Autophagy is a key feature in the pathogenesis of systemic sclerosis

Autophagosomes are formed during autophagy, which is activated by hypoxia and starvation. Autophagy is important for mast cell degranulation. We hypothesized that autophagy is a key feature in the pathogenesis of systemic sclerosis (SSc). We examined SSc clinical features and mast cell density across the presence and severity of autophagy. Skin punch biopsy was performed on 33 SSc patients and 6 healthy controls (HC). Autophagy was evaluated by immunofluorescence on paraffin sections using LC3-FITC staining on these patients. The intensity of staining and mast cell density was examined across clinical features in 19 of the SSc patients. Presence of autophagosome formation was assessed by EM in 17 of the SSc patients and 4 HC. In our SSc study population, 29 of subjects were female and 23 were limited cutaneous. Twenty-nine of 33 SSc patients had autophagy by LC3-FITC staining. Intensity of staining decreased with longer duration of SSc (p = 0.09) and RP (p = 0.10). Bloating and distention differed across level of intensity staining (Wilcoxon signed-rank test, p = 0.05), with the greatest levels among those with moderate intensity. On EM, autophagosome formation was present in 16 of 17 SSc patients and no HC. All SSc patients had perivascular mast cells. Autophagy was present in 29 of 33 SSc patients, and none of our HC suggesting importance in pathogenesis. Autophagy staining was greater among those with shorter duration of SSc. Bloating and distention were higher in patients with moderate autophagy staining. Perivascular mast cells were present in all SSc patients. The role of autophagy in vasculopathy and mast cell activation in SSc warrants further studies.     

Vascular function in systemic sclerosis

Raynaud phenomenon is often the earliest manifestation of systemic sclerosis. This fact highlights the role of vascular dysfunction early on in the disease process. Although this review deals primarily with digital vasculature, recent research confirms that vascular dysfunction is widespread, and affects large as well as small vessels. Abnormalities of vascular function and structure are interdependent, and together result in the ischemic atrophy so characteristic of SSc. Key areas of research include the pathophysiology of the imbalance between vasodilation and vasoconstriction, with particular interest in understanding the relative contributions of endothelial-dependent and endothelial-independent vasodilation, and the development of new methodologies by which to quantify vascular function.     

Genetic implications in the pathogenesis of systemic sclerosis

Systemic sclerosis (SSc) is a chronic autoimmune disease of the connective tissues of unknown etiology, characterized mainly by fibrosis of the skin, vascular abnormalities, and systemic involvement of other organs, such as gastrointestinal tract, kidneys, lungs, and heart. SSc has been associated with a complex etiology with the involvement of both environmental and genetic factors in the onset and outcome of the disease. Although several major histocompatibility complex (MHC) and non‐MHC genes have been associated with the disease risk, there are several questions to answer. This article's purpose was to provide an extensive overview of the identified genetic factors in the etiopathogenesis of SSc.     

Hypothesis: pathogenesis of systemic sclerosis

A hypothesis for the pathogenesis of systemic sclerosis (SSc) is proposed. Transforming growth factor-beta (TGF-beta) has received attention as an essential factor in the pathogenesis of various fibrotic disorders, including SSc, although some unknown additional factor has been sought as the second mediator of fibrotic disorders. Connective tissue growth factor (CTGF) has been shown to be closely related to the pathogenesis of SSc as follows: (1) CTGF mRNA expression was observed in the fibrotic lesions but not in the early nonfibrotic lesions or atrophic lesions. (2) Serum CTGF protein concentrations were significantly elevated, and correlated with skin sclerosis and lung fibrosis. (3) In our animal model, TGF-beta-induced subcutaneous fibrosis and subsequent CTGF application caused persistent fibrosis. Based on these data, we hypothesize that a 2-step process of fibrosis occurs in SSc: that is, TGF-beta induces fibrosis in the early stage and afterwards CTGF acts to maintain tissue fibrosis.     

Apoptosis and myofibroblasts in the pathogenesis of systemic sclerosis

Tissue fibrosis is the result of a complex series of events focusing on regulation of fibroblast proliferation, synthesis of extracellular matrix, and apoptosis. Transforming growth factor-beta is important for the stimulation of the fibrotic response by promoting the production of extracellular matrix proteins, by promoting the differentiation of the myofibroblast cell morphology, and by protecting these cells against apoptotic stimuli. Other cytokines such as interleukin-1 may have stimulatory and counter-regulatory effects on fibrosis. The effects of these signaling molecules depend on cellular environment and are organ specific. Furthermore, intercellular interactions and cell-matrix interactions can stimulate or inhibit the apoptotic pathway. Through selective inhibition of apoptosis in myofibroblasts, fibrosis can become dysregulated and lead to diseases such as systemic sclerosis.     

Urotensin-II in systemic sclerosis: a new peptide in pathogenesis

Systemic sclerosis (SSc) is a rare multisystem chronic disease and its etiology is still unknown. To obtain and generate reasonable treatment methods, new mediators or targets are needed. Urotensin-II (U-II) is predominantly a vasoactive peptide with fibrotic and prothrombotic features. Like endothelin-1 (ET-1), U-II could play an important role in SSc pathogenesis given its properties of convenient one-to-one SSc pathogenetic pathways. A consecutive group of 55 patients diagnosed with SSc and 30 healthy controls were included in the study. Patients and healthy controls were evaluated for clinical and laboratory manifestations, specific organ involvement, autoantibodies, and activity scores specific for SSc. In addition, plasma ET-1 and plasma levels of U-II-like immunoreactivity of both groups were compared. ET-1 level significantly increased in the SSc group in contrast to the healthy controls (6.38 ± 1.39 and 0.99 ± 0.27 pg/ml; p = 0.006). U-II was also significantly elevated in patients, and the plasma levels of U-II-like immunoreactivity were positively correlated with ET-1 (8.19 ± 1.74 and 1.02 ± 0.19 pg/ml; p = 0.003 and p = 0.0001; r = 0.887). For reasonable treatment of SSc, we need to focus on new targets such as ET-1 and U-II. This study hypothesized that these mediators could have a role in SSc pathogenesis, and U-II antagonist might be a potential alternative therapy for these patients.     

Monocyte chemoattractant proteins in the pathogenesis of systemic sclerosis

Activation of the immune system and increased synthesis of extracellular matrix proteins by fibroblasts are hallmarks in the pathogenesis of SSc. The molecular mechanisms underlying the infiltration of inflammatory cells into the skin and the subsequent activation of fibroblasts are still largely unknown. Chemokines are a family of small molecules that are classified according to the position of the NH(2)-terminal cysteine motif. Recent data indicate that chemokines and in particular two members of the subfamily of monocyte chemoattractant proteins, MCP-1 (CCL-2) and MCP-3 (CCL-7), might be involved in the pathogenesis of SSc. MCP-1 and -3 are overexpressed by SSc fibroblasts and in skin lesions from SSc patients compared to healthy controls. MCP-1 and -3 are chemotactic for inflammatory cells and stimulate their migration into the skin. In addition to their pro-inflammatory effects, MCP-1 and -3 contribute to tissue fibrosis by activating the synthesis of extracellular matrix proteins in SSc fibroblasts. Therapeutic strategies targeting MCP-1 have revealed promising results in several animal models of SSc. Antagonists against the receptor CCR2 are currently tested in clinical trials of a variety of diseases and also represent interesting candidates for target-directed therapy in SSc.     

Vascular complications in systemic sclerosis: a prospective cohort study

Clinical Rheumatology - Two major complications in scleroderma patients that cause substantial morbidity and mortality are ischemic digital lesions (DL) and pulmonary hypertension (PH). The...     

Platelet contributions to the pathogenesis of systemic sclerosis

PURPOSE OF REVIEW: The purpose of this review is to focus attention on platelet contributions, in general, to systemic sclerosis. There have also been recent advances in characterization of the phenotype of platelets in systemic sclerosis which will be reviewed. RECENT FINDINGS: An extensive literature provides strong support for varying degrees of platelet activation and aggregation in different forms and stages of systemic sclerosis. A recent finding is that systemic sclerosis platelets overexpress a specific nonintegrin 65 kDa receptor for type I collagen as well as expressing enhanced phosphilidylinositol-3 kinase as an activation signature. Overexpression of a type I collagen receptor would make systemic sclerosis platelets more susceptible to binding to exposed type I collagen in the subendothelial lining of damaged blood vessels, facilitating the cycle of platelet aggregation and release of preformed bioactive molecules that include a host of inflammatory and fibrogenic, chemokines, cytokines and growth factors. This activation phenotype of systemic sclerosis platelets may be secondary to autoimmunity and driven by cytokines from autoreactive T cells. SUMMARY: The contributions of platelets to the pathogenesis of systemic sclerosis is likely substantial and may not be adequately represented in gene profiling of systemic sclerosis tissue due to the small amounts of RNA contained in platelets.     

Impaired angiogenesis as a feature of digital ulcers in systemic sclerosis

Impaired angiogenesis in systemic sclerosis has a major role in tissue injury pathogenesis. Our objective was to determine whether angiogenic biomarkers (vascular endothelial growth factor (VEGF), endoglin, and endostatin) are related to microvascular damage and to determine their predictive value for new digital ulcers (DU). The main outcome of the study was the occurrence of a new digital ulcer during 3-year follow-up. This prospective longitudinal study was performed between October 2011 and December 2014. Seventy-seven patients definitely diagnosed with systemic sclerosis where divided into two groups: those with active DU at baseline and those with no DU until enrollment. Patients were matched by sex and age with healthy controls. Serum levels of VEGF, endoglin, and endostatin were measured at enrollment, and several nailfold videocapillaroscopies were performed during the 3-year follow-up. Serum levels of VEGF were lower (245.06, 158.68–347.33; p?<?0.001) and those of endoglin were higher (3.013, 1.463–7.023; p?<?0.001) in patients with active DU than those with no DU history (339.49, 202.00–730.93/1.879, 0.840–3.280), and they were higher than those found in controls (178.030, 101.267–222.102)/0.277, 0.154–0.713), respectively. No differences in endostatin levels were found between groups (p?=?0.450). Endoglin was the only biomarker significantly different (p?=?0.031) between patients with diffuse versus limited systemic sclerosis and between early, active, and late patterns (p?=?0.020). VEGF was identified as an independent predictor for the development of new DU. Our study confirmed the relationship between angiogenic vascular biomarkers and the occurrence of DU. Endoglin and VEGF serum levels are potential risk factors, and VEGF has a predictive value for the occurrence of new DU.     

Role of B cells in the pathogenesis of systemic sclerosis

Systemic sclerosis (SSc) is an orphan disease characterized by progressive fibrosis of the skin and internal organs. Aside from vasculopathy and fibrotic processes, its pathogenesis involves an aberrant activation of immune cells, among which B cells seem to play a significant role. Indeed, B cell homeostasis is disturbed during SSc: the memory subset is activated and displays an increased susceptibility to apoptosis, which is responsible for their decreased number. This chronic loss of B cells enhances bone marrow production of the naïve subset that accounts for their increased number in peripheral blood. This permanent activation state can be explained mainly by two mechanisms: a dysregulation of B cell receptor (BCR) signaling, and an overproduction of B cell survival signals, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). These disturbances of B cell homeostasis induce several functional anomalies that participate in the inflammatory and fibrotic events observed during SSc: autoantibody production (some being directly pathogenic); secretion of pro-inflammatory and pro-fibrotic cytokines (interleukin-6); direct cooperation with other SSc-involved cells [fibroblasts, through transforming growth factor-β (TGF-β) signaling, and T cells]. These data justify the evaluation of anti-B cell strategies as therapeutic options for SSc, such as B cell depletion or blockage of B cell survival signaling.     

Chemokines and chemokine receptors in the pathogenesis of systemic sclerosis

 Activation of the immune system and increased synthesis of extracellular matrix proteins by fibroblasts are hallmarks in the pathogenesis of systemic sclerosis (SSc). The mechanisms that initiate the accumulation of inflammatory cells are still unknown. Chemokines are a family of small molecules that are divided into subfamilies according to the position of NH₂-terminal cysteine motif. A new nomenclature for chemokines recently has been introduced in an attempt to overcome the confusion resulting from a number of different names for the same chemokines. Recent data indicate that chemokines, and in particular MCP-1 (CCL2), might be involved in the pathogenesis of SSc at different levels. MCP-1 is highly upregulated in skin specimens from SSc patients compared with those from healthy controls. Dermal fibroblasts release MCP-1, which is able to induce and perpetuate the migration of inflammatory cells into the skin. Interestingly, data from animal models, as well as from in vitro studies, indicate that MCP-1 might also be involved in the increased synthesis of extracellular matrix proteins, by either direct or indirect mechanisms. In conclusion, chemokines represent interesting candidates for target-directed therapies for SSc. This concept has to be confirmed by further studies using animal models for SSc and other fibrotic diseases. Received: September 18, 2001 / Accepted: November 16, 2001     

The role of infectious agents in the pathogenesis of systemic sclerosis

Over the past few years, increasing evidence has accumulated to implicate infectious agents in the etiology of systemic sclerosis (SSc) and Raynaud phenomenon. Infection rates in patients with SSc compared with those in control populations do not provide clear support for any specific pathogen. However, increased antibody titers, a preponderance of specific strains in patients with SSc, and evidence of molecular mimicry inducing autoimmune responses suggest mechanisms by which infectious agents may contribute to the development and progression of SSc. Here we review studies examining the potential involvement of, cytomegalovirus, and parvovirus B19 in SSc pathogenesis.     

Infectious disease as aetiological factor in the pathogenesis of systemic sclerosis

Systemic sclerosis is an autoimmune disease characterised by vascular obliteration, excessive extracellular matrix deposition and fibrosis of the connective tissues of the skin, lungs, gastrointestinal tract, heart, and kidneys. The pathogenesis of systemic sclerosis is extremely complex; at present, no single unifying hypothesis explains all aspects. Over the last 20 years increasing evidence has accumulated to implicate infectious agents in the aetiology of systemic sclerosis. Increased antibody titres, a preponderance of specific strains in patients with systemic sclerosis, and evidence of molecular mimicry inducing autoimmune responses suggest mechanisms by which infectious agents may contribute to the development and progression of systemic sclerosis. Here we review the current state of knowledge of infectious risk factors in systemic sclerosis and the possible mechanisms by which infectious exposures might induce pathologic processes.     

Animal models of systemic sclerosis: insights into systemic sclerosis pathogenesis and potential therapeutic approaches

PURPOSE OF REVIEW: Animal models have been extremely valuable in contributing to a better understanding of the pathogenesis of systemic sclerosis. Discussed here are recent studies that have examined the molecular pathways and potential therapeutic approaches for systemic sclerosis using animal models. RECENT FINDINGS: Reported evidence further indicates that the immune system plays a role in modulating the fibrosis observed in the tight skin-1/+ mouse model for systemic sclerosis. CD19, interleukin-6, and interleukin-4 are involved. The injection of spleen cells into immune-compromised mice resulted in fibrotic, vascular, and immunologic alterations quite similar to those of systemic sclerosis. Transforming growth factor-beta and its signaling pathway (JAK kinase and STAT-6, Smad2/3, and Smad7) appear to play a central role in the development of fibrosis as well as monocyte chemoattractant protein-1, CCR-2, platelet-derived growth factor C, and excessive apoptosis. Viruses were shown to be possible cofactors. The therapeutic agents hepatocyte growth factor and halofuginone were shown to prevent fibrosis in animal models of systemic sclerosis. SUMMARY: The transforming growth factor-beta signaling pathway is a common mechanism of tissue fibrosis in animal models of systemic sclerosis, although numerous additional molecules modulate this pathway or have a direct effect on fibrosis.     

Association of the CD226 Ser307 variant with systemic sclerosis: Evidence of a contribution of costimulation pathways in systemic sclerosis pathogenesis

Objective

The nonsynonymous polymorphism rs763361 of the CD226 gene, which encodes DNAX accessory molecule 1, which is involved in T cell costimulation pathways, has recently been identified as a genetic risk factor for autoimmunity. The purpose of this study was to test for association of the CD226 rs763361 polymorphism with systemic sclerosis (SSc) in European Caucasian populations.

Methods

CD226 rs763361 was genotyped in 3,632 individuals, consisting of a discovery sample (991 SSc patients and 1,008 controls) and a replication sample (999 SSc patients and 634 controls). All study subjects were of European Caucasian origin. Expression of CD226 was assessed on peripheral blood mononuclear cells obtained from 21 healthy donors genotyped for CD226 rs763361.

Results

The CD226 rs763361 T allele was found to be associated with SSc in both the discovery and the replication samples, showing the following results in the combined populations: odds ratio (OR) 1.22 (95% confidence interval [95% CI] 1.10–1.34), P = 5.69 × 10^–5. The CD226 T allele was also associated with various SSc subsets, highlighting a potential contribution to disease severity. The most remarkable associations of the CD226 TT risk genotype were observed with the diffuse cutaneous SSc subtype, the anti–topoisomerase I antibody–positive, and SSc‐related fibrosing alveolitis subsets: OR 1.86 (95% CI 1.42–2.43), P = 5.15 × 10^–6, OR 1.82 (95% CI 1.38–2.40), P = 2.16 × 10^–5, and OR 1.61 (95% CI 1.25–2.08), P = 2.73 × 10^–4, respectively. CD226 expression was not significantly influenced by CD226 rs763361 genotypes whatever the T cell subtype investigated.

Conclusion

Our results establish CD226 as a new SSc genetic susceptibility factor underlying the contribution of costimulation pathways in the pathogenesis of SSc. Further work is nevertheless needed to define the causal variant at the CD226 locus as well as the functional consequences.