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Systemic sclerosis: New evidence re-enforces the role of B cells
AUTREV-01775; No of Pages 7 Autoimmunity Reviews xxx (2015) xxx–xxx
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Review
Systemic sclerosis: New evidence re-enforces the role of B cells Lazaros I. Sakkas a,b,⁎, Dimitrios P. Bogdanos a,c a b c
Department of Rheumatology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa 41 110, Greece Center for Molecular Medicine, Old Dominion University, Norfolk, VA, USA Division of Transplantation Immunology and Mucosal Biology, Kings College School of Medicine, London SE5 9RS, UK
a r t i c l e
i n f o
Article history: Received 4 October 2015 Accepted 17 October 2015 Available online xxxx Keywords: Systemic sclerosis Autoantibodies B cells Bregs Fibrosis Vasoconstriction
a b s t r a c t Systemic sclerosis (SSc) is characterized by widespread fibrosis, microangiopathy (vasospasms and stenosis), and formation of autoantibodies. T cell activation has been shown to contribute to fibrosis and microvasculopathy in SSc. However, recent evidence suggests that B cells are also likely to contribute in the pathogenesis of the disease. B cells are hyperactivated in SSc, as indicated by the overexpression of the stimulatory CD19 receptor and impairment of the inhibitory CD22 receptor. They lead to the production of many autoantibodies, some of which induce collagen production and vasoconstriction. They promote fibroblast collagen production through cell contact. Furthermore, B cells can function as antigen-presenting cells to T cells and induce dendritic cell maturation that promotes profibrotic Th2 response. Lately, interleukin (IL)-10-producing B regulatory cells, which induce generation of T regulatory cells and can ameliorate autoimmune diseases, were found to be reduced in SSc, favoring autoaggression of B cells in this disease. Finally, B cell depletion with rituximab improves or stabilizes skin fibrosis and lung function. These finding suggest that new therapeutic strategies targeting B cell function(s) can be developed for SSc. © 2015 Elsevier B.V. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . 2. B cells are hyperactivated in SSc . . . . . . . . . . . . . . 3. B cells can produce profibrotic cytokines . . . . . . . . . . 4. Autoantibodies promote fibrosis/inflammation in SSc . . . . 5. IL-10-producing regulatory B cells (Bregs) are decreased in SSc 6. B cells promote profibrotic Th2 response . . . . . . . . . . 7. B cells in models of human SSc . . . . . . . . . . . . . . 8. B cell-based treatment in SSc . . . . . . . . . . . . . . . 9. Future perspectives . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Systemic sclerosis (SSc) is chronic multisystem disease characterized by widespread fibrosis, autoantibodies, and microangiopathy. Fibrosis involves the skin and internal organs, including lung, gastrointestinal tract, and heart. Microangiopathy is characterized by vasospastic episodes and fibrointimal proliferation causing vascular ⁎ Corresponding author at: Department of Rheumatology, Medical School, University of Thessaly, Biopolis, Larissa 41 110, Greece. E-mail address: [email protected] (L.I. Sakkas).
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stenosis that leads to digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. The etiopathogenesis of SSc is incompletely understood [1,2]. Environmental factors play a major role [3], since in a twin study the concordance rate of SSc in monozygotic twins is low and equal to that in dizygotic twin [4]. Fibrosis of the skin and internal organs is the hallmark of the disease, and for years the pathogenesis of SSc has been evolved around fibroblasts. However, the evolution of SSc in the skin, an easily accessible organ to study, has shown that there are lymphocytic infiltrates early in the disease process before even histological fibrosis [5]. In the early inflammatory skin stage, there is also apoptosis of endothelial cells. In
http://dx.doi.org/10.1016/j.autrev.2015.10.005 1568-9972/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Sakkas LI, Bogdanos DP, Systemic sclerosis: New evidence re-enforces the role of B cells, Autoimmun Rev (2015), http:// dx.doi.org/10.1016/j.autrev.2015.10.005
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L.I. Sakkas, D.P. Bogdanos / Autoimmunity Reviews xxx (2015) xxx–xxx
fact, endothelial cells were the first cell type to undergo apoptosis in UCD 200/206 chicken, an avian model of scleroderma [6]. Autoantibodies and microangiopathy, as detected by nailfoldcapillaroscopy, may occur years before clinical skin fibrosis and are now included in the new classification criteria for SSc [7–9]. These findings alluded to the possibility that immune cells might activate fibroblasts to produce excess collagen. T cells and macrophages are the predominant mononuclear cell infiltrates in the skin of SSc [5,10,11]. T cells in SSc skin are activated. They express the early activation antigen CD69 [11], and suction blisters in SSc skin contain elevated levels of soluble IL-2 receptor [12]. T cells in SSc are of TH2 type producing the profibrotic cytokines IL-4 and IL-13 [1]. The finding that T cells in SSc skin lesions exhibit oligoclonal expansion and certain T cell clones persist in skin lesions over time indicates an antigen-driven immune response and further re-enforces the concept of T cell involvement in SSc pathogenesis [1,13]. In recent years, the role of B cells in the pathogenesis of SSc has become increasingly apparent. B cells can promote fibrosis by cytokines, autoantibodies, and cell–cell contact.
Table 1 Autoantibody targets in patients with SSc. Autoantibody target
Comments
Ref
Topoisomerase I Centromere RNA polymerase III Th/To Platelet-derived growth factor receptor (PDGFR) Endothelial cell
Associated with dcSSc Associated with lcSSc Associated with dcSSc Associated with scleroderma renal crisis Stimulatory, inducing fibroblast activation and collagen production Induce endothelial cell activation and/or apoptosis Activate endothelial cells Stimulatory, strong predictors of digital ulcers Stimulatory, associated with pre-eclampsia and malignant hypertension
[32] [33] [35] [36] [37]
Mimicry targets, cross-reactive with endothelial cells Inhibit the inhibitory CD22 signals Inhibit collagenolyticactivity, thus increased intracellular matrix Increase fibroblast collagen production
[52]
ICAM-1 Endothelin type A receptor (ETAR) Angiotensin II type 1 receptor (AT1R) hCMV-derived UL94 CD22 Matrix metalloproteinase I
Fibrillin
[41] [42] [47] [44,48]
[23] [39]
[50]
2. B cells are hyperactivated in SSc B cells infiltrates in SSc lesions are variable[14–18], yet there is convincing evidence for the participation of B cells in the pathogenesis of the disease. B cells in SSc are hyperactive, as exemplified by the presence of hyper-γ-globulinemia, autoantibodies, and increased serum free light chains of immunoglobulins [19]. B cells from patients with SSc overexpress the B cell stimulatory receptor CD19 by 54% in patients with early SSc and by 28% in patients with long-standing disease [20]. Overexpression of CD19 in SSc, although to a lesser degree, was also reported earlier [21]. It should be mentioned that small increase (15–29%) in B cell CD19 expression in transgenic mice–induced autoantibody production [21]. B cell activating factor (BAFF), a B cell survival factor, is increased in SSc [22]. In contrast, the function of CD22, an inhibitory B cell molecule, is inhibited by anti-CD22 autoantibodies present in patients with SSc [23]. B cells are also activated in a model of systemic sclerosis, namely, chronic graft-versus-host disease (cGVHD), a condition that develops after allogeneic hematopoietic stem cell transplantation, and shares clinical and serological features with human SSc [24] and in tight-skin (TSK) mice, another model of SSc [25]. 3. B cells can produce profibrotic cytokines Activated B cells can produce profibrotic cytokines IL-6, and TGFβ. IL-6 can induce fibroblast collagen production [26] through the bone morphogenetic protein (BMP) antagonist gremlin and the canonical TGFβ signaling [27]. Serum IL-6 was elevated in SSc patients [28–30], and skin IL-6 expression was also increased [30]. TGFb, increased in scleroderma, is a powerful profibrotic cytokine [31]. 4. Autoantibodies promote fibrosis/inflammation in SSc The hyperactivity of B cells in SSc is exemplified by the presence of a plethora of autoantibodies. Some of autoantibodies found in patients with SSc promote fibrosis and/or pro-inflammatory response. These autoantibodies, and their specific action, are shown in Table 1. Antitopoisomerase I [32] and anti-centromere antibodies are diseasespecific antibodies associated with diffuse cutaneous (dcSSc) and limited cutaneous disease (lcSSc), respectively. More interestingly, anti-Topoisomerase I and anti-centromere antibodies were associated more closely with clinical manifestations than cutaneous SSc subsets were [33]. Anti-topoisomerase I antibodies recognize their target that is released from apoptotic endothelial cells and binds to fibroblast membrane [32]. Anti-fibroblast antibodies induce fibroblast production of
chemokines CCL2 (monocyte chemoattractant protein-1) and CXCL8 (interleukin-8) [34]. Anti-RNA polymerase III antibodies are associated with dcSSc [35] and anti-Th/To antibodies are associated with lcSSc and scleroderma renal crisis in some studies [36]. Autoantibodies against platelet-derived growth factor receptor (PDGFR) stimulated activation and collagen production in normal human fibroblasts [37]. Stimulatory anti-PDGFR autoantibodies inducing collagen production were also found cGVHD [38]. Anti-matrix metalloproteinase(MMP)-1 antibodies and anti-MMP-3 antibodies, found in SSc, are functional and inhibit MMP-1 and MMP-3 collagenase activity, respectively, thus reducing extracellular matrix breakdown and promoting accumulation of extracellular matrix [39,40]. Anti-endothelial cell antibodies cause endothelial cell apoptosis [41] and/or endothelial cell activation. Also, anti-ICAM-1 antibodies, frequently detected in SSc patients, cause increased endothelial cell production of reactive oxygen species (ROS) and expression of VCAM-1 [42]. Anti-endothelin-1 type A receptor (ETAR) autoantibodies and anti-angiotensin II type 1 receptor (AT1R) autoantibodies, detected in most SSc patients, are agonist antibodies and cause fibrosis and vasoconstriction [43–45]. They activate vascular endothelial cell production of TGFβ (a powerful profibrotic cytokine), IL-8, and vascular cell adhesion molecule-1 (VCAM-1) [43,46]. SSc-IgG with anti-ETAR and anti-AT1R antibodies, but not normal IgG, when injected to mice, caused obliterative vasculopathy [45]. Anti-ETAR autoantibodies are strong predictors of digital ulcers in patients with SSc [47]. Anti-AT1R autoantibodies are associated with hypertensive entities, such as pre-eclampsia, and severe kidney transplant rejection with malignant hypertension [44]. Furthermore, pregnant mice develop pre-eclampsia when injected with affinity-purified anti-AT1R autoantibodies from women with pre-eclampsia [48]. It should be noted that angiotensin II increased fibroblast production of TGFβ and collagen via its type 1 receptor [49]. Anti-fibrillin antibodies activate fibroblast collagen production [50]. Another autoantibody found in SSc targets CD22, a major inhibitory B cell receptor. Anti-CD22 autoantibodies inhibit CD22 signals and are associated with enhanced skin fibrosis, as detected by the Rodnan skin score [23] (Fig. 1 and Table 1). The targets of autoantibodies in SSc, apart from contributing to disease pathogenesis, may also serve as mimicry targets of immune response to foreign agents. For instance, anti-topoisomerase I monoclonal antibodies recognize a pentapeptide of topoisomerase I from SSc patients that shares homology with human CMV-derived UL70 protein [51]. Also, many SSc patients have antibodies against human CMVderived UL94 protein that shares homology with NAG-2 (tetraspan novel antigen-2), expressed on endothelial cell surface. Furthermore,
Please cite this article as: Sakkas LI, Bogdanos DP, Systemic sclerosis: New evidence re-enforces the role of B cells, Autoimmun Rev (2015), http:// dx.doi.org/10.1016/j.autrev.2015.10.005
L.I. Sakkas, D.P. Bogdanos / Autoimmunity Reviews xxx (2015) xxx–xxx
Breg
B cell
3
B cell anti -CD22
a-fibrillin
a-ETAR a-AT1R
a-PDGFR
a-ECs a-ICAM1 a-MMP
Inhibition of inhibitory CD22
a-fib fibroblast
ECs
CXCL8 TGFβ VCAM-1
collagen
apoptosis ROS VCAM-1
CCL2 CXCL8
vasoconstriction
Extracellular Matrix
Fig. 1. Autoantibodies promote B cell hyperactivity, fibrosis, and vasoconstriction. In a hypothetical model, Bregs inhibit B cell hyperactivity through Tregs. ECs: endothelial cells; fib: fibroblast; MMP: metalloproteinase I; ETAR: endothelin A receptor; AT1T: angiotensin II type 1 receptor; ROS: reactive oxygen species.
anti-UL94 peptide antibodies bind to NAG-2 on endothelial cells and induce their apoptosis [52]. 5. IL-10-producing regulatory B cells (Bregs) are decreased in SSc Regulatory B cells (Bregs) are recently described subsets of B cells that downregulate inflammation, by inhibiting the differentiation of TH1 and TH17 cells and by inducing Tregs, and ameliorate autoimmune diseases through cytokines, such as IL10, TGFβ, and antigendependent-, CD40-dependent interaction with T cells and the help of IL-21 or IL-35[53–55]. Although the phenotypes of Bregs are still evolving, a subset of Bregs mediates their regulatory function through IL-10 production (B10 cells) [56]. B10 cells are reported to be mainly
CD24(hi) CD38(-) CD27(+) memory B regs (blue)
included within CD19 + CD24highCD38high (transitional Bregs) or CD19 + CD24highCD27+ (memory Bregs) phenotypes [57,58]. New data showing that B10 cells are decreased in SSc re-enforce the role of B cells in this disease. In SSc, we showed that phenotypic memory Bregs were decreased particularly in long-standing disease and in SScassociated pulmonary fibrosis (SSc-PF) [20]. IL-10-producing Bregs were also impaired particularly in SSc-PF (Fig. 2). Furthermore, after B cell receptor and TLR9 stimulation of naive and memory B cells STAT3 and p38MAPK activation was impaired. Another study also reported reduced IL-10-producing Bregs in SSc and an inverse correlation between Bregs and the titre of anti-topoisomerase I antibodies and anticentromere antibodies [59]. Similarly, in cGVHD, B cells were found to be activated [24] and Bregs to be deficient [60].
CD24(hi) CD38(hi) CD27(-) transitional B regs cells (green)
CD19
SSC
CD24
Healthy control
CD38
FSC
CD27
SSC
CD24
CD19
earlySSc
FSC
CD38
CD27
Fig. 2. Flow cytometry profile of memory (blue color) and transitional (green color) in a representative healthy individual and a patient with early SSc. Bregs are decreased in early SSc.
Please cite this article as: Sakkas LI, Bogdanos DP, Systemic sclerosis: New evidence re-enforces the role of B cells, Autoimmun Rev (2015), http:// dx.doi.org/10.1016/j.autrev.2015.10.005
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Induction of autoantibody production Anti-Topo I Anti-CEN
Naïve B cells
Naïve T cells
Naïve B cells
Effector Effector B cells T cells
Naïve T cells
Effector Effector B cells T cells
Bregs Decrease of Bregs and Tregs Tregs
Healthy Immunological Tolerance
SSc at diagnosis SSc with pulmonary fibrosis Loss of Immunological Tolerance
Fig. 3. Suggestive status of B cells and T cells in health and disease. Effector B cells and T cells are increased in SSc whereas Bregs and Tregs are decreased, particularly in long-standing disease and SSc-associated pulmonary fibrosis. The decreased number/function of Bregs correlates with high titre of disease-specific autoantibodies.
Reduced IL-10-producing Bregs were also associated with increased autoantibody titres in ANCA-associated vasculitis. In the latter disease, IL-10-producing Bregs were reduced in active disease and normalized in disease remission which was accompanied with reduction of ANCA titres [61]. Based on these findings, we propose a scheme of Bregs involvement in autoantibody production (Figs. 3 and 4). 6. B cells promote profibrotic Th2 response B cells, through cell contact, induce dendritic cell maturation that promotes profibrotic Th2 differentiation [62] (Fig. 5). They can also serve as antigen-presenting cells [63]. Although still evolving, there is increasing evidence suggesting that antigen presentation by B cells interplaying with dendritic cells favors Th2 response [64–66]. In human x-linked agammaglobulinemia, a primary deficiency of the B cell compartment, T cell response is preferentially Th1 [67].
Breg
7. B cells in models of human SSc There are various animal models of SSc that offer the sequence of events leading to fibrosis, as well as access to study the effect of manipulation of various cells and cytokines on animal manifestations. As already mentioned, in cGVHDB cells are activated [24] and Bregs are deficient [60]. Furthermore, Bregs derived from donor suppress cGVHD in mice [68]. Serum IL-6 was increased in murine cGVHD [69]. In tight-skin (TSK) mice, a genetic model of SSc characterized by skin fibrosis and autoantibodies, B cell activation is important for autoantibody production and fibrosis [25]. CD19 is overexpressed whereas CD22 function is impaired in TSK mice [21,25,70]. Small increase (15–29%) in the expression of B cell CD19 results in spontaneous autoantibody production [21,70]. In contrast, CD19 deficiency significantly decreased skin fibrosis and CD19 loss completely abrogated autoantibody production in TSK mice [25]. Serum BAFF levels were increased
Breg
CD4 T cell
CD4 T cell
Th2
B cell Treg
Th2
AutoAbs
B cell
AutoAbs
Treg
Healthy Individual
Systemic Sclerosis
Fig. 4. Bregs maintain Tregs which in turn inhibit activated T cells. In a hypothetical scheme, this leads to downregulation of B cells with subsequent reduction of autoantibodies production. In SSc, B regs are deficient and inadequate to sustain Tregs. This in turn facilitates Th2 activation and autoantibodies production.
Please cite this article as: Sakkas LI, Bogdanos DP, Systemic sclerosis: New evidence re-enforces the role of B cells, Autoimmun Rev (2015), http:// dx.doi.org/10.1016/j.autrev.2015.10.005
L.I. Sakkas, D.P. Bogdanos / Autoimmunity Reviews xxx (2015) xxx–xxx Activated B cell
DC
Th2
5
It is worth mentioning the therapeutic efficacy of high-dose intravenous immunoglobulin (IVIg) in SSc ([83] and reviewed in Cantarini et al [84]). IVIg has multiple actions on different immune cells and mediators including its effect through anti-idiotypic antibodies [85]. All evidence outlined above supports a role for B cell involvement in SSc (Table 2).
IL-13
9. Future perspectives
IL-4
Fibroblast activation Collagen accumulation
fibrosis Fig. 5. Activated B cells through cell contact promote dendritic cell (DC) maturation that favors Th2 response and leads to fibrosis.
in TSK mice, whereas a BAFF antagonist prevented skin fibrosis and autoantibody production [71]. Another model of SSc, bleomycin-induced fibrosis, is caused by subcutaneous injection of bleomycin and characterized by skin and lung fibrosis and autoantibodies. In this model, bleomycin induced hyaluronan production which activated B cells mainly through tolllike receptor 4, whereas CD19 deficiency resulted in attenuation of fibrosis and autoantibody production [72]. A similar effect of CD19 deficiency was found in a bleomycin-induced lung fibrosis mouse model, caused by intratracheal injection of bleomycin [73]. A new mice model of SSc develops after injection of topoisomerase I with complete Freud's adjuvant [74]. These mice develop skin and lung fibrosis along with Th2/Th17 response and increased IL-6 production. Furthermore, loss of IL-6 expression improved skin and lung fibrosis [74].
The finding of increased B cell CD19 expression in early SSc along with greatly reduced IL10-producing Bregs favors autoaggression of B cells and makes B cells an attractive therapeutic target for this disease. It also offers new insights for treatment strategies. For instance, Bregs derived from donor suppress the cGVHD in mice [68]. Also, ex vivo provision of CD40 and IL-21 receptor signals induced the development and expansion of B10 cells that, when infused into mice with established EAE, a model for multiple sclerosis, greatly inhibited the symptoms of the disease [86]. Similarly, ex vivo expansion of Bregs with IL-35 suppressed uveitis in mice by inhibiting TH1 and TH17 responses and promoting the expansion of Tregs [55]. Therefore, B cells are becoming an attractive target for intervention with different approaches in this frequently devastating disease. Take-home messages • Systemic sclerosis is a multisystem disease characterized by widespread fibrosis, microvasculopathy, and autoantibodies. • Autoantibodies may appear years before clinical disease and inflammatory infiltrates in skin appear before histological fibrosis • B cells may participate in disease pathogenesis through cytokines, autoantibodies, and B cell contact with fibroblasts or dendritic cells • The immunoregulatory Bregs producing IL-10 are decreased in SSc. • B cell depleting treatment decreased skin fibrosis and stabilized/ improved lung function.
8. B cell-based treatment in SSc References B cell depleting therapy with anti-CD20 monoclonal antibody (rituximab) in SSc case series improved skin fibrosis and stabilized/ improved lung involvement (function) [15,16,75–79]. The improvement of skin fibrosis by rituximab was associated with attenuation of PDGFR in the skin [80]. Similarly, B cell depletion with anti-CD20 monoclonal antibody in neonatal TSK mice reduced skin fibrosis [81]. Loss of CD19 abrogated autoantibody production and attenuated skin fibrosis [25], whereas BAFF antagonist attenuated skin fibrosis in TSK mice [71]. Bregs derived from donor suppress cGVHD in a mouse model of SSc [68]. Neutralization of IL-6 by tocilizumab (anti-IL-6 receptor monoclonal antibody) improved skin thickness in SSc patients in an observational study [82]. Similarly, anti-IL-6R treatment or immunization with IL-6 peptide reduced skin thickness in bleomycin-induced mouse model of SSc [30]. Anti-IL-6R monoclonal antibody also attenuated murine cGVHD [69]. Table 2 Evidence for B cell involvement in the pathogenesis of SSc. B cells are hyperactivated. B cells can produce cytokines that promote fibrosis/inflammation. B cells produce autoantibodies that promote fibrosis/vasoconstriction/ inflammation. B cell-fibroblast contact promotes fibrosis. B cells through dendritic cell maturation promotes profibrotic TH2 response. Bregs are reduced in SSc. B cell-eliminating therapies reduce/stabilize fibrosis in SSc. B cells are critical for skin fibrosis and autoantibody production in human cGVHD, and animal models of SSc. TSK: tight-skin mice; cGVHD: chronic graft-versus-host disease.
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Review
Systemic sclerosis: New evidence re-enforces the role of B cells Lazaros I. Sakkas a,b,⁎, Dimitrios P. Bogdanos a,c a b c
Department of Rheumatology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa 41 110, Greece Center for Molecular Medicine, Old Dominion University, Norfolk, VA, USA Division of Transplantation Immunology and Mucosal Biology, Kings College School of Medicine, London SE5 9RS, UK
a r t i c l e
i n f o
Article history: Received 4 October 2015 Accepted 17 October 2015 Available online xxxx Keywords: Systemic sclerosis Autoantibodies B cells Bregs Fibrosis Vasoconstriction
a b s t r a c t Systemic sclerosis (SSc) is characterized by widespread fibrosis, microangiopathy (vasospasms and stenosis), and formation of autoantibodies. T cell activation has been shown to contribute to fibrosis and microvasculopathy in SSc. However, recent evidence suggests that B cells are also likely to contribute in the pathogenesis of the disease. B cells are hyperactivated in SSc, as indicated by the overexpression of the stimulatory CD19 receptor and impairment of the inhibitory CD22 receptor. They lead to the production of many autoantibodies, some of which induce collagen production and vasoconstriction. They promote fibroblast collagen production through cell contact. Furthermore, B cells can function as antigen-presenting cells to T cells and induce dendritic cell maturation that promotes profibrotic Th2 response. Lately, interleukin (IL)-10-producing B regulatory cells, which induce generation of T regulatory cells and can ameliorate autoimmune diseases, were found to be reduced in SSc, favoring autoaggression of B cells in this disease. Finally, B cell depletion with rituximab improves or stabilizes skin fibrosis and lung function. These finding suggest that new therapeutic strategies targeting B cell function(s) can be developed for SSc. © 2015 Elsevier B.V. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . 2. B cells are hyperactivated in SSc . . . . . . . . . . . . . . 3. B cells can produce profibrotic cytokines . . . . . . . . . . 4. Autoantibodies promote fibrosis/inflammation in SSc . . . . 5. IL-10-producing regulatory B cells (Bregs) are decreased in SSc 6. B cells promote profibrotic Th2 response . . . . . . . . . . 7. B cells in models of human SSc . . . . . . . . . . . . . . 8. B cell-based treatment in SSc . . . . . . . . . . . . . . . 9. Future perspectives . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Systemic sclerosis (SSc) is chronic multisystem disease characterized by widespread fibrosis, autoantibodies, and microangiopathy. Fibrosis involves the skin and internal organs, including lung, gastrointestinal tract, and heart. Microangiopathy is characterized by vasospastic episodes and fibrointimal proliferation causing vascular ⁎ Corresponding author at: Department of Rheumatology, Medical School, University of Thessaly, Biopolis, Larissa 41 110, Greece. E-mail address: [email protected] (L.I. Sakkas).
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stenosis that leads to digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. The etiopathogenesis of SSc is incompletely understood [1,2]. Environmental factors play a major role [3], since in a twin study the concordance rate of SSc in monozygotic twins is low and equal to that in dizygotic twin [4]. Fibrosis of the skin and internal organs is the hallmark of the disease, and for years the pathogenesis of SSc has been evolved around fibroblasts. However, the evolution of SSc in the skin, an easily accessible organ to study, has shown that there are lymphocytic infiltrates early in the disease process before even histological fibrosis [5]. In the early inflammatory skin stage, there is also apoptosis of endothelial cells. In
http://dx.doi.org/10.1016/j.autrev.2015.10.005 1568-9972/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Sakkas LI, Bogdanos DP, Systemic sclerosis: New evidence re-enforces the role of B cells, Autoimmun Rev (2015), http:// dx.doi.org/10.1016/j.autrev.2015.10.005
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L.I. Sakkas, D.P. Bogdanos / Autoimmunity Reviews xxx (2015) xxx–xxx
fact, endothelial cells were the first cell type to undergo apoptosis in UCD 200/206 chicken, an avian model of scleroderma [6]. Autoantibodies and microangiopathy, as detected by nailfoldcapillaroscopy, may occur years before clinical skin fibrosis and are now included in the new classification criteria for SSc [7–9]. These findings alluded to the possibility that immune cells might activate fibroblasts to produce excess collagen. T cells and macrophages are the predominant mononuclear cell infiltrates in the skin of SSc [5,10,11]. T cells in SSc skin are activated. They express the early activation antigen CD69 [11], and suction blisters in SSc skin contain elevated levels of soluble IL-2 receptor [12]. T cells in SSc are of TH2 type producing the profibrotic cytokines IL-4 and IL-13 [1]. The finding that T cells in SSc skin lesions exhibit oligoclonal expansion and certain T cell clones persist in skin lesions over time indicates an antigen-driven immune response and further re-enforces the concept of T cell involvement in SSc pathogenesis [1,13]. In recent years, the role of B cells in the pathogenesis of SSc has become increasingly apparent. B cells can promote fibrosis by cytokines, autoantibodies, and cell–cell contact.
Table 1 Autoantibody targets in patients with SSc. Autoantibody target
Comments
Ref
Topoisomerase I Centromere RNA polymerase III Th/To Platelet-derived growth factor receptor (PDGFR) Endothelial cell
Associated with dcSSc Associated with lcSSc Associated with dcSSc Associated with scleroderma renal crisis Stimulatory, inducing fibroblast activation and collagen production Induce endothelial cell activation and/or apoptosis Activate endothelial cells Stimulatory, strong predictors of digital ulcers Stimulatory, associated with pre-eclampsia and malignant hypertension
[32] [33] [35] [36] [37]
Mimicry targets, cross-reactive with endothelial cells Inhibit the inhibitory CD22 signals Inhibit collagenolyticactivity, thus increased intracellular matrix Increase fibroblast collagen production
[52]
ICAM-1 Endothelin type A receptor (ETAR) Angiotensin II type 1 receptor (AT1R) hCMV-derived UL94 CD22 Matrix metalloproteinase I
Fibrillin
[41] [42] [47] [44,48]
[23] [39]
[50]
2. B cells are hyperactivated in SSc B cells infiltrates in SSc lesions are variable[14–18], yet there is convincing evidence for the participation of B cells in the pathogenesis of the disease. B cells in SSc are hyperactive, as exemplified by the presence of hyper-γ-globulinemia, autoantibodies, and increased serum free light chains of immunoglobulins [19]. B cells from patients with SSc overexpress the B cell stimulatory receptor CD19 by 54% in patients with early SSc and by 28% in patients with long-standing disease [20]. Overexpression of CD19 in SSc, although to a lesser degree, was also reported earlier [21]. It should be mentioned that small increase (15–29%) in B cell CD19 expression in transgenic mice–induced autoantibody production [21]. B cell activating factor (BAFF), a B cell survival factor, is increased in SSc [22]. In contrast, the function of CD22, an inhibitory B cell molecule, is inhibited by anti-CD22 autoantibodies present in patients with SSc [23]. B cells are also activated in a model of systemic sclerosis, namely, chronic graft-versus-host disease (cGVHD), a condition that develops after allogeneic hematopoietic stem cell transplantation, and shares clinical and serological features with human SSc [24] and in tight-skin (TSK) mice, another model of SSc [25]. 3. B cells can produce profibrotic cytokines Activated B cells can produce profibrotic cytokines IL-6, and TGFβ. IL-6 can induce fibroblast collagen production [26] through the bone morphogenetic protein (BMP) antagonist gremlin and the canonical TGFβ signaling [27]. Serum IL-6 was elevated in SSc patients [28–30], and skin IL-6 expression was also increased [30]. TGFb, increased in scleroderma, is a powerful profibrotic cytokine [31]. 4. Autoantibodies promote fibrosis/inflammation in SSc The hyperactivity of B cells in SSc is exemplified by the presence of a plethora of autoantibodies. Some of autoantibodies found in patients with SSc promote fibrosis and/or pro-inflammatory response. These autoantibodies, and their specific action, are shown in Table 1. Antitopoisomerase I [32] and anti-centromere antibodies are diseasespecific antibodies associated with diffuse cutaneous (dcSSc) and limited cutaneous disease (lcSSc), respectively. More interestingly, anti-Topoisomerase I and anti-centromere antibodies were associated more closely with clinical manifestations than cutaneous SSc subsets were [33]. Anti-topoisomerase I antibodies recognize their target that is released from apoptotic endothelial cells and binds to fibroblast membrane [32]. Anti-fibroblast antibodies induce fibroblast production of
chemokines CCL2 (monocyte chemoattractant protein-1) and CXCL8 (interleukin-8) [34]. Anti-RNA polymerase III antibodies are associated with dcSSc [35] and anti-Th/To antibodies are associated with lcSSc and scleroderma renal crisis in some studies [36]. Autoantibodies against platelet-derived growth factor receptor (PDGFR) stimulated activation and collagen production in normal human fibroblasts [37]. Stimulatory anti-PDGFR autoantibodies inducing collagen production were also found cGVHD [38]. Anti-matrix metalloproteinase(MMP)-1 antibodies and anti-MMP-3 antibodies, found in SSc, are functional and inhibit MMP-1 and MMP-3 collagenase activity, respectively, thus reducing extracellular matrix breakdown and promoting accumulation of extracellular matrix [39,40]. Anti-endothelial cell antibodies cause endothelial cell apoptosis [41] and/or endothelial cell activation. Also, anti-ICAM-1 antibodies, frequently detected in SSc patients, cause increased endothelial cell production of reactive oxygen species (ROS) and expression of VCAM-1 [42]. Anti-endothelin-1 type A receptor (ETAR) autoantibodies and anti-angiotensin II type 1 receptor (AT1R) autoantibodies, detected in most SSc patients, are agonist antibodies and cause fibrosis and vasoconstriction [43–45]. They activate vascular endothelial cell production of TGFβ (a powerful profibrotic cytokine), IL-8, and vascular cell adhesion molecule-1 (VCAM-1) [43,46]. SSc-IgG with anti-ETAR and anti-AT1R antibodies, but not normal IgG, when injected to mice, caused obliterative vasculopathy [45]. Anti-ETAR autoantibodies are strong predictors of digital ulcers in patients with SSc [47]. Anti-AT1R autoantibodies are associated with hypertensive entities, such as pre-eclampsia, and severe kidney transplant rejection with malignant hypertension [44]. Furthermore, pregnant mice develop pre-eclampsia when injected with affinity-purified anti-AT1R autoantibodies from women with pre-eclampsia [48]. It should be noted that angiotensin II increased fibroblast production of TGFβ and collagen via its type 1 receptor [49]. Anti-fibrillin antibodies activate fibroblast collagen production [50]. Another autoantibody found in SSc targets CD22, a major inhibitory B cell receptor. Anti-CD22 autoantibodies inhibit CD22 signals and are associated with enhanced skin fibrosis, as detected by the Rodnan skin score [23] (Fig. 1 and Table 1). The targets of autoantibodies in SSc, apart from contributing to disease pathogenesis, may also serve as mimicry targets of immune response to foreign agents. For instance, anti-topoisomerase I monoclonal antibodies recognize a pentapeptide of topoisomerase I from SSc patients that shares homology with human CMV-derived UL70 protein [51]. Also, many SSc patients have antibodies against human CMVderived UL94 protein that shares homology with NAG-2 (tetraspan novel antigen-2), expressed on endothelial cell surface. Furthermore,
Please cite this article as: Sakkas LI, Bogdanos DP, Systemic sclerosis: New evidence re-enforces the role of B cells, Autoimmun Rev (2015), http:// dx.doi.org/10.1016/j.autrev.2015.10.005
L.I. Sakkas, D.P. Bogdanos / Autoimmunity Reviews xxx (2015) xxx–xxx
Breg
B cell
3
B cell anti -CD22
a-fibrillin
a-ETAR a-AT1R
a-PDGFR
a-ECs a-ICAM1 a-MMP
Inhibition of inhibitory CD22
a-fib fibroblast
ECs
CXCL8 TGFβ VCAM-1
collagen
apoptosis ROS VCAM-1
CCL2 CXCL8
vasoconstriction
Extracellular Matrix
Fig. 1. Autoantibodies promote B cell hyperactivity, fibrosis, and vasoconstriction. In a hypothetical model, Bregs inhibit B cell hyperactivity through Tregs. ECs: endothelial cells; fib: fibroblast; MMP: metalloproteinase I; ETAR: endothelin A receptor; AT1T: angiotensin II type 1 receptor; ROS: reactive oxygen species.
anti-UL94 peptide antibodies bind to NAG-2 on endothelial cells and induce their apoptosis [52]. 5. IL-10-producing regulatory B cells (Bregs) are decreased in SSc Regulatory B cells (Bregs) are recently described subsets of B cells that downregulate inflammation, by inhibiting the differentiation of TH1 and TH17 cells and by inducing Tregs, and ameliorate autoimmune diseases through cytokines, such as IL10, TGFβ, and antigendependent-, CD40-dependent interaction with T cells and the help of IL-21 or IL-35[53–55]. Although the phenotypes of Bregs are still evolving, a subset of Bregs mediates their regulatory function through IL-10 production (B10 cells) [56]. B10 cells are reported to be mainly
CD24(hi) CD38(-) CD27(+) memory B regs (blue)
included within CD19 + CD24highCD38high (transitional Bregs) or CD19 + CD24highCD27+ (memory Bregs) phenotypes [57,58]. New data showing that B10 cells are decreased in SSc re-enforce the role of B cells in this disease. In SSc, we showed that phenotypic memory Bregs were decreased particularly in long-standing disease and in SScassociated pulmonary fibrosis (SSc-PF) [20]. IL-10-producing Bregs were also impaired particularly in SSc-PF (Fig. 2). Furthermore, after B cell receptor and TLR9 stimulation of naive and memory B cells STAT3 and p38MAPK activation was impaired. Another study also reported reduced IL-10-producing Bregs in SSc and an inverse correlation between Bregs and the titre of anti-topoisomerase I antibodies and anticentromere antibodies [59]. Similarly, in cGVHD, B cells were found to be activated [24] and Bregs to be deficient [60].
CD24(hi) CD38(hi) CD27(-) transitional B regs cells (green)
CD19
SSC
CD24
Healthy control
CD38
FSC
CD27
SSC
CD24
CD19
earlySSc
FSC
CD38
CD27
Fig. 2. Flow cytometry profile of memory (blue color) and transitional (green color) in a representative healthy individual and a patient with early SSc. Bregs are decreased in early SSc.
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Induction of autoantibody production Anti-Topo I Anti-CEN
Naïve B cells
Naïve T cells
Naïve B cells
Effector Effector B cells T cells
Naïve T cells
Effector Effector B cells T cells
Bregs Decrease of Bregs and Tregs Tregs
Healthy Immunological Tolerance
SSc at diagnosis SSc with pulmonary fibrosis Loss of Immunological Tolerance
Fig. 3. Suggestive status of B cells and T cells in health and disease. Effector B cells and T cells are increased in SSc whereas Bregs and Tregs are decreased, particularly in long-standing disease and SSc-associated pulmonary fibrosis. The decreased number/function of Bregs correlates with high titre of disease-specific autoantibodies.
Reduced IL-10-producing Bregs were also associated with increased autoantibody titres in ANCA-associated vasculitis. In the latter disease, IL-10-producing Bregs were reduced in active disease and normalized in disease remission which was accompanied with reduction of ANCA titres [61]. Based on these findings, we propose a scheme of Bregs involvement in autoantibody production (Figs. 3 and 4). 6. B cells promote profibrotic Th2 response B cells, through cell contact, induce dendritic cell maturation that promotes profibrotic Th2 differentiation [62] (Fig. 5). They can also serve as antigen-presenting cells [63]. Although still evolving, there is increasing evidence suggesting that antigen presentation by B cells interplaying with dendritic cells favors Th2 response [64–66]. In human x-linked agammaglobulinemia, a primary deficiency of the B cell compartment, T cell response is preferentially Th1 [67].
Breg
7. B cells in models of human SSc There are various animal models of SSc that offer the sequence of events leading to fibrosis, as well as access to study the effect of manipulation of various cells and cytokines on animal manifestations. As already mentioned, in cGVHDB cells are activated [24] and Bregs are deficient [60]. Furthermore, Bregs derived from donor suppress cGVHD in mice [68]. Serum IL-6 was increased in murine cGVHD [69]. In tight-skin (TSK) mice, a genetic model of SSc characterized by skin fibrosis and autoantibodies, B cell activation is important for autoantibody production and fibrosis [25]. CD19 is overexpressed whereas CD22 function is impaired in TSK mice [21,25,70]. Small increase (15–29%) in the expression of B cell CD19 results in spontaneous autoantibody production [21,70]. In contrast, CD19 deficiency significantly decreased skin fibrosis and CD19 loss completely abrogated autoantibody production in TSK mice [25]. Serum BAFF levels were increased
Breg
CD4 T cell
CD4 T cell
Th2
B cell Treg
Th2
AutoAbs
B cell
AutoAbs
Treg
Healthy Individual
Systemic Sclerosis
Fig. 4. Bregs maintain Tregs which in turn inhibit activated T cells. In a hypothetical scheme, this leads to downregulation of B cells with subsequent reduction of autoantibodies production. In SSc, B regs are deficient and inadequate to sustain Tregs. This in turn facilitates Th2 activation and autoantibodies production.
Please cite this article as: Sakkas LI, Bogdanos DP, Systemic sclerosis: New evidence re-enforces the role of B cells, Autoimmun Rev (2015), http:// dx.doi.org/10.1016/j.autrev.2015.10.005
L.I. Sakkas, D.P. Bogdanos / Autoimmunity Reviews xxx (2015) xxx–xxx Activated B cell
DC
Th2
5
It is worth mentioning the therapeutic efficacy of high-dose intravenous immunoglobulin (IVIg) in SSc ([83] and reviewed in Cantarini et al [84]). IVIg has multiple actions on different immune cells and mediators including its effect through anti-idiotypic antibodies [85]. All evidence outlined above supports a role for B cell involvement in SSc (Table 2).
IL-13
9. Future perspectives
IL-4
Fibroblast activation Collagen accumulation
fibrosis Fig. 5. Activated B cells through cell contact promote dendritic cell (DC) maturation that favors Th2 response and leads to fibrosis.
in TSK mice, whereas a BAFF antagonist prevented skin fibrosis and autoantibody production [71]. Another model of SSc, bleomycin-induced fibrosis, is caused by subcutaneous injection of bleomycin and characterized by skin and lung fibrosis and autoantibodies. In this model, bleomycin induced hyaluronan production which activated B cells mainly through tolllike receptor 4, whereas CD19 deficiency resulted in attenuation of fibrosis and autoantibody production [72]. A similar effect of CD19 deficiency was found in a bleomycin-induced lung fibrosis mouse model, caused by intratracheal injection of bleomycin [73]. A new mice model of SSc develops after injection of topoisomerase I with complete Freud's adjuvant [74]. These mice develop skin and lung fibrosis along with Th2/Th17 response and increased IL-6 production. Furthermore, loss of IL-6 expression improved skin and lung fibrosis [74].
The finding of increased B cell CD19 expression in early SSc along with greatly reduced IL10-producing Bregs favors autoaggression of B cells and makes B cells an attractive therapeutic target for this disease. It also offers new insights for treatment strategies. For instance, Bregs derived from donor suppress the cGVHD in mice [68]. Also, ex vivo provision of CD40 and IL-21 receptor signals induced the development and expansion of B10 cells that, when infused into mice with established EAE, a model for multiple sclerosis, greatly inhibited the symptoms of the disease [86]. Similarly, ex vivo expansion of Bregs with IL-35 suppressed uveitis in mice by inhibiting TH1 and TH17 responses and promoting the expansion of Tregs [55]. Therefore, B cells are becoming an attractive target for intervention with different approaches in this frequently devastating disease. Take-home messages • Systemic sclerosis is a multisystem disease characterized by widespread fibrosis, microvasculopathy, and autoantibodies. • Autoantibodies may appear years before clinical disease and inflammatory infiltrates in skin appear before histological fibrosis • B cells may participate in disease pathogenesis through cytokines, autoantibodies, and B cell contact with fibroblasts or dendritic cells • The immunoregulatory Bregs producing IL-10 are decreased in SSc. • B cell depleting treatment decreased skin fibrosis and stabilized/ improved lung function.
8. B cell-based treatment in SSc References B cell depleting therapy with anti-CD20 monoclonal antibody (rituximab) in SSc case series improved skin fibrosis and stabilized/ improved lung involvement (function) [15,16,75–79]. The improvement of skin fibrosis by rituximab was associated with attenuation of PDGFR in the skin [80]. Similarly, B cell depletion with anti-CD20 monoclonal antibody in neonatal TSK mice reduced skin fibrosis [81]. Loss of CD19 abrogated autoantibody production and attenuated skin fibrosis [25], whereas BAFF antagonist attenuated skin fibrosis in TSK mice [71]. Bregs derived from donor suppress cGVHD in a mouse model of SSc [68]. Neutralization of IL-6 by tocilizumab (anti-IL-6 receptor monoclonal antibody) improved skin thickness in SSc patients in an observational study [82]. Similarly, anti-IL-6R treatment or immunization with IL-6 peptide reduced skin thickness in bleomycin-induced mouse model of SSc [30]. Anti-IL-6R monoclonal antibody also attenuated murine cGVHD [69]. Table 2 Evidence for B cell involvement in the pathogenesis of SSc. B cells are hyperactivated. B cells can produce cytokines that promote fibrosis/inflammation. B cells produce autoantibodies that promote fibrosis/vasoconstriction/ inflammation. B cell-fibroblast contact promotes fibrosis. B cells through dendritic cell maturation promotes profibrotic TH2 response. Bregs are reduced in SSc. B cell-eliminating therapies reduce/stabilize fibrosis in SSc. B cells are critical for skin fibrosis and autoantibody production in human cGVHD, and animal models of SSc. TSK: tight-skin mice; cGVHD: chronic graft-versus-host disease.
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Please cite this article as: Sakkas LI, Bogdanos DP, Systemic sclerosis: New evidence re-enforces the role of B cells, Autoimmun Rev (2015), http:// dx.doi.org/10.1016/j.autrev.2015.10.005