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Graßhoff, H.;  Fourlakis, K.;  Comdühr, S.;  Riemekasten, G. Autoantibodies as Biomarker in Systemic Sclerosis. Encyclopedia. Available online: (accessed on 21 April 2024).
Graßhoff H,  Fourlakis K,  Comdühr S,  Riemekasten G. Autoantibodies as Biomarker in Systemic Sclerosis. Encyclopedia. Available at: Accessed April 21, 2024.
Graßhoff, Hanna, Konstantinos Fourlakis, Sara Comdühr, Gabriela Riemekasten. "Autoantibodies as Biomarker in Systemic Sclerosis" Encyclopedia, (accessed April 21, 2024).
Graßhoff, H.,  Fourlakis, K.,  Comdühr, S., & Riemekasten, G. (2022, November 11). Autoantibodies as Biomarker in Systemic Sclerosis. In Encyclopedia.
Graßhoff, Hanna, et al. "Autoantibodies as Biomarker in Systemic Sclerosis." Encyclopedia. Web. 11 November, 2022.
Autoantibodies as Biomarker in Systemic Sclerosis

Systemic sclerosis (SSc) is a rare connective tissue disorder characterized by immune dysregulation evoking the pathophysiological triad of inflammation, fibrosis and vasculopathy. In SSc, several alterations in the B-cell compartment have been described, leading to polyclonal B-cell hyperreactivity, hypergammaglobulinemia and autoantibody production. Autoreactive B cells and autoantibodies promote and maintain pathologic mechanisms. In addition, autoantibodies in SSc are important biomarkers for predicting clinical phenotype and disease progression. Autoreactive B cells and autoantibodies represent potentially promising targets for therapeutic approaches including B-cell-targeting therapies, as well as strategies for unselective and selective removal of autoantibodies.

systemic sclerosis autoreactive B cells autoantibodies

1. Introduction

Systemic sclerosis (SSc) is a rare connective tissue disorder characterized by immune dysregulation evoking the pathophysiological triad of inflammation, fibrosis and vasculopathy. This pathophysiological triad results in a heterogenous disease course involving the skin and internal organs such as the lung, the gastrointestinal tract, the heart, or the kidneys.
Several genes have been identified increasing disease susceptibility and several susceptibility haplotypes show an association to defined autoimmune profiles [1][2]. However, exposure to environmental agents and infectious pathogens is thought to play a major role in disease development and maintenance [3][4]. Furthermore, there are hints that the exposure to certain environmental factors leads to distinct clinical phenotypes and possibly also to a distinct autoantibody profile [5][6]. According to clinical and laboratory characteristics, SSc is divided into the limited cutaneous form (lcSSc) and the diffuse cutaneous form (dcSSc). In addition to this classification, further disease subsets have been distinguished, e.g., SSc-overlap syndromes, SSc sine scleroderma or paraneoplastic SSc. Beyond these classifications, however, the disease expression, the course of the disease, as well as the development of secondary disease complications and the mortality of the individual patient are heterogeneous. This heterogeneity has been a major obstacle in performing and analyzing clinical trials in SSc. For example, the risk of death varies greatly depending on the organ manifestations. Therefore, stratification of patients is essential in the therapy of SSc to predict disease progression and response to therapy.

2. Autoantibodies against Nuclear Antigens (ANAs)

A diagnostically important feature of SSc is the presence of circulating ANAs directed against nuclear or nucleolar proteins involved in transcription, splicing or cell proliferation. ANAs can be detected by indirect immunofluorescence. However, this technique is insufficient to identify specific ANAs except for anti-centromere antibodies. Therefore, additional techniques such as ELISA, immunodiffusion or Western immunoblotting can be used to determine the patients’ individual specific antigenic targets [7].
The determination of ANAs as well as specific ANAs is well-established in diagnosing SSc and is part of the ACR/EULAR 2013 classification criteria for SSc [8]. ANAs can be detected in >90% of SSc patients [9][10]. The group of ANA-negative patients constitutes a distinct clinical subtype characterized by predominantly male patients with a severe disease course, involvement of the lower gastrointestinal tract with corresponding symptoms and less vasculopathy [11]. Another study revealed an association between ANA negativity and gastric antral vascular ectasia (GAVE) [12].
Until now, a variety of SSc-specific ANAs (anti-topoisomerase I, anti-centromere, anti-RNA polymerase III, anti-Th/To, anti-eukaryotic initiation factor 2B (anti-eIF2B), anti-U11/U12 RNP) and ANAs not exclusively specific for SSc (anti-Pm/Scl-100, anti-Pm/Scl-75, anti-Ro52, anti-Ku, anti-fibrillarin (U3-RNP), anti-U1 RNP, anti-NOR90/hUBF, anti-RuvBL1/2) have been identified. Each of these autoantibodies has been associated with a unique set of disease manifestations, enabling the prediction of disease course, development of organ manifestations and an individual prognosis [13]. To further explain clinical differences of ANA subspecificities, Clark et al. performed a transcriptional and proteomic analysis of blood and skin of SSc patients with anti-topoisomerase I and anti-RNA polymerase III antibody specificities, revealing pathogenetic differences between ANA-based subgroups [14]. For the association of SSc-specific ANAs with corresponding clinical phenotypes, researchers refer to recently published reviews, e.g., by Cavazzana et al. [7] or Stochmal et al. [15]. In addition, recently, further ANAs were identified in subsets of SSc patients. These autoantibodies target telomerase and shelterin proteins and show an association with severe interstitial lung disease [16]. Moreover, detection of ANA subspecificities in patients suffering from SSc-associated diseases such as primary biliary cholangitis can be used to identify patients at increased risk for developing SSc [17][18].
A remarkable observation is that the ANA titers and specific ANAs remain relatively stable over the disease course, which makes them a valuable diagnostic tool [19].
Moreover, in most patients, only few ANA subspecificities are detected in parallel, so mutual exclusivity is assumed. Against this background, however, the simultaneous occurrence of various SSc-specific autoantibodies has been detected in several studies in small subgroups of patients [20][21]. In particular, the joint occurrence of anti-centromere and anti-topoisomerase I antibodies was investigated. Depending on the ethnicity of the patients examined and the techniques used to determine the ANA subspecificities, divergent results were found. So far, no clear clinical cluster has been identified that is associated with the simultaneous presence of anti-centromere and anti-topoisomerase I autoantibodies. Currently, there is no proven pathophysiological concept that explains the relative mutual exclusivity of the autoantibodies. Hypotheses suggest that the different ANA subspecificities might be epiphenomena based on different environmental conditions or due to differences in antigen processing by B cells showing associations with particular HLA alleles [22][23][24].
Currently, due to increasing possibilities for quantitative measurements of ANA subspecificities, it has been investigated whether these measurements could provide additional information to predict disease progression. These analyses revealed evidence that levels of anti-topoisomerase I antibodies are associated with disease severity [25][26]. However, the results of large multicenter studies need to be awaited.
In addition to the well-established role of ANAs in diagnostics and predicting disease progression, data on a pathogenic role in disease onset or maintenance are rare in SSc. In 1996, Rudnicka et al. demonstrated an altered activity of the topoisomerase I enzyme in SSc and suggested to evaluate topoisomerase I inhibitors as a potential therapeutic approach [27]. Moreover, studies suggest a pathogenic role of anti-topoisomerase I autoantibodies. This assumption is based on the observation that anti-topoisomerase I autoantibodies bind to the cellular surface of fibroblasts [28]. Moreover, binding of anti-topoisomerase I autoantibodies to fibroblasts stimulates adhesion and activation of monocytes in vitro [29]. Another study brought further evidence for a pathogenicity of anti-topoisomerase I and anti-centromere autoantibodies by stimulating human dermal fibroblasts with these autoantibodies and, as a result, inducing an increase in pro-fibrotic markers and apoptosis resistance [30].
Although these findings do not necessarily prove a substantial role of ANA in disease pathogenesis, these data provide first evidence for the use of immunosuppressive treatment in early SSc.

3. Anti-Neutrophil Cytoplasmic Antibodies (ANCAs)

The term ”anti-neutrophil cytoplasmic antibodies” (ANCAs) refers to autoantibodies against enzymes in primary granules of neutrophils or lysosomes of monocytes. ANCA subspecificities differ by indirect immunofluorescence, namely a cytoplasmic pattern (c-ANCA, e.g., autoantibodies against proteinase 3 (PR3)), a perinuclear pattern (p-ANCA, e.g., autoantibodies against myeloperoxidase (MPO)) and an atypical pattern showing aberrant patterns or a combination of c- and p-ANCA patterns (a-ANCA/x-ANCA). In addition to PR3 and MPO, ANCAs can be directed against further proteins such as elastase, cathepsin G, lactoferrin, α-enolase, catalase, azurocidin or actin [31]. The detection of ANCAs against PR3 and MPO is the hallmark of ANCA-associated vasculitis (AAV). In AAV, ANCAs lead to an activation of neutrophils primed by complement fragment C5a or cytokines (TNF-α, IL-1β), resulting in a translocation of PR3 or MPO to the cellular surface. After interaction between ANCAs with the target antigens PR3 or MPO and Fcγ receptors IIa or IIIb, intravascular near-wall degranulation of neutrophils and subsequent endothelial cell damage occurs [32][33][34]. ANCA-induced monocyte activation is mediated by a similar mechanism [35][36]. Subsequently, leukocyte migration and organ infiltration lead to secondary organ damage [37]. However, ANCAs can be detected in various other diseases (e.g., inflammatory bowel diseases, autoimmune hepatitis, primary sclerosing cholangitis), too [38].
Detection of ANCAs is a common phenomenon in SSc: the prevalence of ANCAs in SSc ranges up to 35% [39]. However, most studies report ANCA prevalence in 5–12% of SSc patients. The main antigenic targets are PR3 and MPO [40][41][42]. Although the presence of ANCAs is a common phenomenon in SSc, the development of systemic vasculitis in patients is rare [42][43]. The occurrence of systemic small-vessel vasculitis in SSc is grouped under the term SSc-AAV and is associated with a severe clinical phenotype involving the kidney, lung, peripheral and, rarely, the central nervous system, typically with a microscopic polyangiitis-like disease pattern [42]. In addition, patients may develop necrotizing vasculitis with critically reduced acral perfusion. Patients with renal manifestations typically present with pauci-immune glomerulonephritis or rapidly progressive glomerulonephritis. Patients with pulmonary involvement typically develop alveolar hemorrhage [42]. To date, there is limited evidence regarding promising treatment options for SSc-AAV. Randomized controlled trials are lacking. Possible treatment options that have been used so far include high-dose steroids, cyclophosphamide, rituximab, and plasma exchange. Before using high-dose steroids, the potential risk of developing a renal crisis should be considered in SSc [44]. In addition to autoantibodies against PR3 and MPO, autoantibodies with BPI and cathepsin G as antigenic targets have also been described in SSc [39]. Patients with ANCAs against BPI display lower skin scores.

4. Anti-Phospholipid Antibodies (aPL)

aPL comprise a group of antibodies directed against phospholipids and their cofactors, such as β2-glycoprotein I, prothrombin, annexin V and protein C or S. Phospholipids are components of the cell membrane and, together with the cofactors mentioned, play a role in hemostasis. In recent years, progress has been made in deciphering the pathomechanisms by which the binding of these autoantibodies to the protein–phospholipid complexes leads to increased blood coagulation, especially for the anti-β2-glycoprotein I antibodies.
aPL binding to β2GPI evoke a prothrombotic situation in endothelial cells through increased expression of adhesion molecules and tissue factor as well as reduced expression of the tissue factor pathway inhibitor [45][46]. In addition, complement activation is described [47]. Furthermore, in platelets, incubation with antibodies results in an activation of the glycoprotein IIa/IIIb (GPIIb/IIIa) receptor [48]. Moreover, activation of neutrophil granulocytes and monocytes by aPL has also been demonstrated [49][50][51].
aPL can be detected primarily without association to an underlying disease. In addition, aPL may be secondarily associated with autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, infections and cancers, but also with the use of medications such as oral contraceptives.
The detection of aPL also occurs frequently in SSc, with a prevalence of 9–20% [52]. In SSc, an association of anti-β2 glycoprotein 1 (β2GP1) positivity with active digital ulcerations has been demonstrated [53]. Moreover, a meta-analysis by Merashli et al. revealed an association between antibody positivity and pulmonary arterial hypertension, renal disease, thrombosis, miscarriage and digital ischemia compared to patients without aPL [54]. The association to venous thrombosis and miscarriage was confirmed in a meta-analysis by Sobanski et al. [52].

5. Autoantibodies Recognizing G-Protein-Coupled Receptors, Growth Factors and Their Respective Receptors

In addition to ANAs, ANCAs and aPL described in the previous sections, a new group of autoantibodies has recently been described which, in addition to their significance as biomarkers, are also becoming increasingly important in the pathophysiology of SSc. These comprise self-reactive autoantibodies recognizing GPCRs, growth factors and their respective receptors [55]. Anti-GPCR autoantibodies are present in healthy individuals and are thought to play a role in the regulation of immune cell homeostasis. These autoantibodies form a distinct, disease-specific network. It is hypothesized that this network reflects the patient’s individual exposure to a specific environmental condition [56].
To investigate functional effects of the autoantibody network in a disease, several in vitro and in vivo technologies were established. In vitro stimulation of cell lines or isolated cells with purified IgG fractions of SSc patients and healthy donors is an established technology which led to the formation of autoantibody classes with the same cellular target, e.g., anti-endothelial cell autoantibodies (AECA) or anti-fibroblast autoantibodies (AFA). Since it has not yet been possible to purify target-specific autoantibodies, the effects of target-specific autoantibodies can only be studied by using receptor blockers. Applying this technology, Murthy et al. stimulated cells of the monocytic cell line THP-1 with IgG purified from patients with SSc. Stimulation with SSc–IgG induced a change to a pro-fibrotic and pro-inflammatory phenotype with IgG donor–individual alterations. Moreover, SSc–IgG induced pathways including AP-1, TAK/IKK-β/NFκB and ERK1/2, driving secretion of CCL18 and CXCL8 from stimulated cells [57].
Moreover, several strategies have been established to transfer autoantibody-induced pathologies to animal models and build a platform to further investigate the respective pathomechanisms. These strategies involve the transfer of (a) serum [58], (b) IgG purified from serum [59] and (c) PBMC from diseased patients and healthy donors. A further strategy involves immunization with special agents, e.g., GPCR-overexpressing membrane extracts, (d), leading to the generation of autoantibodies and secondary to pathogenic effects [60][61]. These strategies were also applied to develop animal models of SSc mirroring autoantibody-mediated pathologies.
In 2014, Becker et al. transferred IgG purified from serum of SSc patients to C57BL/6J mice. These mice developed histological signs of an inflammatory pulmonary vasculopathy [62]. In addition, SSc–IgG positive for anti-AT1R and anti-ETAR autoantibodies induced increased neutrophil counts in bronchoalveolar fluid, pulmonary cellular infiltrations and cellular density after repeated passive transfer to C57BL/6J mice [63]. In a further study, a monoclonal AT1R autoantibody was injected into mice, which led to skin and lung inflammation. Interestingly, skin and lung inflammation did not occur in mice deficient in AT1Ra/b. This observation suggests a compelling involvement of autoantibody–receptor interaction in pathophysiological mechanisms [64].
In 2021, Yue et al. transferred PBMC of patients with SSc and granulomatosis with polyangiitis (GPA), as well as that of healthy donors, to Rag2-/-/IL2rg-/- mice. Subsequently, mice engrafted with PBMC developed an ANA pattern similar to the respective donor [65]. In a subsequent study, performed by the same group, membrane-embedded human AT1R or empty membranes as controls were transferred to C57BL/6J mice [64]. Immunization with membrane-embedded human AT1R resulted in detectable levels of AT1R autoantibodies in mice and induced skin and lung inflammation as well as skin fibrosis.
These studies support the pathophysiological concepts of SSc described in the previous sections. Moreover, these studies provide animal models of SSc resembling human pathophysiology and, thus, these animal models enable evaluation of potential therapeutic approaches.

6. Functional Autoantibodies against GPCR

In the following, data on specific autoantibodies targeting GPCR is summarized. GPCRs form a large family of receptors in vertebrates and are characterized by seven transmembrane domains with intervening extracellular and intracellular amino acids. These receptors are named for their interaction with G-proteins, which mediate intracellular signal transduction. In addition to the G-proteins, G-protein-independent pathways for signal transduction have been described. In recent years, an increasing number of GPCRs that are recognized by autoantibodies have been identified. Studies have shown that the occurrence of these autoantibodies is not linked to diseases, but that physiological levels of autoantibodies that recognize GPCRs can also be detected in healthy controls [55]. Subsequently, altered levels of these autoantibodies were described for numerous diseases, e.g., solid organ or stem-cell transplantations, cardiovascular diseases, cancer, neurological, endocrine, pulmonary or rheumatic systemic diseases.

Anti-AT1R and Anti-ETAR Autoantibodies

Anti-AT1R Autoantibodies are well-investigated autoantibodies involved in the pathophysiology of several diseases, e.g., kidney transplant rejection, preeclampsia, diabetes mellitus [66], lupus nephritis [67] or COVID-19 disease [68]. Autoantibodies directed against AT1R were first described in 1999. Specifically, Wallukat et al. described the occurrence of autoantibodies that recognize AT1R in patients with preeclampsia [69]. AT1R is a GPCR whose binding of the endogenous ligand angiotensin results in Gq-mediated calcium release, β-arrestin-mediated cell signaling and the production of reactive oxygen species. Further research in 2005 demonstrated the role of these antibodies as biomarkers predicting rejection in kidney transplantation [70]. In the meantime, the measurement of AT1R autoantibodies in transplantation medicine is well-established in clinical routine. Furthermore, in addition to the role of AT1R autoantibodies as biomarkers, the pathophysiological mechanisms mediated by the antibodies in transplant rejection could be deciphered. Anti-AT1R autoantibodies bind to two different epitopes, namely AFHYESQ and ENTNIT, and act as allosteric agonists at the AT1R. Thus, they lead to sustained activation [70][71][72]. Interaction of the anti-AT1R autoantibody with the receptor results in vasoconstriction as well as the formation of proinflammatory, profibrotic and procoagulatory conditions in the microvascular circulation. The proinflammatory and procoagulatory processes are activated by the receptor activation-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and subsequent activation of the transcription factors activator protein 1 (AP-1) and nuclear factor kB (NFκB) in the endothelium and smooth muscle vascular cells. Expression of AT1R on the surface of immune cells, especially polymorphonuclear leukocytes, monocytes, T and B lymphocytes, results in pro-inflammatory gene expression (IL-1, IL-6, IL-8, IL-17, TNF-α, IFN-γ), which may even maintain AT1R expression on endothelial cells [73][74][75]. Moreover, microvascular inflammation and vasoconstriction induced by anti-AT1R autoantibodies promotes thrombosis, endarteritis and fibrinoid necrosis. Here, the interaction between receptor and autoantibody depends on the AT1R expression level. The AT1R expression level varies due to genetic and non-genetic factors. Genetic factors involve polymorphisms in the AT1R gene [76]. Non-genetic factors that increase AT1R expression are inflammation, endothelial damage or disturbances in microcirculation [74][77]. For further information on anti-AT1R autoantibodies in kidney transplant rejection, researchers refer to a review published by Sorohan et al. [78].
Interestingly, similar mechanisms are assumed to be involved in the pathogenesis of preeclampsia. Here, the epitope, targeted by anti-AT1R autoantibody, is AFHYESQ which has also been described in kidney transplant rejection [69]. A further mechanism proposed for mediating effects of anti-AT1R autoantibodies in preeclampsia is the long-term presence of anti-AT1R autoantibodies which reduces aldosterone production in vitro [79].
The similarity of the autoantibody binding sites and the secondary processes in kidney transplant rejection and preeclampsia suggest similar pathophysiologic processes in other diseases. However, the epitope to which anti-AT1R autoantibodies—which mediate pathologies—bind in SSc has not yet been identified.
In SSc, elevated levels of angiotensin II (AngII) and endothelin-1 (ET-1) were detected in blood and tissue samples [80][81]. Therefore, the corresponding receptors were discussed as potential therapeutic targets; endothelin-1 receptor blockers are recommended for treatment of pulmonary arterial hypertension [82]. Moreover, bosentan showed beneficial effects in the treatment of Raynaud’s phenomenon and SSc-related digital ulcers [83][84][85][86].
In the majority of SSc patients, anti-AT1R and anti-ETAR autoantibodies are detectable. In addition, levels of anti-AT1R and anti-ETAR autoantibodies show a strong correlation with each other. Furthermore, both autoantibodies display the ability to exert functional activity at the respective receptor [56]. Regarding functional activity, in vitro experiments with IgG and receptor blockers for AT1R and ETAR proved that anti-AT1R and anti-ETAR autoantibodies bind to endothelial cells, exert phosphorylation of extracellular signal-regulated kinase 1/2 and increase TGFβ gene expression [87]. Moreover, Kill et al. demonstrated that anti-AT1R and anti-ETAR autoantibodies activate human microvascular endothelial cells in vitro, promoting secretion of proinflammatory chemokines and increased expression of adhesion molecules, enabling migration of neutrophils through an endothelial cell layer. Furthermore, using the same experimental setup, Kill et al. induced profibrotic processes in fibroblasts [63]. Günther et al. investigated the effects of PBMC stimulation with IgG from SSc patients and healthy controls, revealing an increased induction of IL-8 and CCL18 by SSc–IgG compared to healthy controls. These effects could be diminished by adding AT1R and ETAR blockers to the experimental setup [88].
In addition, anti-AT1R and anti-ETAR autoantibodies amplified vasoconstrictive effects of Ang II and ET-1 in small-vessel myography of intralobar pulmonary rat artery ring segments [62]. The amplification of Ang II- and ET-1-mediated effects by anti-AT1R and anti-ETAR autoantibodies was confirmed in in vitro analyses using the technology ”dynamic mass redistribution” [64].
High levels of these autoantibodies showed an association with severe disease complications. Anti-ETAR autoantibodies—together with acute digital ulcers or ulcers in a patient’s history—can be used to predict development of subsequent digital ulcers [89]. Moreover, anti-AT1R and anti-ETAR autoantibodies can predict the development of pulmonary arterial hypertension in SSc. Moreover, comparing levels of anti-AT1R and anti-ETAR autoantibodies in forms of pulmonary hypertension revealed highest levels for pulmonary arterial hypertension in SSc and connective tissue diseases. The same study revealed anti-AT1R and anti-ETAR autoantibodies as predictors of mortality in SSc [62]. Further information on the role of anti-AT1R and anti-ETAR autoantibodies are summarized in a review by Cabral-Marques and Riemekasten [90].

Anti-Muscarinic-3 Acetylcholine Receptor (M3R) Autoantibodies

Anti-M3R autoantibodies have been associated with intestinal dysmotility: a cardinal pathological condition and cause of the most gastrointestinal manifestations in patients with SSc [91]. Kumar et al. suggested a model of sequentially developing dysmotility: anti-M3R autoantibodies initially inhibit the release of acetylcholine (Ach) at the myenteric cholinergic neurons, inducing neuropathy through the blockage of cholinergic neurotransmission. Consequently, myopathy develops as a result of an anti-M3R autoantibody-related inhibition of Ach at the smooth muscle cells of the gastrointestinal tract. Smooth muscle fibrosis and atrophy ensue [92]. It can thus be hypothesized that an early and sustained elimination of anti-M3R autoantibodies could possibly lead to a reversal of SSc-associated dysmotility at the neuropathic and myopathic stages. Indeed, Kumar et al. presented evidence that application of IVIGs decreases binding intensity of anti-M3R autoantibodies and, thus, could probably decrease SSc-related gastrointestinal symptoms [92]. Accordingly, Raja et al. confirmed a significant improvement of gastrointestinal symptoms after repeated IVIG administration [93].

Anti-CXCR3 and Anti-CXCR4 Autoantibodies

Weigold et al. showed that autoantibody levels differ among subgroups of patients suffering from SSc, with dcSSc patients having the highest levels of autoantibodies directed to the N-terminal domain of CXCR3 and CXCR4. Comparable to anti-AT1R and anti-ETAR autoantibodies, anti-CXCR3 and anti-CXCR4 autoantibody levels also correlate with one another. Moreover, in SSc patients with interstitial lung disease, levels of autoantibodies directed to the N-terminus of CXCR3 and CXCR4 were lower in patients with progressive disease than in patients with stable disease [94]. Therefore, these autoantibodies might be a valuable tool to predict disease course of SSc patients with interstitial lung disease. A proposed hypothesis for an association between low autoantibody levels and disease progression is that the corresponding autoantibodies might be predominantly present in the tissues and, accordingly, detection of autoantibody levels in the blood may give lower levels [56]. So far, however, no studies have been conducted to bring evidence to this hypothesis. Currently, it is unclear whether autoantibodies directed to CXCR3 and CXCR4 exhibit functional activity. As shown for the AT1R autoantibody, functional activity of an autoantibody depends on the respective epitope. Therefore, Recke et al. applied a peptide-based epitope mapping for CXCR3. In this analysis, they could show differences in epitopes of anti-CXCR3 autoantibodies between SSc and healthy controls. Whereas autoantibodies from SSc patients preferentially bind to intracellular CXCR3 epitopes, autoantibodies of healthy controls bind to epitopes in the N-terminal domain [95].

Anti-PAR-1 Autoantibodies

Further potentially interesting autoantibodies in SSc are anti-PAR-1 autoantibodies. A first hint that anti-PAR-1 autoantibodies might exhibit functional activity in SSc was based on the observation that IL-6 release of HMECs stimulated with IgG from SSc patients could be reduced by a PAR-1 inhibitor. Moreover, stimulation of HMECs with IgG from SSc patients resulted in an increased expression of phosphorylated pAKT, p70S6K and pERK1/2, whereas this increase in expression was not observed after stimulation with IgG from healthy controls. Further experiments revealed an increased transcriptional activity of c-FOS and AP-1 after stimulation with SSc–IgG, which finally results in IL-6 mRNA expression and, subsequently, secretion of IL-6. To sum this up, anti-PAR-1 autoantibodies resemble the signaling pathway of thrombin, one of the natural ligands, which also leads to IL-6 secretion after binding to PAR-1 [96]. However, currently, the role of IL-6 in scleroderma renal crisis is obscure. Additional evidence for the pathomechanism described here provides a study showing an improvement in creatinine levels during therapy with tocilizumab in scleroderma renal crisis [97].


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