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B Cells
Chapter 3
B Cells: A Main Player in the Development of Autoimmunity Elias Toubi Bnai-Zion Medical Center, Faculty of Medicine, Haifa, Israel
B CELLS ARE ANTIGEN-PRESENTING CELLS The role of B lymphocytes as APCs in activating autoreactive T-cell responses was appreciated almost two decades ago. B cells utilize the specialized major histocompatibility complex class II (MHCII), BCR-bound antigens, and their internalization to present relevant peptides to CD4+ T cells. Effective antigen presentation by B cells involves intracellular and several molecular events. These are: (1) antigen capture and uptake. (2) Creating antigen/BCR complexes with MHCII in cellular compartments. (3) Generation of MHCII/peptide complexes. (4) exocytic transport for presentation of MHCII/ peptide complexes at the surface of B cells. Autoantigen presentation by B cells in autoimmune diseases, such as systemic lupus erythematosus (SLE), is a key step in the activation of autoreactive CD4+ T cells and the production of many proinflammatory cytokines [1,2]. T-cell infiltrates in organs such as kidneys and skin were shown to be important features in SLE patients in many early studies. In this respect, the complete absence of T-cell infiltrates in MRL-lpr/lpr mice that lack B cells raised the assumption that B cells are required as APCs for priming autoreactive T cells in SLE. The antigenpresenting function of B cells in autoimmune responses was established by showing that the proliferation of wild-type splenocytes to self-antigens was completely inhibited by blocking the surface Ig-mediated capture by B cells, suggesting again that B cells are required as APCs to induce pathogenic autoimmune T-cell responses [3,4]. In a later study, MHCII-antigen presentation by both B and dendritic cells were shown to be both required (in cooperation) for optimal follicular helper T (Tfh) cells and germinal B-cell differentiation response and the development of high-affinity class-switched antibodies and memory B cells [5]. In line with this, antigen presentation by B cells was shown to be of special importance during germinal center (GC) colonization where B cells engage with Tfh cells leading to their clonal selection and specific antibody affinities. It was well shown that intercellular adhesion molecule 1 (ICAM-1) and ICAM-2 on B cells are essential for longlasting Tfh/B cell interactions and the selection of low-affinity B-cell clones for proliferative clonal expansion. These data suggest that the expression of ICAMs on B cells is important for their effective antigen presentation [6]. In another study, the development of mucosal-associated invariant T (MAIT) cells was shown to be dependent on antigen presentation by B cells. In this case, antigen presentation requires MHC-related protein 1 (MR1) expression as well as commensal bacteria. Treating B cells with toll-like receptor 9 (TLR9) agonists increased MR1 surface expression and related bacterial presentation. This indicates that endosomal TLR9 activation is important for the efficiency of antigen presentation by B cells [7]. Autoantigen presentation by B cells in patients with autoimmune thyroiditis was also studied. In this case, antigen-loaded B cells (by thyroid tissue) have been shown to be capable of inducing the proliferation of auto-specific CD4+ T cells and the development of immune-mediated inflammation [8]. In a very recent study, IgE–immune complexes (IgE-IC) were shown to bind CD23 on B cells leading to their internalization in B cells. Then, B cells recycle IgE-IC in native form to the cell surface followed by the uptake of IgE-IC by DCs in cocultures. Cell-to-cell contact between B cells and DCs was followed by increased upregulation of CD86 and MHCII on DCs. In this study, B cells are shown to act as antigen-presenting cells transferring antigens to more efficient APCs such as DCs. Alternatively, B cells can directly induce DC maturation enhancing by that T-cell stimulation [9].
ACTIVATED B CELLS IN AUTOIMMUNITY The breakdown of self-tolerance and the development of autoimmune diseases such as SLE is closely related to B-cell hyperactivity and disturbed B-cell homeostasis. The understanding of how B cells are activated in the process of immunemediated diseases and how memory B cells are switched to become autoreactive is complex. Early studies defined the Mosaic of Autoimmunity. https://doi.org/10.1016/B978-0-12-814307-0.00003-7 Copyright © 2019 Elsevier Inc. All rights reserved.
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importance of CD5 and CD95 expression on B cells from SLE patients. It was found that activated B cells are characterized by having increased expression of CD5, and that this expression is in correlation with SLE disease activity. The expression of CD95 on B cells was also evaluated in normal and in SLE patients. In this case, inactive SLE patients were found to have higher proportion of CD95 high B cells being sensitive to undergo apoptosis. This implies that autoantibody-producing B cells are derived from CD95 low B cells thought to be resistant to apoptosis [10]. The differentiation process of naive B cells into IgG-secreting plasma cells is complex, involving many signals and pathways of activation. Looking into one of these, CD27neg B cells with enhanced expression of basal spleen tyrosine kinase (Syk) bright were found to be expanded in patients with SLE. These B cells were characterized as CD38neg but CD20 high and exhibited somatically mutated IgVH rearrangements and showed an enhanced differentiation into IgG-secreting plasma cells in contrast to Syk low B cells. CD27-Syk bright B cells but not Syk low B cells exhibited increased differentiation into CD27 high IgG–secreting cells and were highly inducible when cocultured with IFN-ɤ or TNF-α. This allows using intracellular markers such as Syk in distinguishing between naïve and memory B-cell subsets and being the source of increased plasma cells in SLE [11]. The role of activated memory B cells in systemic sclerosis (SSc) was also analyzed. Phenotypic characteristics of B cells were assessed in 28 patients with early form of SSc (9 with limited SSc and 19 with diffuse) and in 15 healthy individuals (controls). The following phenotypic subtypes were evaluated: CD19+CD27−IgD+ naïve; CD19+CD27+ memory; CD19+CD27+IgD+ nonswitched memory; CD19+CD27+IgD− switched memory. In addition, CD80+ or CD95+ activated cells were also identified. The proportion of naïve B cells was higher in SSc than in controls, but with decreased numbers of nonswitched memory B cells. In diffuse SSc patients switched memory B cells were found to be significantly higher compared with that in limited SSc. The percentage of CD95+CD27+ memory B cells was also significantly increased in diffused SSc. Increased switched and activated memory B cells are of pathogenic potential role by producing proinflammatory cytokines and autoantibodies [12]. The combination of CpG/TLR9 and IFN-α was shown to increase the differentiation of CD27+IgD+ unswitched memory B cells into CD27 high CD38 high plasmablasts. Whereas, CpG alone induced the differentiation of unswitched memory B cells into B cells with high cytokine production, this differentiation was suppressed by IFN-α. In addition, high m TORC1 activation was noted in CD19+ B cells of patients with SLE and correlated with plasmablasts differentiation and disease activity. The above-described activation pathways of human unswitched memory B cells into plasmablasts seem to be highly important in the pathogenesis of SLE [13]. The identification of human CD43+ B cells and their relation with memory B cells and plasmablasts was recently reported. CD19+CD43+ B cells were found to be of increased proliferating properties than naïve and even memory B cells. Though expressed on both memory B cells and on plasmablasts, CD43+ B cells gave rise to plasmablasts more efficiently than do memory B cells, which suggest that they are closely related to plasmablasts and therefore may be involved in the pathogenesis of autoimmunity [14]. The spontaneous production of IL-10, IL6, and TNF by B cells is minimal. When CD27+ memory B cells are activated with anti-Ig antibodies and CpG, IL-6, and TNF are strongly produced, whereas IL-10 is produced modestly and the capacity of TGF-β production is reduced. Thus, B-cell activation may lead to the development of enhanced immune responses and autoimmunity by decreasing TGF-β production and increasing their proinflammatory properties [15]. The excess of B-cell activating factor (BAFF) leads to the expansion of marginal zone (MZ) B cells and to their capacity in activating T cells. Increased BAFF level has been detected in the serum of many autoimmune diseases such as SLE, RA, and Sjogren’s syndrome and in correlation with disease activity. Decreased BAFF receptor expression on peripheral B cells was found to be in association with enhanced disease activity of Sjogren’s syndrome (pSS) and SLE. B cells from 20 patients with pSS, 19 with SLE, and 15 controls were analyzed by flow cytometry to assess the expression of BAFF receptor. The expression of BAFF receptor on memory CD27+ B cells was significantly decreased in patients with pSS and SLE. Serum BAFF level is inversely correlated with BAFF receptor expression. Decreased BAFF receptor expression was found to be in correlation with SLE disease activity index. This downregulation is suggested to be the consequence of chronic increase in BAFF. BAFF receptor levels on B cells may serve as a biomarker for assessing autoimmune disease activity [16]. The expression of BAFF receptor 3 (BR3) on B cells from SLE patients was further examined in a later study. Here also, BAFF levels were increased in the serum of these patients and in positive correlation with SLE disease activity but negatively with BR3 expression. Reduced BR3 expression was found to be on CD27− and CD27+ B cells of all SLE patients, but this was more in patients with lupus nephritis. This reduction is again suggested to act as a biomarker for active SLE, namely the occurrence of lupus nephritis [17]. The capacity of endogenous BAFF and IL-21 and exogenous factors such as CpG to induce the production of PR3-ANCA in granulomatosis with polyangiitis (GPA) was studied. Here, the stimulation with BAFF and IL-21 significantly increased ANCA production. This production was further increased by the addition of CpG-ODN. These data demonstrate how toll-like receptor 9 synergizes with IL-21 and with BAFF leading to increased ANCA production [18]. The abovementioned data support the notion that B-cell activation is complex and many signaling pathways are required for the development of autoreactivity and proinflammatory B cells leading to the development of autoimmune diseases.
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PROINFLAMMATORY B CELLS AND AUTOIMMUNITY Humoral immune responses begin when B lymphocytes are activated by antigens followed by the secretion of relevant antibodies. GCs are formed in the follicles of peripheral lymphoid organs when activated B cells migrate into the follicles and proliferate. Antigen-activated B cells are produced in GCs and obtain the ability to survive for long periods. These are memory B cells capable of rapid responses to previously recognized antigens. The production of large quantities of isotype-switched, high-affinity antibodies is increased after second exposure to antigens, usually following the activation of memory cells in GCs and the formation of immune complexes. In addition to their antibody-producing ability, activated B cells via the BCR, CD40 and toll-like receptors are also the source of many proinflammatory cytokines such as IL-10, IL-6, and IFNs.
IL-10-Producing B Cells in Autoimmunity IL-10 has an important role in the growth, survival, and differentiation of B cells in SLE patients. Increased IL-10 production induces B-cell hyperreactivity resulting in antibody production by switching plasma cells and the development of immune complexes [19]. Increased IL-10 in the serum of SLE patients was suggested in many reports to be associated with SLE disease activity. The loss of B-cell tolerance in the elderly is characterized by the increased prevalence of autoantibodies and rheumatoid factor. The issue of how and which cytokine these B cells produce and how this is related to autoimmunity was assessed. Absolute numbers of circulating B cells were similar in both young and old individuals. However, numbers of transitional B cells (CD19+CD27−CD38hiCD24hi) were decreased in old individuals. Following a short term in vitro stimulation of whole blood, the number of B cells capable of producing TNF-α was similar in young and old individuals, however, IL-10-producing B cells were decreased only in old individuals. Decreased IL-10-producing B cells was mainly noticed in old individuals in which ANA was positive but was retained in those in which RF was positive. These findings suggest that IL-10+ B cells may impact the development of ANAs and RFs in the elderly [20]. When pre-naïve B cells are stimulated through CD40, they produce large amounts of IL-10 but are unable to suppress CD4+ T-cell cytokine production. Differentiated pre-naïve B cells are autoreactive, thus, they produce IgM autoantibodies with reactivity to single-stranded deoxyribonucleic acid. In SLE, pre-naïve B cells have increased expression of costimulatory molecules but reduced ability of producing IL-10, resulting in increased CD4+ T-cell proliferation and the development of autoimmunity [21].
IL-6-producing B Cells and Autoimmunity Activated B cells are a source of IL-6 production, promoting by that Tfh cell differentiation. The lack of IL-6-producing B cells was shown to decrease spontaneous GC formation in a mouse model of SLE, thus, inhibiting the development of autoimmunity and the formation of switched autoantibodies. This finding suggests that IL-6-producing B cells contribute to autoimmunity through local IL-6 production, inducing by that Tfh differentiation and autoimmune GC formation [22]. IL-6 drives terminal B-cell differentiation and secretion of immunoglobulins. In one study, SLE-like disease parameters were studied in IL-6-deficient BXSB mice. Survival of IL-6-deficient mice was significantly prolonged in association with reduced autoimmune manifestations. B cells costimulated with TLR7 and BCR produced high levels of IL-6 which was further enhanced by IFN-1 stimulation. This suggests that high production of IL-6 by B cells increased by IFN-1 and TLR7 accelerates autoimmunity and the progression of SLE-like disease [23]. In a recent study, high sensitive C-reactive proteins (hs-CRP) and IL-6 levels were analyzed in SLE in relation with SLE disease activity. Mean hs-CRP levels were significantly higher in SLE than in controls. Similarly, IL-6 levels were significantly higher in active SLE as compared with inactive SLE. This study confirms a good correlation between IL-6 and disease activity indicating its direct involvement in SLE-related inflammation [24]. The distribution of transitional B-cell subsets in patients with systemic sclerosis was found to be altered in association with increased IL-6 production and altered self-tolerance. Defects in B-lymphocyte tolerance exist in parallel with altered apoptosis following BCR signaling and the failure to suppress autoreactive B cells, namely, the failure in regulating Scl-70 production. These data emphasize the role of autoreactive IL-6-producing transitional B cells in the pathogenesis of systemic sclerosis [25]. In a most recent study, anti-IL-6 therapy restored abnormal B-cell functions, namely, cytokine-mediated inflammation and autoreactivity. Rheumatoid arthritis B cells produce higher amounts of proinflammatory cytokines such as IL-8, IL-6, and others. Being continuously hyperactive, they become defective in their ability to maintain protective functions. Anti-IL-6 therapy reversed B-cell abnormalities including increased cytokine levels and loss of tolerance, indicating that abnormal IL-6 signaling is responsible for most humoral defects in RA [26].
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IFNs and B Cells in Autoimmunity When B cells are stimulated by the TLR9 agonists-CpGs they proliferate and they secrete antibodies and many cytokines including IL-6. Toll-like receptor 9 agonists are also used in many adjuvants to boost both innate and adaptive immunity. In response to these adjuvants, B cells secrete proinflammatory cytokines such as type 1 IFNs pointing to the different pathways of stimulation by which they play role in different immune responses [27]. The mechanisms by which autoreactive B cells generate somatically mutated and class-switched pathogenic autoantibodies within developed GCs are continuously investigated. A possible mechanism in this respect is that B-cell-intrinsic IFN-γ receptor and STAT1 signaling are required for GC and Tfh cell formation. B-cell-specific IFN-γ receptor deficiency in autoimmune mice models resulted in reduced Tfh responses and altered titers of autoantibodies. IFN-γ deficiency did not affect GC, Tfh cell, or antibody responses against T-cell-dependent foreign antigens, suggesting that IFN-γ receptor signaling is uniquely important for autoantibody responses, but not for polyclonal antibody production. This suggests that IFN-γ signaling is central for the development of autoimmunity and therefore can be a potential target for a better beneficial treatment of SLE [28].
IN SUMMARY The role of B cells in healthy and disease immune responses is increasingly studied. Long-lived plasma cells are important in maintaining antibody secretion against foreign antigens and following vaccinations. In autoimmunity, autoreactive B cells are the source of specific autoantibodies but also of proinflammatory cytokines. Many signaling pathways are recently reported, aiming to identify their complexity. Some of these are summarized in this chapter.
REFERENCES [1] Adler LN, Jiang W, Bhamidipati K, Millican M, Macaubas C, Hung SC, Mellins ED. The other function: class II-restricted antigen presentation by B cells. Front Immunnol 2017;8:319. [2] Choi SC, Morel L. B cell contribution of the CD4+ T cell inflammatory phenotypes in systemic lupus erythematosus. Autoimmunity 2017;50:37–41. [3] Chan O, Shlomchik MJ. A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice. J Immunol 1998;160:51–9. [4] Falcone M, Lee J, Patstone G, Yeung B, Sarvetnick N. B lymphocytes are crucial antigen-presenting cells in the pathogenic autoimmune response to GAD65 antigen in nonobese diabetic mice. J Immunol 1998;161:1163–8. [5] Barnett LG, Simkins HM, Barnett BE, Korn LL, Johnson AL, Wherry EJ, et al. B cell antigen presentation in the initiation of follicular helper T cell and germinal center differentiation. J Immunol 2014;192:3607–17. [6] Zaretsky I, Atrakchi O, Mazor RD, Stoler-Barak L, Biram A, Feigelson SW, et al. ICAMs support B cell interactions with T follicular helper cells and promote clonal selection. J Exp Med 2017;214:3435–48. [7] Liu J, Brutkiewicz RR. The toll-like receptor 9 signaling pathway regulates MRI-mediated bacterial antigen presentation in B cells. Immunology 2017;152:232–42. [8] Kuklina EM, Smirnova EN, Nekrasova IV, Balashova TS. Role of B cells in presentation of autoantigens to CD4+ T cells in patients with autoimmune thyroiditis. Dokl Biol Sci 2015;464:263–6. [9] Engeroff P, Fellmann M, Yerly D, Bachmann MF, Vogel M. A novel recycling mechanism of native IgE-antigen complexes in human B cells facilitates transfer of antigen to dendritic cells for antigen presentation. J Allergy Clin Immunol 2018;142:557–685. [10] Huck S, Jamin C, Younou P, Zouali M. High density expression of CD95 on B cells and underrepresentation of the B-1 cell subset in human lupus. J Autoimmun 1998;11:449–55. [11] Fleischer SJ, Giesecke C, Mei HE, Lipsky PE, Daridon C, Dorner T. Increased frequency of unique spleen tyrosine kinase bright memory B cell population in systemic lupus erythematosus. Arthritis Rheumatol 2014;66:3424–35. [12] Simon D, Balogh P, Bognar A, Kellermayer Z, Engelmann P, Nemeth P, et al. Reduced non-switched memory B cell subsets cause imbalance in B cell repertoire in systemic sclerosis. Clin Exp Rheumatol 2016;34(100):30–6. [13] Torigoe M, Iwata S, Nakayamada S, Sakata K, Zhang M, Hajime M, et al. Metabolic reprogramming commits differentiation of human CD27+IgD+ B cells to plasmablasts or CD27-IgD- cells. J Immunol 2017;199:425–34. [14] Inui M, Hirota S, Hirano K, Fujii H, Sugahara-Tobinai A, et al. Human CD43+ B cells are closely related not only to memory B cells phenotypically but also to plasmablasts developmentally in healthy in heathy individuals. Int Immunol 2015;27:346–55. [15] Molnarfi N, Bjarnadottir K, Benkhoucha M, Juillard C, Lalive PH. Activation of human B cells negatively regulates TGF-β production. J NeuroInflamm 2017;14:13. [16] Sellam J, Miceli-Richard C, Gottenberg JE, Ittah M, Lavie F, Lacabaratz C, et al. Decreased B cell activating factor receptor expression on peripheral lymphocytes associated with increased disease activity in primary Sjogren’s syndrome and systemic lupus erythematosus. Ann Rheum Dis 2007;66:790–7. [17] Zhao LD, Li Y, Smith Jr MF, Wang JS, Zhang W, Tang FL, et al. Expression of BAFF/BAFF receptors and their correlation with disease activity in Chinese SLE patients. Lupus 2010;19:1534–49.
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[18] Lepse N, Land J, Rutgers A, Kallenberg CG, Stegeman CA, Abdulahad WH, Heeringa P. Toll-like receptor 9 activation enhances B cell activating factor and interleukin-21 induced anti-proteinase 3 autoantibody production in vitro. Rheumatology (Oxf) 2016;55:162–72. [19] Peng H, Wang W, Zhou M, Li R, Pan HF, Ye DQ. Role of interleukin-10 and interleukin-10 receptor in systemic lupus erythematosus. Clin Rheumatol 2013;32:1255–66. [20] van der Geest KS, Lorencetti PG, Abdulahad WH, Horst G, Huitema M, Roozendaal C, et al. Aging-dependent decline of IL-10 producing B cells coincides with production of antinuclear antibodies but not rheumatoid factors. Exp Gerontol 2016;75:24–9. [21] Sim JH, Kim HR, Chang SH, Kim IJ, Lipsky PE, Lee J. Autoregulatory function of interleukin-10-producing pre-naïve B cells is defective in systemic lupus erythematosus. Arthritis Res Ther 2015;17:190. [22] Arkatkar T, Du SW, Jacobs HM, Dam EM, Hou B, Buckner JH, et al. B cell derived IL-6 initiates spontaneous germinal center formation during systemic autoimmunity. J Exp Med 2017;214:3207–17. [23] Jain S, Park G, Sproule TJ, Christianson GJ, Leeth CM, Wang H, et al. Interleukin 6 accelerates mortality by promoting the progression of the systemic lupus erythematosus-like disease of BXSB.Yaa mice. PLoS One 2016;11:e0153059. [24] Umare V, Nadkarni A, Nadker M, Rajadhyksha A, Khadilkar P, Ghosh K, Pradhan VD. Do high sensitivity C-reactive protein and serum IL-6 levels correlate with disease activity in systemic lupus erythematosus patients? J Postgrad Med 2017;63:92–5. [25] Taher TE, Ong VH, Bystrom J, Hillion S, Simon Q, Denton CP, et al. Defective regulation of autoreactive IL-6-producing transitional B lymphocytes is associated with disease in patients with systemic sclerosis. Arthritis Rheumatol 2018;70:450–61. [26] Fleischer S, Ries S, Shen P, Lheritier A, Cazals F, Burmester GR, et al. Anti-interleukin-6 signaling therapy rebalances the disrupted cytokine production of B cells from patients with active rheumatoid arthritis. Eur J Immunol 2018;48:194–203. [27] Akkaya M, Akkaya B, Miozzo P, Rawat M, Pena M, Sheehan PW, et al. B cells produce type 1 IFNs in response to the TLR9 agonists CpGs conjugated to cationic lipids. J Immunol 2017;199:931–40. [28] Domeier PP, Chodisetti SB, Soni C, Schell SL, Elias MJ, Wong EB, et al. IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity. J Exp Med 2016;213:715–32.
B Cells: A Main Player in the Development of Autoimmunity Elias Toubi Bnai-Zion Medical Center, Faculty of Medicine, Haifa, Israel
B CELLS ARE ANTIGEN-PRESENTING CELLS The role of B lymphocytes as APCs in activating autoreactive T-cell responses was appreciated almost two decades ago. B cells utilize the specialized major histocompatibility complex class II (MHCII), BCR-bound antigens, and their internalization to present relevant peptides to CD4+ T cells. Effective antigen presentation by B cells involves intracellular and several molecular events. These are: (1) antigen capture and uptake. (2) Creating antigen/BCR complexes with MHCII in cellular compartments. (3) Generation of MHCII/peptide complexes. (4) exocytic transport for presentation of MHCII/ peptide complexes at the surface of B cells. Autoantigen presentation by B cells in autoimmune diseases, such as systemic lupus erythematosus (SLE), is a key step in the activation of autoreactive CD4+ T cells and the production of many proinflammatory cytokines [1,2]. T-cell infiltrates in organs such as kidneys and skin were shown to be important features in SLE patients in many early studies. In this respect, the complete absence of T-cell infiltrates in MRL-lpr/lpr mice that lack B cells raised the assumption that B cells are required as APCs for priming autoreactive T cells in SLE. The antigenpresenting function of B cells in autoimmune responses was established by showing that the proliferation of wild-type splenocytes to self-antigens was completely inhibited by blocking the surface Ig-mediated capture by B cells, suggesting again that B cells are required as APCs to induce pathogenic autoimmune T-cell responses [3,4]. In a later study, MHCII-antigen presentation by both B and dendritic cells were shown to be both required (in cooperation) for optimal follicular helper T (Tfh) cells and germinal B-cell differentiation response and the development of high-affinity class-switched antibodies and memory B cells [5]. In line with this, antigen presentation by B cells was shown to be of special importance during germinal center (GC) colonization where B cells engage with Tfh cells leading to their clonal selection and specific antibody affinities. It was well shown that intercellular adhesion molecule 1 (ICAM-1) and ICAM-2 on B cells are essential for longlasting Tfh/B cell interactions and the selection of low-affinity B-cell clones for proliferative clonal expansion. These data suggest that the expression of ICAMs on B cells is important for their effective antigen presentation [6]. In another study, the development of mucosal-associated invariant T (MAIT) cells was shown to be dependent on antigen presentation by B cells. In this case, antigen presentation requires MHC-related protein 1 (MR1) expression as well as commensal bacteria. Treating B cells with toll-like receptor 9 (TLR9) agonists increased MR1 surface expression and related bacterial presentation. This indicates that endosomal TLR9 activation is important for the efficiency of antigen presentation by B cells [7]. Autoantigen presentation by B cells in patients with autoimmune thyroiditis was also studied. In this case, antigen-loaded B cells (by thyroid tissue) have been shown to be capable of inducing the proliferation of auto-specific CD4+ T cells and the development of immune-mediated inflammation [8]. In a very recent study, IgE–immune complexes (IgE-IC) were shown to bind CD23 on B cells leading to their internalization in B cells. Then, B cells recycle IgE-IC in native form to the cell surface followed by the uptake of IgE-IC by DCs in cocultures. Cell-to-cell contact between B cells and DCs was followed by increased upregulation of CD86 and MHCII on DCs. In this study, B cells are shown to act as antigen-presenting cells transferring antigens to more efficient APCs such as DCs. Alternatively, B cells can directly induce DC maturation enhancing by that T-cell stimulation [9].
ACTIVATED B CELLS IN AUTOIMMUNITY The breakdown of self-tolerance and the development of autoimmune diseases such as SLE is closely related to B-cell hyperactivity and disturbed B-cell homeostasis. The understanding of how B cells are activated in the process of immunemediated diseases and how memory B cells are switched to become autoreactive is complex. Early studies defined the Mosaic of Autoimmunity. https://doi.org/10.1016/B978-0-12-814307-0.00003-7 Copyright © 2019 Elsevier Inc. All rights reserved.
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importance of CD5 and CD95 expression on B cells from SLE patients. It was found that activated B cells are characterized by having increased expression of CD5, and that this expression is in correlation with SLE disease activity. The expression of CD95 on B cells was also evaluated in normal and in SLE patients. In this case, inactive SLE patients were found to have higher proportion of CD95 high B cells being sensitive to undergo apoptosis. This implies that autoantibody-producing B cells are derived from CD95 low B cells thought to be resistant to apoptosis [10]. The differentiation process of naive B cells into IgG-secreting plasma cells is complex, involving many signals and pathways of activation. Looking into one of these, CD27neg B cells with enhanced expression of basal spleen tyrosine kinase (Syk) bright were found to be expanded in patients with SLE. These B cells were characterized as CD38neg but CD20 high and exhibited somatically mutated IgVH rearrangements and showed an enhanced differentiation into IgG-secreting plasma cells in contrast to Syk low B cells. CD27-Syk bright B cells but not Syk low B cells exhibited increased differentiation into CD27 high IgG–secreting cells and were highly inducible when cocultured with IFN-ɤ or TNF-α. This allows using intracellular markers such as Syk in distinguishing between naïve and memory B-cell subsets and being the source of increased plasma cells in SLE [11]. The role of activated memory B cells in systemic sclerosis (SSc) was also analyzed. Phenotypic characteristics of B cells were assessed in 28 patients with early form of SSc (9 with limited SSc and 19 with diffuse) and in 15 healthy individuals (controls). The following phenotypic subtypes were evaluated: CD19+CD27−IgD+ naïve; CD19+CD27+ memory; CD19+CD27+IgD+ nonswitched memory; CD19+CD27+IgD− switched memory. In addition, CD80+ or CD95+ activated cells were also identified. The proportion of naïve B cells was higher in SSc than in controls, but with decreased numbers of nonswitched memory B cells. In diffuse SSc patients switched memory B cells were found to be significantly higher compared with that in limited SSc. The percentage of CD95+CD27+ memory B cells was also significantly increased in diffused SSc. Increased switched and activated memory B cells are of pathogenic potential role by producing proinflammatory cytokines and autoantibodies [12]. The combination of CpG/TLR9 and IFN-α was shown to increase the differentiation of CD27+IgD+ unswitched memory B cells into CD27 high CD38 high plasmablasts. Whereas, CpG alone induced the differentiation of unswitched memory B cells into B cells with high cytokine production, this differentiation was suppressed by IFN-α. In addition, high m TORC1 activation was noted in CD19+ B cells of patients with SLE and correlated with plasmablasts differentiation and disease activity. The above-described activation pathways of human unswitched memory B cells into plasmablasts seem to be highly important in the pathogenesis of SLE [13]. The identification of human CD43+ B cells and their relation with memory B cells and plasmablasts was recently reported. CD19+CD43+ B cells were found to be of increased proliferating properties than naïve and even memory B cells. Though expressed on both memory B cells and on plasmablasts, CD43+ B cells gave rise to plasmablasts more efficiently than do memory B cells, which suggest that they are closely related to plasmablasts and therefore may be involved in the pathogenesis of autoimmunity [14]. The spontaneous production of IL-10, IL6, and TNF by B cells is minimal. When CD27+ memory B cells are activated with anti-Ig antibodies and CpG, IL-6, and TNF are strongly produced, whereas IL-10 is produced modestly and the capacity of TGF-β production is reduced. Thus, B-cell activation may lead to the development of enhanced immune responses and autoimmunity by decreasing TGF-β production and increasing their proinflammatory properties [15]. The excess of B-cell activating factor (BAFF) leads to the expansion of marginal zone (MZ) B cells and to their capacity in activating T cells. Increased BAFF level has been detected in the serum of many autoimmune diseases such as SLE, RA, and Sjogren’s syndrome and in correlation with disease activity. Decreased BAFF receptor expression on peripheral B cells was found to be in association with enhanced disease activity of Sjogren’s syndrome (pSS) and SLE. B cells from 20 patients with pSS, 19 with SLE, and 15 controls were analyzed by flow cytometry to assess the expression of BAFF receptor. The expression of BAFF receptor on memory CD27+ B cells was significantly decreased in patients with pSS and SLE. Serum BAFF level is inversely correlated with BAFF receptor expression. Decreased BAFF receptor expression was found to be in correlation with SLE disease activity index. This downregulation is suggested to be the consequence of chronic increase in BAFF. BAFF receptor levels on B cells may serve as a biomarker for assessing autoimmune disease activity [16]. The expression of BAFF receptor 3 (BR3) on B cells from SLE patients was further examined in a later study. Here also, BAFF levels were increased in the serum of these patients and in positive correlation with SLE disease activity but negatively with BR3 expression. Reduced BR3 expression was found to be on CD27− and CD27+ B cells of all SLE patients, but this was more in patients with lupus nephritis. This reduction is again suggested to act as a biomarker for active SLE, namely the occurrence of lupus nephritis [17]. The capacity of endogenous BAFF and IL-21 and exogenous factors such as CpG to induce the production of PR3-ANCA in granulomatosis with polyangiitis (GPA) was studied. Here, the stimulation with BAFF and IL-21 significantly increased ANCA production. This production was further increased by the addition of CpG-ODN. These data demonstrate how toll-like receptor 9 synergizes with IL-21 and with BAFF leading to increased ANCA production [18]. The abovementioned data support the notion that B-cell activation is complex and many signaling pathways are required for the development of autoreactivity and proinflammatory B cells leading to the development of autoimmune diseases.
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PROINFLAMMATORY B CELLS AND AUTOIMMUNITY Humoral immune responses begin when B lymphocytes are activated by antigens followed by the secretion of relevant antibodies. GCs are formed in the follicles of peripheral lymphoid organs when activated B cells migrate into the follicles and proliferate. Antigen-activated B cells are produced in GCs and obtain the ability to survive for long periods. These are memory B cells capable of rapid responses to previously recognized antigens. The production of large quantities of isotype-switched, high-affinity antibodies is increased after second exposure to antigens, usually following the activation of memory cells in GCs and the formation of immune complexes. In addition to their antibody-producing ability, activated B cells via the BCR, CD40 and toll-like receptors are also the source of many proinflammatory cytokines such as IL-10, IL-6, and IFNs.
IL-10-Producing B Cells in Autoimmunity IL-10 has an important role in the growth, survival, and differentiation of B cells in SLE patients. Increased IL-10 production induces B-cell hyperreactivity resulting in antibody production by switching plasma cells and the development of immune complexes [19]. Increased IL-10 in the serum of SLE patients was suggested in many reports to be associated with SLE disease activity. The loss of B-cell tolerance in the elderly is characterized by the increased prevalence of autoantibodies and rheumatoid factor. The issue of how and which cytokine these B cells produce and how this is related to autoimmunity was assessed. Absolute numbers of circulating B cells were similar in both young and old individuals. However, numbers of transitional B cells (CD19+CD27−CD38hiCD24hi) were decreased in old individuals. Following a short term in vitro stimulation of whole blood, the number of B cells capable of producing TNF-α was similar in young and old individuals, however, IL-10-producing B cells were decreased only in old individuals. Decreased IL-10-producing B cells was mainly noticed in old individuals in which ANA was positive but was retained in those in which RF was positive. These findings suggest that IL-10+ B cells may impact the development of ANAs and RFs in the elderly [20]. When pre-naïve B cells are stimulated through CD40, they produce large amounts of IL-10 but are unable to suppress CD4+ T-cell cytokine production. Differentiated pre-naïve B cells are autoreactive, thus, they produce IgM autoantibodies with reactivity to single-stranded deoxyribonucleic acid. In SLE, pre-naïve B cells have increased expression of costimulatory molecules but reduced ability of producing IL-10, resulting in increased CD4+ T-cell proliferation and the development of autoimmunity [21].
IL-6-producing B Cells and Autoimmunity Activated B cells are a source of IL-6 production, promoting by that Tfh cell differentiation. The lack of IL-6-producing B cells was shown to decrease spontaneous GC formation in a mouse model of SLE, thus, inhibiting the development of autoimmunity and the formation of switched autoantibodies. This finding suggests that IL-6-producing B cells contribute to autoimmunity through local IL-6 production, inducing by that Tfh differentiation and autoimmune GC formation [22]. IL-6 drives terminal B-cell differentiation and secretion of immunoglobulins. In one study, SLE-like disease parameters were studied in IL-6-deficient BXSB mice. Survival of IL-6-deficient mice was significantly prolonged in association with reduced autoimmune manifestations. B cells costimulated with TLR7 and BCR produced high levels of IL-6 which was further enhanced by IFN-1 stimulation. This suggests that high production of IL-6 by B cells increased by IFN-1 and TLR7 accelerates autoimmunity and the progression of SLE-like disease [23]. In a recent study, high sensitive C-reactive proteins (hs-CRP) and IL-6 levels were analyzed in SLE in relation with SLE disease activity. Mean hs-CRP levels were significantly higher in SLE than in controls. Similarly, IL-6 levels were significantly higher in active SLE as compared with inactive SLE. This study confirms a good correlation between IL-6 and disease activity indicating its direct involvement in SLE-related inflammation [24]. The distribution of transitional B-cell subsets in patients with systemic sclerosis was found to be altered in association with increased IL-6 production and altered self-tolerance. Defects in B-lymphocyte tolerance exist in parallel with altered apoptosis following BCR signaling and the failure to suppress autoreactive B cells, namely, the failure in regulating Scl-70 production. These data emphasize the role of autoreactive IL-6-producing transitional B cells in the pathogenesis of systemic sclerosis [25]. In a most recent study, anti-IL-6 therapy restored abnormal B-cell functions, namely, cytokine-mediated inflammation and autoreactivity. Rheumatoid arthritis B cells produce higher amounts of proinflammatory cytokines such as IL-8, IL-6, and others. Being continuously hyperactive, they become defective in their ability to maintain protective functions. Anti-IL-6 therapy reversed B-cell abnormalities including increased cytokine levels and loss of tolerance, indicating that abnormal IL-6 signaling is responsible for most humoral defects in RA [26].
18 SECTION | II Cellular and Molecular Mechanisms
IFNs and B Cells in Autoimmunity When B cells are stimulated by the TLR9 agonists-CpGs they proliferate and they secrete antibodies and many cytokines including IL-6. Toll-like receptor 9 agonists are also used in many adjuvants to boost both innate and adaptive immunity. In response to these adjuvants, B cells secrete proinflammatory cytokines such as type 1 IFNs pointing to the different pathways of stimulation by which they play role in different immune responses [27]. The mechanisms by which autoreactive B cells generate somatically mutated and class-switched pathogenic autoantibodies within developed GCs are continuously investigated. A possible mechanism in this respect is that B-cell-intrinsic IFN-γ receptor and STAT1 signaling are required for GC and Tfh cell formation. B-cell-specific IFN-γ receptor deficiency in autoimmune mice models resulted in reduced Tfh responses and altered titers of autoantibodies. IFN-γ deficiency did not affect GC, Tfh cell, or antibody responses against T-cell-dependent foreign antigens, suggesting that IFN-γ receptor signaling is uniquely important for autoantibody responses, but not for polyclonal antibody production. This suggests that IFN-γ signaling is central for the development of autoimmunity and therefore can be a potential target for a better beneficial treatment of SLE [28].
IN SUMMARY The role of B cells in healthy and disease immune responses is increasingly studied. Long-lived plasma cells are important in maintaining antibody secretion against foreign antigens and following vaccinations. In autoimmunity, autoreactive B cells are the source of specific autoantibodies but also of proinflammatory cytokines. Many signaling pathways are recently reported, aiming to identify their complexity. Some of these are summarized in this chapter.
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