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 Table of Contents  
Year : 2017  |  Volume : 12  |  Issue : 6  |  Page : 142-148

The pathogenesis of scleroderma

1 Division of Rheumatology, Perelman School of Medicine, University of Philadelphia, Philadelphia, Pennsylvania, USA
2 Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Web Publication23-Nov-2017

Correspondence Address:
Latika Gupta
Division of Rheumatology, Perelman School of Medicine, University of Philadelphia, Philadelphia, Pennsylvania
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-3698.219083

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Systemic sclerosis (SSc) results from the complex interplay between the immune system, vasculature and tissue-repair mechanisms. Endothelial injury is the prime event; environmental triggers in the susceptible individual trigger the pathologic process, which translates into fibrosis. The outcome of SSc is not as bleak as it looked a couple of decades ago. With a greater understanding of older pathways, as well as elucidation of newer ones, the potential targets to block and even reverse fibrosis bring around a revolution in the way we look at this once dreaded disease.

Keywords: Endothelial dysfunction, endothelial progenitor cells, endothelial to mesenchymal transition, fibrosis, hypoxia, serotonin, transforming growth factor-beta

How to cite this article:
Gupta L, Ahmed S, Zanwar A. The pathogenesis of scleroderma. Indian J Rheumatol 2017;12, Suppl S1:142-8

How to cite this URL:
Gupta L, Ahmed S, Zanwar A. The pathogenesis of scleroderma. Indian J Rheumatol [serial online] 2017 [cited 2022 Aug 16];12, Suppl S1:142-8. Available from:

  Introduction Top

Systemic sclerosis (SSc) is a multisystem disorder with varied disease manifestations. The prevalence varies considerably in different parts of the world, with reports ranging from 38 to 660 cases/million.[1] The two subtypes – diffuse and limited SSc, are distinct entities as seen from the trajectory of their natural histories. It has been known for decades that the true onset of limited SSc is marked by the onset of Raynaud's phenomenon years before the diagnosis is made. It is much later in the disease course that the patient developed sclerodactyly and gastrointestinal manifestations. Telangiectasias appear even later. On the other hand, dcSSc presents with generalized skin thickening much sooner after the onset of Raynaud's; although, skin thickening is seen to regress at a time when fibrosis within internal organs stabilizes. Thus, the phenotype for each subtype may evolve over time to accrue additional, though trajectories of the two subtypes features do not overlap. This concept was further strengthened by Milano et al. in 2008 by distinct gene expression signatures that characterized different clinical phenotypes in their cohort.[2] Interestingly, dcSSc further formed two unsupervised clusters, based on predominant expression of inflammation verses vasculopathy phenotype. The clusters remained stable over time, suggesting disease heterogeneity and not natural history. Thus, inflammatory phenotypes may exist in this disease that was otherwise though to be predominantly noninflammatory in older times.

Despite ongoing research since ages, the field of fibrosis has largely failed to find good disease-modifying drugs. In recent times, there is considerable change in our understanding of disease pathogenesis. With this knowledge, attempts to target specific molecules have met limited success.[3] In this article, we review pathogenesis of SSc and its recent advances.

The pathogenesis of SSc involves the interplay between the immune system, vasculature and connective tissue repair mechanisms. Endothelial injury is thought to be the prime event, and appropriate environmental triggers in the susceptible individual trigger the pathologic process.

  The Triggers Top

Like in most other autoimmune disease, here too, infections were thought to be the prime triggers. Bacteria were implicated to start with, but initial studies of pan-bacterial polymerase chain reaction in the skin of eighteen disease individuals failed to demonstrate bacterial DNA.[4] However, enthusiasm picked up again, when antibodies to the protein epitopes of cytomegalovirus (CMV) were found in patients with SSc.[5] It was soon established that anti-topoisomerase antibodies (ATA), the prototypic antibody in dcSSc, could also cross react with some viral proteins. The proteins of CMV bore sequence homology with human antigens such as heterogeneous nuclear ribonucleoproteins and fibrillarin. This was later confirmed by molecular characterization studies. More importantly, antibodies to UL94 (the CMV protein implicated) could induce endothelial cell apoptosis in cultures, and even endothelial to mesenchymal transition (EMT) at times.[5] This was the forerunner for fibroblast activation, proliferation, and collagen production-all pathological hallmarks of fibrosis. Curiously, similar changes are seen in chronic allograft vasculopathy, another disease where CMV is implicated.

Other potential triggers such as silica, heavy metals, bleomycin, and L-tryptophan have been uncommonly reported in past.[6],[7],[8] Although mechanism of such triggers inducing scleroderma-like illness is not very clear, most accepted explanation is, once endothelial activation occurs, intravascular micro-thrombosis, ischemia, production of reactive oxygen species, reperfusion injury after lysis and intimal proliferation ensues, culminating in a vicious cycle of further endothelial injury.

  The Pathogenesis of Vasculopathy Top

Endothelial injury

Endothelial injury and apoptosis are the inciting events in pathogenesis of the disease. This is seen in Fra-2 transgenic mice, which is the best-fit animal model of vasculopathy. In these mice, endothelial apoptosis occurred at 9 weeks, before the onset of fibrosis and micro-vasculopathy at 12 weeks.[9] It was fascinating to see that these changes occurred independent of cytokines like transforming growth factor-β (TGF) or vascular endothelial growth factor. Thus, immune pathways may be engaged after the first hit occurs in the disease.

In humans, anti-endothelial antibodies are postulated as one of the mechanisms of vascular endothelial cell apoptosis; but are present in only a small proportion of cases.[10]

Endothelial dysfunction

The endothelium in the physiological state exerts vasodilator and antithrombotic properties through several mediators, most important being nitric oxide (NO). NO is synthesized by endothelial NO synthase (eNOS), and it exerts vaso-protective effects. Dysfunctional endothelium produces less constitutive eNOS although inducible nitric oxide synthase (iNOS) levels remains normal. Reduced endothelial expression of NO synthase has been demonstrated in various studies.[11] As a result of these, the basal NO levels fall, and vasoconstriction occurs in the small vessels of the extremities. Hypoxic injury is capable of inducing free radicals and further endothelial damage.

Endothelin-1 (ET) production is another important molecule produced by the dysfunctional endothelium.[12] It forms an important link between fibrosis and vasculopathy. After release from the endothelial cells, it increases EMT transition and release of pro-fibrotic mediators. Attenuation of bleomycin-induced fibrosis is seen in endothelin receptor B knockout mice.[13]

This functionally defective endothelium has a pro-inflammatory and thrombotic phenotype and is prone to mesenchymal transition. Activated endothelium in SSc has greater expression of adhesion molecules such as VCAM, ICAM-1 and E-selectin and several studies have shown good correlation with serum levels of soluble adhesion molecules with disease severity, vital capacity decline, and long-term prognosis [14],[15] Endothelial activation also leads to releases of thrombin and platelet activation markers.

Endothelial to mesenchymal transition

Myofibroblast proliferation is an important pathologic hallmark of SSC. These cells either arise from proliferation of existing cells or transformation from neighboring cells like epithelial, endothelial cell and pericytes [16],[17] The epithelial cells lose basal polarity and cell-to-cell contact due to actin reorganization. They cease to express epithelial markers and start expressing α-SMA. They have increased contractile ability, less apoptosis, more proliferative potential and secrete excess extracellular matrix (ECM). Normally this is a transient event in wound repair, but the process continues unabated in the setting of SSc, leading to a vicious cycle of proliferation and fibrosis.[16] Hypoxia, reactive oxygen species, Wnt, TGF β and ET promote EMT, while endothelin receptor antagonist, and bone morphogenic protein 7 inhibits the same [18],[19]

  Circulating Endothelial Precursor Cells Top

Endothelial progenitors cells (EPCs) contribute to vascular repair. Classic progenitors cells are decreased in circulation in SSc. Monocytic EPCs are increased in number, but hey have less vasculogenic potential.[20]

  Role of Platelets Top

Platelet activation has an important role in aggravating the endothelial injury once it has begun. Platelets in SSc have higher expression of activation markers such as P-selectin, GP IIb/IIIa, and CD40 L.[21] Serotonin released from activated platelets is critical in initiating dermal fibrosis.[22] The lung is an important organ in catabolism of serotonin; increased serotonin due to platelet activation may be a possible explanation for lung fibrosis in SSc. Bleomycin mice fail to develop fibrosis when serotonin 5 HT2c receptors are knocked out.[22]

  Role of Hypoxia Top

Hypoxia is key to the development of Raynaud's phenomenon, the clinical hallmark of SSc. It is typically observed at the tips of the extremities; areas which have high density of arteriovenous connections for thermoregulation. These connections are innervated by sympathetic nervous system, which evokes vasoconstriction on cold exposure. Hypoxia leads to Rho kinase activation and consequent translocation of adrenergic α 2A/2C receptors to the surface of the blood vessels, leading to exaggerated vasoconstriction.[Figure 1] Normally the upstream nutrient arteries are spared from these effects due to release of vasodilatory factors from the endothelium. However, hypoxia causes endothelial dysfunction and compromised flow in the nutrient arteries as well. This culminates in tissue necrosis and digital ulcers.
Figure 1: The pathogenesis of Raynaud's phenomenon in healthy and Systemic Scelrosis patients

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Apart from propagating Raynaud's hypoxia also accentuates most of the steps in SSc pathogenesis. Most of these effects are mediated through the transcription factor hypoxia-inducible factor-1α.[23] Apart from induction of ET-1, it causes chemokine release, monocyte recruitment, endothelial apoptosis and EMT as well as the release of profibrotic mediators.[24]

  The Pathogenesis of Fibrosis Top

Widespread fibrosis of the skin and internal organs is the pathologic characteristic of SSc. All the implicated pathways converge onto fibrosis, be it immune-mediated or otherwise. Finally, it is the activation of fibroblasts that signals the release of collagen into the tissues.

It is intriguing to know that tissue fibroblasts behave differently from fibroblasts in culture, where extinction of activation is seen in serial cultures. This emphasizes the importance of the appropriate milieu to let the process continue unabated.[25] In SSc, nonfibrillar collagen type 7 is increased in the skin, whereas the routine dominant fibrillar type 2 and 3 of normal skin remain the same.[26]

TGF-β is the most crucial cytokine in the induction of fibrosis in various chronic inflammatory diseases. It is released following inflammatory responses leading to increased production of ECM components; as well as mesenchymal cell proliferation, migration, and accumulation. TGF-β signaling invokes various intracellular signaling cascades. The canonical Smad pathway utilizes sequential activating phosphorylation of the type I TGF-β receptor, Smad2 and Smad3, finally followed by formation of hetero-complexes of Smad2 and Smad3 with Smad4. These then translocate to the nucleus and induce transcription of various pro-fibrotic genes [Figure 2]. In the case of type I collagen gene, recruitment of the histone acetylase p300/CBP is essential for stimulation of transcription.[25]
Figure 2: (a) Canonical TGF β signaling, (b) Non canonical TGF β signaling pathway. TGFβ: Transforming Growth Factor - β, TGFβRI and II: TGF β Receptor Subunits I and II, pSmads (3,4,5): Phosphorylated Smad Adaptor Proteins, TAK1: Transforming growth factor-β activated kinase 1, JNK: c-Jun N-terminal kinases, TRAF: TNF (Tumor Necrosis Factor) Receptor Associated Protein, p38: Negative Regulator of Ras, MAP-K: Mitogen-activated Protein Kinase, Erk1: Extracellular signal Regulated Kinase 1, RhoA: Small GTPase protein of Rho family, ROCK: Rho-associated protein kinase, Jun and Fos: c-Jun and c-Fos forms the AP-1 early response transcription factor

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There are Smad independent noncanonical pathways that involve activation of kinases such as ERK, JNK, and p38. Connective tissue growth factor and platelet-derived growth factor (PDGF) are ligands that initiate while Wnt β catenin is a facilitator of these pathways.[25]

  Pathology of Connective Tissue Repair Top

SSc has been long viewed as unregulated tissue repair due to unchecked fibroblast proliferation. Skin biopsies show collagen fiber accumulation most prominently in the reticular (deep) dermis. This gradually invades the subjacent adipose layer with entrapment of fat cells. In early stages of SSc, a perivascular cellular infiltrates seen composed of T lymphocytes and monocytes and less commonly mast cells and eosinophils.[27] The number of myofibroblasts is increased and with disease progression, the skin atrophies with thinning of the epidermis and effacement of the rete pegs and accumulation of compact hyalinized collagen bundles in the dermis. Dermal capillaries are sparse even in the clinically uninvolved “normal” skin.

  Immune Pathogenesis of Systemic Sclerosis Top

It was not until very long ago when SSc was thought to be a predominantly noninflammatory disease. With the discovery of various antibodies, it was thought to be an antibody-mediated disease. Numerous experiments to elucidate the pathological role of these autoantibodies have proved futile most of the times. They may still be the inciting agents or just an epiphenomenon in the pathogenesis of Ssc.

  Role of the Innate Immune System Top

IFN α pathway is up regulated in SSc. Type 1 IFN signature seen in scleroderma, more so in early and noncutaneous disease.[28] IFN release can induce TLR 3 expression on the surface of fibroblasts, causing pro-collagen production. Ligands for Toll-like receptors (TLRs) stimulate dendritic cells to produce IFN-α and interleukin (IL)-6, which in turn activate Th2 cells, produce IL-4 and IL-13, and stimulate pro-fibrotic “M2” macrophages.[29] Macrophages produce TGF-β and PDGF, the harbingers of fibrosis.

Apart from inducing fibroblast activation, TLRs are crucial to activation of the innate immune system. Infections are the usual triggers, although sometimes endogenous ligands can propagate proliferation even after the initial stimulus is over. Tenascin-C (TNC) is one such endogenous ligand; it is a large extracellular matrix glycoprotein that is expressed by myeloid cells in response to pathogen-associated molecular patterns. The C-domain of TNC interacts with TLR-4 on monocyte, monocyte-derived macrophages and dendritic cells and led to secretion of pro-inflammatory cytokines such as TNFα, IL6, and IL8 production in a dose–dependent manner. It is normally repressed as soon as the process of inflammation and repair in the tissue is completed and is undetectable in healthy tissues. However, its uncontrolled expression can lead to an autocrine-loop involving myeloid cells that amplifies chronic inflammation in the absence of pathogens. Tenascin-C is elevated in SSc including skin biopsies and in SSc fibroblasts.[30] In experiments, tenascin-C stimulates TLR4 leading to myofibroblast transformation with collagen gene expression. Tenascin-C knockout mice have an attenuation of skin and lung fibrosis, with a resolution of fibrosis.[31] Thus, Tenascin-C may both be a biomarker of disease activity in SSc, as well as a potential target to block fibrosis.

  Role of the Inflammasome: the New Player on the Block Top

Revelations of strong interferon signature from gene expression profiling data led to renewed interest in studying the involvement of the innate immune pathways in the disease. It was soon discovered that TLR activation is not just crucial to this response, but also the driving force for several other downstream pathways.

The inflammasome pathway is one such; it can be induced by TLRs through MyDD88 (Myeloid differentiation primary response gene 88), the key adaptor molecule in transmitting signals from most membrane based TLRs. This then forms a platform for activation of caspase 1 and subsequent IL-1 β release. A potent inflammatory loop thus results, a discovery that was surprising for most people working on this fibrosis dominant disease. However, the role of IL-1 β in fibrosis could not be denied; as bleomycin-induced lung fibrosis could be prevented by IL-1R knockout.[32] Knocking out genes for the various inflammasome adaptor proteins, such as ASC, also lead to abrogation of fibrosis at the outset. Direct involvement of the inflammasome has now been confirmed by the prevention of fibrosis in mice with knock out of NLRP3. Over the years, more evidence gathered in the form of preventive role of caspase 1 inhibitors in mice.

In humans, NLRP1 polymorphisms are associated with increased risk for ILD.[33] NLRP3 signature is upregulated in SSc skin, and the levels correlate with ET-1, suggesting that this may be the link between endotheliopathy and inflammation.[34] Hence, it remains to be seen if inflammasome pathway inhibitors such as Naclynamide and felodipine will be helpful in treatment. Unfortunately, successful therapeutic outcomes in established fibrosis have been limited; and inflammasome pathway inhibitors are no exception, as seen from the LOTUSS trial of Pirfenidone.[35]

  Role of the Adaptive Immune System Top

As mentioned above, the Th2 paradigm is dominant in SSc. In addition, T-cytotoxic cells may contribute to the injury of endothelial cells through granzyme and Fas/FasL. The resulting apoptotic cell debris may be a source for altered antigens that contribute to activation of B cells for production of autoantibodies.

The only evidence of the direct pathogenic role of autoantibodies has been demonstrated for ATA. ATA bound to DNA/RNA complexes, and related proteins can be internalized into the endosomes by Fc γRIIa on the surface of plasmacytoid dendritic cells (pDCs).[36] Endosomal TLR-7 and TLR-9 activation triggers downstream pathways of fibrosis such as Interferon regulatory factor (IRF) 5 and 7 and eventually IFN α[36] [Figure 3].
Figure 3: Endogenous TLR signalling by the Anti-Topoisomerase antibodies.FcγR: Fc Gamma receptor, TLR9: Toll like Receptor 9, NFκB: Nuclear Factor – κB, IRF 7: Interferon Response Factor 7, IFN γ: Interferon γ

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Indirect evidence of the possible pathological role of antibodies has been with experiments wherein specific pathways were shown to be activated by the implicated autoantibodies. When these pathways were experimentally disrupted, the disease could be abrogated in animal models. Such antibodies are called as functional autoantibodies [Table 1].
Table 1: Functional auto-antibodies in Systemic Sclerosis

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  Genetics of Systemic Sclerosis Top

Various gene polymorphisms are associated, but the effects are at best modest, ranging from RR 1.5–2.0. Most susceptibility loci are shared with other autoimmune diseases. Major histocompatibility complex, interferon response factor 5 and signal transducer and activator of transcription 4 gene regions have found an association in most genome-wide association study cohorts.[42] Numerous mi RNAS have been implicated, but cause-effect relationship is still not clear.

  Treatment Modalities Based on Pathogenesis Top

Over the years, the discovery of novel inflammatory as well as nonimmune pathways in the disease SSc has sparked the quest to bring fibrosis inhibitors from the bench to bedside. Though successful in animal models, only a minuscule number of drugs have made it to clinical trials. A few of the promising ones are monoclonal antibody to TGF-β-Fresolimumab, Phosphodiesterase 5 inhibitors, Tyrosine kinase inhibitors such as Nilotinib and stem cell therapy.[3],[43],[44]

After demonstrating success in animal models, Fresolimumab was seen to decrease biomarkers of skin fibrosis and modified Rodnan skin score after a single intravenous dose in eight patients. As in other inflammatory diseases, where the ones with greater inflammation at baseline are the ones to respond better, here too, the cases with high Thrombospondin 1 expression benefitted the most.[3]

Although IL-6 has also been implicated among the numerous inflammatory pathways that converge onto fibrosis, the results of subcutaneous tocilizumab in the FaSScinate trial were disappointing with respect to the skin and the lung.[45]

There was a brief period of enthusiasm regarding the tyrosine kinase inhibitor Imatinib, as it was believed to target the fibrotic pathways in a subset of patients. Many patients developed effusions, and the dose limitation by drug toxicity dampened the excitement.[46] Nilotinib, another member of the same family, was recently tried in 10 adults with early dc SSc. Although the skin scores decreased by >20%, QTc prolongation was a problem.[43] Improvers on Nilotinib had higher TGFBR and PDGFR expression at baseline in these patients, suggesting a biomarker-driven approach may be useful to selectively pick out those likely to respond to these drugs.

Autologous adipose-derived stromal vascular fraction significantly impaired hand function and quality of life in twelve patients with significant hand disability from contractures.[47]

  Conclusion Top

The outcome of SSc is not as bleak as it seemed a couple of decades ago. With a greater understanding of older pathways, as well as elucidation of newer ones, the potential targets to block and even reverse fibrosis can be seen glistering at the horizon. However, all that glitters in animal experiments do not translate into gold for human therapy. Anyhow, cautious steps are slowly but surely bring around a revolution in the way we look at this once dreaded disease.

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Conflicts of interest

There are no conflicts of interest.

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