeutic approaches for modulating B cells in autoimmunity. Disruption of B cell activation or engagement of inhibitory checkpoint receptors (part ), B cell depletion (part ), inhibition of pro-inflammatory soluble factors (part and trafficking blockade (part ) are being used to target B cells in autoimmunity. : O # D C P F / ) & H W P E V K Q P D [ D K P F K P I D Q V J V J G N Q Y C H H K P K V [ K O O W P Q I N Q D W N K P ( E T G I K Q P T G E G R V Q T + + D \n ( ERIIb) and components that are positioned P G C T | V J G $ E G N N T G E G R V Q T \n $ % 4 D T K P I K P I V J K U K P J K D K V Q T [ T G E G R V Q T K P E N Q U G R T Q Z K O K V [ V Q V J G $ % 4 V Q K P J K D K V $ % 4 U K I P C N N K P I & C R K T Q N K \ W O C D R G I Q N C P F / ' & + V C T I G V % & N K I C P F \n % & . C P F + % 1 5 T G U R G E V K X G N [ C N V J Q W I J V J G U G T G E G R V Q T U C T G P Q V P Q T O C N N [ G Z R T G U U G F Q P $ E G N N U V J G [ C T G G Z R T G U U G F Q P 6 | E G N N U C P F D K P F V Q T G E G R V Q T U Q P $ E G N N U \n % & C P F + % 1 5 . V Q O G F K C V G $ E G N N s 6 E G N N K P V G T C E V K Q P U $ # ( ( 4 $ E G N N C E V K X C V K P I H C E V Q T T G E G R V Q T + . 4 + . T G E G R V Q T + . 4 + . T G E G R V Q T , C P W U M K P C U G 2 + - R J Q U R J Q K P Q U K V K F G M K P C U G ; TACI, transmembrane activator and calcium modulator. clinic, with promising results for multiple autoimmune diseases(TABLE . In addition, CD40 agonizing antibodies are being pursued for antitumour therapySimilarly, inhibition of interactions between ICOS and ICOSL (also known as ICOSLG) (expressed on T cells and B cells, respectively) to disrupt T cellB cell interactions is being pursued for the treatment of autoimmune diseases. Antibodies that block ICOSL (AMG557 ) or ICOS (MEDI-570 ) are being developed. Both MEDI-570 and AMG557 can block T cellB cell interactions and the production of autoantibodies and have shown promise in clinical trials for SLE treatmentThere is also considerable interest in targeting CD22 for the treatment of autoimmune disease. As CD22 has three ITIMs, promoting the inhibitory function of this receptor could have potent inhibitory effects on B cells. However, treatment with the anti-CD22 antibody epratuzumab (an antibody that is thought to promote the function of CD22 and thereby inhibit BCR activation134) did not result in improved response rates in patients with SLE in a phase II clinical trialAnother approach being pursued is the co-engagement of a B cell inhibitory receptor with a surface receptor on the same B cells. For example, the anti-CD19 antibody XmAb5871 contains an Fc region that is engineered to have an increased affinity and selectivity for the inhibitory Fc RIIb receptor. XmAb5871, hence, co-engages CD19 and Fc RIIb on B cells, bringing the inhibitory receptor in close proximity to the BCR to inhibit downstream signalling. In clinical trials for the treatment of SLE and IgG4-related disease, this dual-targeting antibody decreased the production of ACPAs and rheumatoid factor by B cells from patients with RA138139A similar approach for simultaneously targeting a B cell inhibitory receptor and a B cell surface receptor to modulate B cell function makes use of a bispecific antibody platform termed dual-affinity retargeting molecules (DARTs). DARTs target two molecules by linking together single-chain variable fragments derived from two different monoclonal antibodies. One DART therapy that is currently being developed (MGD010) targets Fc RIIb and Ig on B cells in an effort to disrupt BCR signalling. This molecule is in early-phase clinical trials and might be developed for RA or other disease indications for which B cells and/or autoantibodies contribute to disease pathogenesis. Overall, antibody-based constructs are an attractive approach for targeting B cell activity, as they can be highly engineered and customized for bioactivity and biocompatibility using the growing antibody knowledge base.Finally, the inhibition of signalling molecules involved in B cell activation is being pursued as a strategy to abrogate B cell activation in autoimmune disease. Following BCR engagement, the tyrosine kinase BTK initiates intracellular signalling networks that result in B cell activation. Ibrutinib is a small-molecule drug that covalently binds BTK to inhibit its function, resulting in B cell apoptosis. This inhibitor is FDA-approved for the treatment of B cell malignancies, and next-generation BTK inhibitors are being developed for the treatment of multiple autoimmune diseases, including SLE, RA and other autoimmune rheumatic diseases(TABLE . In addition, several companies are pursuing the development of BTK inhibitors in combination with other small-molecule kinase inhibitors for the treatment of B cell malignancy and autoimmunity. Similar efforts are directed towards developing inhibitors of PI3K, another important molecule in the signalling cascade downstream of the BCR 6 C T I G V K P I E [ V Q M K P G UAn alternative approach t
o targeting autoimmune B cells themselves is inhibiting the soluble factors that activate B cells. Examples of these strategies include inhibiting the BAFF signalling pathway and cytokines such as IL-6.Several therapeutic strategies that target soluble B cell activating factors are either FDA-approved or are under development. For example, belimumab, a monoclonal antibody that targets BAFF (and prevents BAFF from binding to its three receptors) is approved for the treatment of SLE. In patients with SLE, treatment with belimumab reduces the number of CD20-positive B cells and plasma cells in the blood and lowers the titres of anti-dsDNA antibodies. Alternatively, atacicepta fusion protein of the extracellular domain of TACI and a human IgG1 Fc, is currently in clinical trials for the treatment of SLE. Treatment with atacicept leads to a reduction in the total number of B cells and a dose-dependent reduction in antibody titres. In contrast to the ability of belimumab to bind BAFF, atacicept binds and blocks both BAFF and a proliferation-inducing ligand (APRIL, or TNFSF13, another B cell stimulatory molecule), preventing their signalling via BAFFR and TACI, respectively, on B cells, which could potentially lead to greater potency(TABLE Targeting IL-6 has shown efficacy in the treatment of several autoimmune diseases. This cytokine is produced by a variety of leukocytes and promotes the differentiation of CD40-activated B cells into plasma cells. The concentration of IL-6 is increased in the serum and synovial tissue of patients with RA as well as in the serum of patients with other inflammatory diseases including Crohns disease, SLE and multiple sclerosis. The downstream inflammatory effects of IL-6 can be offset by treatment with conventional therapies including corticosteroids and NSAIDs. However, antibodies that directly block the actions of IL-6 are also available. Both tocilizumab, a humanized anti-IL-6R monoclonal antibody, and sarilumab, a fully human anti-IL-6R monoclonal antibody, are approved for the treatment of RA, whereas additional IL-6-targeting therapies are showing promise in clinical trials for various other autoimmune diseasesJAKs mediate signalling by the IL-6R and many other cytokine receptors. Small-molecule inhibitors of JAKs are available, such as tofacitinib and baricitinib, that block the effects of these pro-inflammatory cytokines. JAK inhibition is an effective strategy in the treatment of RA and other autoimmune diseaseswhich is possibly in part dependent on the inhibition of IL-6-mediated B cell survival, maturation and activation. Indeed, blockade of JAK1-mediated and JAK3-mediated signalling with tofacitinib inhibits B cell activationAdditional JAK inhibitors are being developed to treat chain variable fragmentsingle polypeptide fusion proteins of the variable regions of the heavy and light chains of an antibody connected by a peptide linker. malignancy and/or autoimmunity, many of which are being engineered to have a greater specificity for specific JAK family members.Molecules that target IL-21 are under development for the treatment of autoimmunity owing to its function in driving T cell-dependent B cell maturation. NNC114-0005 (also known as NNC0114-0006) is an anti-IL-21 neutralizing monoclonal antibody in phase II clinical trials for the treatment of RA. Moreover, JAK inhibitors such as tofacitinib also interfere with IL-21 signalling, as JAKs mediate signalling events downstream of IL-21IL-21 receptor binding.Other FDA-approved therapeutics for autoimmune disease might also exert their beneficial effects by inhibiting B cells or their effector functions. For example, natalizumab, a humanized monoclonal antibody against 4 integrin (CD49d), inhibits leukocyte trafficking and is FDA-approved for the treatment of multiple sclerosis and Crohns disease. Although the beneficial effects of natalizumab treatment are widely thought to be caused by blockade of T cell trafficking, this antibody also inhibits B cell trafficking, which might also contribute to its efficacy ( W V W T G V J G T C R G W V K E R T Q U R G E V UAlthough several targeted therapies for autoimmune diseases currently exist, therapies that target more specialized subsets of B cells such as activated or autoreactive B cells could have improved efficacy and a lower risk of adverse effects. Several monoclonal antibody therapies that target subsets of B cells, such as targeting of CD138B cells by indatuximab ravtansine, and factors that promote B cell activation, such as IL-21, are in development. Dual-targeting strategies with engineered bispecific proteins also hold promise.Therapies that block inhibitory checkpoint proteins on T cells, such as PD1 and CTLA4, to promote immune responses are being used to treat patients with cancer. The use of these treatments can result in secondary autoimmune complications, suggesting that these inhibitory checkpoints could potentially be targeted with agonists to treat autoimmunity. Notably, PD1 is expressed on both T cells and B cells, and although anti-PD1 therapy is known to promote antitumour T cell responses in patients with cancer, this strategy could potentially also promote antitumour B cell responses. As blockade of these inhibitory receptors has proved revolutionary for the treatment of cancer, activating the same targets might be useful for inducing tolerance in the context of autoimmunity. Many of the proteins targeted by checkpoint immunotherapy on T cells and NK cells are also expressed on B cells, where they regulate B cell functions that contribute to autoimmunity. Therefore, targeting these inhibitory checkpoints could enable a more fine-tuned approach to modulating B cell responses and reducing their pathogenic cellular activitiesThe field is also working to develop molecules that target specific pathogenic B cell subsets or functions, such as antigen presentation or antibody production, to minimize unnecessary immunosuppressive effects and to maximize their potency in restricting autoimmunity. In the future, autoantigen-specific B cell-tolerizing therapies might also be developed to precisely target pathogenic B cells.ConclusionsMultiple B cell effector functions contribute to the pathogenesis of autoimmune disease, and targeting the checkpoints that control B cell activation
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Research in the laboratory of W.H.R. is supported by US National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants R01 AR063676, U19 AI11049103 and U01 AI101981.Author contributionsThe authors contributed equally to all aspects of the article.Competing interestsThe authors declare no competing interests.Publishers noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affili