New insights into B cell biology in systemic lupus... : Current Opinion in Rheumatology (original) (raw)

INTRODUCTION

Systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) are distinct diseases clinically but share critical common dysregulated immune pathways including the key role of B cells as well as type I interferon activation and ectopic lymphoneogenesis. Both diseases also have significant unmet needs with SLE still associated with three to five-fold increased mortality compared with the general population and pSS lacking disease-modifying therapeutic interventions. The need for more effective therapies with less toxic side effects has propelled interest in targeted biologic therapies on the basis of an expanding understanding about disease pathogenesis in both diseases. Here, we highlight new insights into B cell roles in disease pathogenesis with a focus on novel interactions between the adaptive and innate immune systems and how this has revealed new treatment targets.

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TARGET TISSUE EFFECTS

B cells can provide a critical link between the development of tertiary lymphoid tissue within both the lupus kidney and pSS salivary glands (ectopic lymphoid structures- ELS) and the propagation of the autoimmune process. This contention has been supported historically by the finding of aggregates of B cells and in some instances germinal centre (GC) structures within target tissue. The precise requirements for the generation of these lymphoid structures, their frequency and role in the pathogenesis of disease have remained unclear. Chang et al. [1] have demonstrated well circumscribed T:B cell aggregates or GCs containing follicular dendritic cells within lupus nephritis biopsies associated with intrarenal B cell clonal expansion and ongoing somatic hypermutation. Similar structures have been identified within the salivary glands of pSS patients. These results implicate ELS in the pathogenesis of lupus tubulointerstitial inflammation [1] and possibly antigen-driven B cell selection in pSS salivary gland. Novel cell distance mapping approaches were used to identify T follicular helper (TFH) cells in cognate interactions with in-situ B cells in the lupus kidney, suggesting that this key cell population is instrumental in propagating humoral immunity in target tissue [2▪▪].

Factors driving the accumulation of TFH, B cells and ELS in target tissue have recently been identified. Studies in rheumatoid arthritis (RA) have demonstrated abundant synovial expression of CXCL13 (a major B cell attractant), as well as CCL19 (a T cell attractant) and BAFF (B cell activation factor). CXCL13 can be produced by synoviocytes and follicular dendritic cells in the RA synovium and was also found to be secreted by RA synovial T cells, indicating a direct role for both the inflamed synovial stroma and synovial T cells in the recruitment and organization of B cells [3]. Interestingly, it has recently been shown by Wang _et al._[4▪] that there is an increase in renal expression of B cell survival factors [BAFF, APRIL-a proliferation-inducing ligand, and interleukin (IL)-6] and B cell and plasma cell (PC)-attracting chemokines (CXCL13 and CXCL12) coincident with enrichment of autoreactive dsDNA Ab-secreting cells in the kidney of lupus-prone mice. Notably, prolonged B cell depletion altered this B cell survival niche by affecting renal macrophage expression of key survival factors, including BAFF, APRIL, and IL6 [4▪]. B cell borne lymphotoxin α can also have a profound effect on secondary and tertiary lymphoid architecture. It was shown that B cell depletion alters lymphoid architecture by eliminating LTα-bearing and tumour necrosis factor (TNF)-secreting B cells [5], resulting in a prolonged delay in memory B cell reconstitution [6]. B cells are involved in the formation and/or maintenance of ELS, as these tissues do not efficiently develop in B cell deficient mice [7]. It was shown that B cells can produce multiple cytokines (IFNγ, IL-6, TNFα, LTα) directly within ELS [7]. However, the impact of B cell depletion on ELS requires further study.

Tissue-specific expression of LTα in the kidney and pancreas causes inflammation and formation of ELS in the mouse with promotion of antigen-specific responses [8▪]. In combination with LTβ, LTα enhances ectopic lymphoid neogenesis. Thus, evidence in patients with pSS and animal models have demonstrated that ectopic lymphoneogenesis is dependent on the ectopic expression of LT and lymphoid chemokines CXCL13, CCL19, CCL21 and CXCL12. Infiltrating immune cells as well as resident epithelial and stromal cells can produce these factors during chronic inflammation in pSS [9]. In pSS animal models, spontaneous development of splenic GCs precedes the lymphocytic infiltration of the salivary gland suggesting that tertiary lymphoid structures may arise from trafficking of activated T and B cells to sites of inflammation [10]. Interestingly, blockade of CXCL13 was sufficient to disrupt follicular architecture of the spleen but did not impact tertiary lymphoid structures in the salivary gland [11]. A recent study also implicated Epstein Barr virus (EBV) dysregulation in the formation of ectopic lymphoid structures in pSS with evidence of EBV infection in B cells and plasma cells in the salivary gland of pSS patients with ectopic structures. Importantly, perifollicular PCs displaying Ro52 reactivity were frequently infected by EBV, and transplantation of pSS salivary gland tissue to SCID mice supported the production of Ro antibodies and anti-EBV antibodies [12▪].

Recent data have also elucidated unique cellular initiators of lymphoneogenesis possibly in ectopic locations, including haematopoietic-derived lymphoid tissue inducer cells (LTi cells), IL17-secreting CD4+ T cells and T follicular helper cells (TFH) [13]. More is known about the role of LTi cells in secondary lymphoid organogenesis. Thus, the accumulation and survival of LTi cells is coordinated by the expression of CXCL13, RANKL and IL7. There is a critical interplay between LTi cells and mesenchymal-derived lymphoid organizer stromal cells, the latter producing IL7 and RANKL and inducing the expression of LTα1β2 on LTi cells, in turn engaging the LTβ receptor on lymphoid tissue organizer cells. LTβ receptor signalling on lymphoid tissue organizer cells, leading to the production of critical chemokines such as CCL19, CCL21 and CXCL12 [14], plays a key role in lymph node development. Stromal tissue cells may acquire lymphoid tissue organizer cell-like properties within the RA synovium [15]. However, the relevance of these findings to ELS in SLE and pSS remains to be defined. It is even unclear whether the development of tertiary lymphoid structures is dependent on LTi cells. Robust tertiary lymphoid tissue develops in the lung and during colitis in RORγt-deficient mice, which lack both LTi and Th17 cells, and was dependent on LTβ expressed by B cells [16]. These findings raise the intriguing possibility that B cells can assume an LTi function.

THE B CELL INNATE IMMUNE SYSTEM INTERFACE

Data have continued to expand regarding the mechanisms by which innate immune signals regulate the B cell compartment [17]. A recent elegant study [18] described a population of neutrophils normally colonizing the human splenic marginal zone that promote B cell activation and differentiation through the production of BAFF, APRIL and IL21, termed ‘B helper neutrophils’. Puga et al. proposed that this unique neutrophil subset may be important for rapid humoral immune responses to blood-borne microorganisms. It is unknown whether this unique neutrophil population is dysregulated in autoimmune disease. Intriguingly, splenic neutrophil location was perturbed in a single lupus spleen examined with infiltration into the GC, suggesting that B helper neutrophils may provide aberrant B cell help in SLE. The Cerutti group has also recently demonstrated that RORγt+ innate lymphoid cells (ILCs) (LTi cells are part of this expanding cell family) can enhance antibody production by marginal zone B cells in the human spleen [19▪▪]. Interestingly, ILCs stimulate circulating neutrophils to acquire a B helper phenotype and induced neutrophil extracellular trap (NET) formation [19▪▪]. The investigation of ILCs in autoimmunity including SLE and pSS is an important area for future study.

It has also been described recently that neutrophils can be primed by interferon and autoantibodies to release NETs as a source of immunogenic DNA, histones and neutrophil proteins contributing to pDC activation [20,21]. The development of autoantibodies to both self-DNA and antimicrobial peptides in NETs suggests that NETs could also serve as autoantigens to trigger B cell activation. NETs clearly can trigger pDCs to produce large quantities of IFNα, a key cytokine acting at the centre of an amplification loop in SLE, indirectly contributing to B cell abnormalities and promoting the differentiation of activated B cells into plasmablasts. Notably, IFN can act in conjunction with Toll-like receptor (TLR) stimulation to trigger B cell expansion [22] and a lowered activation threshold for autoreactive B cells [23]. In turn, B cells can produce anti-DNA and anti-RNA autoantibodies further promoting NETosis. A novel role for IFNα activation has also been reported in the bone marrow of SLE patients by decreasing B cell lymphopoeisis, contributing to B cell lymphopenia, and theoretically decreasing the stringency of B cell negative selection [24▪].

It is notable that the induction of NETosis and activation of pDCs via NETs is dependent on Fc receptors and TLR signalling delivered in part via RNA or DNA-containing autoantigen/autoantibody immune complexes. This adds to the accumulating evidence that B cell derived autoantibodies can play an active role in propagating the autoimmune process in SLE, through TLR-dependent immune cell activation [25]. In addition to the well described activation of pDCs by costimulation of TLRs and FcRs via immune complex binding, relevant for both SLE and pSS, B cell responses can also be modified by TLR signalling. The concept is that RNA and DNA-associated autoantigens are bound by the BCR and transported to a TLR-compartment wherein TLR detection of DNA or RNA provides a second signal promoting B cell activation. Intriguingly, a recent study [26] demonstrated the surprising finding in UNC-93B deficient lupus-prone mice that the development of nonnuclear autoantibody specificities, including anti-red blood cell and in other contexts anti-myeloperoxidase (MPO), was dependent on TLR signalling in B cells. One possible explanation for the dependence of nonnuclear antibodies on nucleic acid-TLR signalling is that they act as autoantigens only when associated with nucleic acids, for example on apoptotic cells or NETs.

Recent literature has also uncovered new findings about the impact of both TLR7 and TLR9 on autoantibody formation and disease progression in murine models of SLE. The contribution of TLR7 to SLE has been more straightforward, correlating positively with autoimmunity as exemplified by the TLR7 duplication Yaa lupus susceptibility locus in mice and the abrogation of disease in TLR7-deficient mice. On the contrary, there has been conflicting evidence regarding whether the role of TLR9 is protective or deleterious in SLE. Although TLR9 is required for development of antidsDNA and antichromatin consistent with the importance of BCR-delivered TLR stimulation, TLR9 deficiency surprisingly enhances disease in multiple murine lupus models [27]. This paradox was partially resolved by recent literature demonstrating that TLR9 promotes tolerance by restricting survival of anergic anti-DNA B cells but is also essential for their activation and differentiation to antibody secreting cell in extra-follicular reactions [28]. The differential outcome of TLR9 signalling remains unexplained but could relate to B cell developmental state, location and/or other extrinsic signals. An unsuspected tolerogenic role for TLR signalling was also supported by recent work demonstrating defective central and peripheral B cell tolerance checkpoints in patients deficient for interleukin-1 receptor-associated kinase 4 (IRAK-4), myeloid differentiation factor 88 (MyD88) and UNC-93B, key for signalling via multiple TLRs [29]. In mice, the exacerbation of clinical disease and production of anti-RNA antibodies in the absence of TLR9 was dependent on type I IFN signalling [30] and was B cell intrinsic [31,32]. The enhanced production of anti-RNA antibodies is consistent with other data that TLR9 deficiency upregulates TLR7 in B cells [33]. Adding to the complexity, TLR8 was also reported to negatively regulate murine SLE possibly by restraining TLR7 responses [34▪].

Intriguingly, TLR7 and TLR9 also appear to have opposing roles in the formation of spontaneous GCs, with B cell intrinsic TLR7 expression essential for the development of GCs and breaking of GC tolerance checkpoints and TLR9 providing a negative regulatory function [35▪]. The mechanisms driving these differences in response are not clear. TLR7 overexpression in B cells was also recently shown to promote the proliferation and PC differentiation of transitional type 1 B cells [36], highlighting the multiple stages of B cell development that may be affected by TLR signalling. Another recent study in human lupus highlighted the importance of activation of naïve B cells during disease flare, with autoantibody secreting cells surprisingly derived from newly activated naïve B cells as opposed to memory B cells [37]. A polyclonal increase in both anti-microbial and autoreactive antibody secreting cell specificities supports the contribution of bystander B cell activation, possibly via TLRs.

CONTRIBUTION OF DYSREGULATED B CELLS TO DISEASE EXPRESSION VIA CYTOKINES

Another mechanism by which B cells contribute to SLE and pSS is via the production of cytokines. Similarly to T cells, cytokine-producing human B cells can be polarized, and actually induce Th1 and Th2 cells (termed Be1 and Be2 cell, respectively) [38]. CD27+ Be1 cells may accumulate in the salivary glands in pSS [39]. A recent elegant study [40] in experimental autoimmune encephalomyelitis demonstrated that B cell production of IL6 drives Th17 responses, and moreover, B cell depletion alleviates disease through ablation of IL6-producing B cells. As detailed earlier, cytokine-producing B cells can also regulate lymphoid tissue formation and maintenance, including the formation and/or maintenance of tertiary lymphoid tissues [7]. On the contrary, growing evidence is accumulating for regulatory B cells capable of preventing or suppressing autoimmunity in different mouse models [41]. This protective role can be mediated by inducing T cell anergy during antigen presentation or inducing Treg expansion or activity [41]. B cells may also directly suppress Th1 and Th17-mediated diseases [42]. These activities are mediated, at least in part, by the production of IL10 or transforming growth factor-beta (TGFβ) and may control a variety of auto-inflammatory diseases, including inflammatory arthritis, inflammatory bowel disease, autoimmune diabetes, SLE and pSS [43].

Recent data have further elucidated the nature of both murine and human Bregs. Mouse Breg activity has been variously assigned to cells with a transitional (in particular, T2-marginal zone precursors – T2/MZP), marginal zone or B1/transitional/marginal zone intermediate phenotype, and lupus resistance has been associated with the expansion of marginal zone cells [43,44]. Our observation that expansion of transitional B cells correlates with long-term remission in SLE patients treated with B cell depletion therapy is consistent with a regulatory nature [45]. Two recent articles have further characterized the human counterpart of the regulatory B cell. Thus, Iwata _et al._[46] identified a small fraction of CD24hiCD27+ B cells in human peripheral blood that express IL10 and regulate monocyte production of TNFα. In contrast, Blair et al. identified a CD19+CD24hiCD38hiCD1d+ B cell, likely a transitional subset, with a high propensity to produce IL10 and suppress T cell cytokine production. Notably, the suppressive function of this cell subset appeared to be defective in SLE, but not in pSS [47].

Additional data have further defined the factors that control the development and function of B regulatory cells. For example, Rosser _et al._[48▪▪] have found that gut microbiota promote the differentiation of Bregs in the spleen and mesenteric lymph nodes in an IL6 and IL1-dependent fashion. This was important in the regulation of inflammatory arthritis in a mouse model, but the relevance for SLE and pSS remains unclear. Another study demonstrated that Tim-1, a type I transmembrane glycoprotein important in apoptotic cell clearance, is critical for IL10 production by regulatory B cells. Thus, Tim-1 mutant mice, particularly on an autoimmune-prone background, developed accelerated systemic autoimmunity with accumulation of double-negative T cells and autoantibodies to a number of lupus-associated autoantigens [49]. The authors suggest that one possible mechanism by which Tim-1 maintains Breg IL10 production may be through the interaction of Tim-1 with apoptotic cells. Of note, apoptotic cells have been shown to promote Bregs, which inhibited collagen-induced arthritis in an IL10-dependent manner. A more recent extension of this study found that IL10 production by Bregs in response to apoptotic cells was dependent on recognition of DNA-containing complexes via TLR9, and CD27+ human B cells also responded to DNA-bearing apoptotic cells by secreting IL10 [50]. This seems to challenge the existing paradigm that TLR9 ligation must generate an inflammatory signal. Bregs may also mediate their effects by mechanisms other than cytokine production. For example, Khan _et al._[51▪] recently identified a PD-L1 (the ligand for an inhibitory programmed death receptor) expressing B cell within the mouse marginal zone and human-naive compartment that suppressed TFH but was not IL10 mediated.

B CELL TARGETED IMMUNOTHERAPIES

The data above begin to highlight potential novel therapeutic approaches in SLE and pSS as well as insights into the variable success of B cell depletion therapy. Inadequate response to B cell depletion may be due to incomplete depletion of B cells in the target tissue, particularly within the local inflammatory microenvironment of ELS. In accordance with this, studies have shown a clear discrepancy between peripheral blood B cell depletion and depletion in the salivary gland in pSS. One study found clonal expansions of IgA- and IgG-expressing cells in pSS parotid tissue and even higher mutational load after rituximab. These results suggest that local somatic hypermutation, isotype switch and PC differentiation continue to occur in residual tissue cells in ectopic locations after rituximab treatment [52]. More efficacious ways to interrupt ectopic lymphoneogenesis are under investigation, including blockade of LTβ receptor signalling with the decoy receptor baminercept. Although baminercept failed to show clinical efficacy in early phase clinical trials in RA, its utility in pSS is currently under investigation in a trial sponsored by the Autoimmunity Centers of Excellence (National Institute of Allergy and Infectious Diseases). Combination therapies, for example B cell depletion and LTβ receptor blockade or inhibition of B cell attracting chemokines (e.g. CXCL13) or B cell survival cytokines (e.g. BAFF or IL6), may also have merit. Given the recently elucidated roles of Th17 and TFH cells in ectopic lymphoid structures, the cytokines IL21 and IL17 are additional attractive targets.

Another issue with B cell depletion is that it may indiscriminately deplete pro-inflammatory B cells and Breg populations. On the contrary, the recently described PD-L1 expressing Bregs appear to be relatively resistant to B cell depletion therapy, possibly due to increased expression of BAFF receptors (BAFF-R, TACI and BCMA) [51▪]. Understanding the imbalance between opposing B cell functions in disease and how this imbalance may be restored after targeted biologic therapies remains an important area of investigation. Another potential reason for variable efficacy of B cell depletion is the persistence of long-lived CD20 negative plasma cells and pathogenic autoantibodies. This observation has raised interest in the possibility of targeting the plasma cell compartment. Bortezomib is a proteasome inhibitor that effectively depletes even long-lived plasma cells, has efficacy in the treatment of murine lupus [53] and was recently reported to have beneficial effects in a small open-label trial in human SLE [54]. Novel immunoproteasome inhibitors with a lower toxicity profile were also recently described to create a powerful synergistic effect in the treatment of murine SLE by targeting plasma cells and IFNα production by pDCs [55].

CONCLUSION

Given the disappointing clinical trial results with targeted B cell depletion, a better understanding of the multiple pathways leading to autoreactive B cell activation and the diverse roles for B cells in both SLE and pSS is clearly important. New studies defining the functional interactions between B cells and other critical cell populations within target tissue have great potential to yield novel insights into disease pathogenesis and unveil new treatment targets. Combination therapy directed at multiple steps in disease pathogenesis needs to be considered.

Acknowledgements

We would like to thank Dr Javier Rangel-Moreno for critical review of the manuscript.

Financial support and sponsorship

Dr Anolik has been supported by several grants, including Accelerating Medicines Partnership UH2AR067690-01, R01 AI077674-01, P01 AI1078907-01, U19 Autoimmunity Center of Excellence AI563262-06, the Lupus Foundation of American, the Lupus Research Institute and the Bertha and Louis Weinstein research fund.

Conflicts of interest

J.H.A. is currently receiving grants from Karyopharm and Medimmune. The remaining authors have no conflicts of interest.

Papers of particular interest, published within the annual period of review, have been highlighted as:

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Keywords:

autoimmunity; B cells; Sjögren's syndrome; systemic lupus erythematosus

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