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Allergy Apr 2022Systemic sclerosis (SSc) is a multiorgan autoimmune disease characterized by inflammation, vascular modification, and progressive fibrosis of the skin and several...
BACKGROUND
Systemic sclerosis (SSc) is a multiorgan autoimmune disease characterized by inflammation, vascular modification, and progressive fibrosis of the skin and several visceral organs. Innate and adaptive immune cells, including myeloid, B and T cells, are believed to be central to the pathogenesis of SSc. However, the role and functional state of neutrophil granulocytes (neutrophils) are ill-defined in SSc.
METHODS
We performed a prospective study of neutrophils freshly isolated from SSc patients and healthy donors (HD) by measuring in these neutrophils (i) functional cell surface markers, including CD16, CD62L, CD66b, CD66c, CXCR1, CXCR2, and CXCR4; (ii) cytokine-activated intracellular signal transducer and activator of transcription (STAT) pathways, such as phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6; (iii) production of neutrophil extracellular traps (NET) and intracellular myeloperoxidase (MPO); and (iv) phagocytosis of bacteria by the neutrophils.
RESULTS
Neutrophils of SSc patients expressed lower CD16 and CD62L and higher pSTAT3 and pSTAT6 compared to HD. Moreover, neutrophils of SSc patients lacked CXCR1 and CXCR2, the receptors responding to the potent neutrophil chemoattractant CXCL8. Neutrophils of SSc patients were also deficient in MPO levels, NET formation, and phagocytosis of bacteria.
CONCLUSIONS
Neutrophils of patients with SSc display several functional defects affecting cell migration, NET formation, and phagocytosis of bacteria.
Topics: Extracellular Traps; Humans; Neutrophils; Phagocytosis; Prospective Studies; Scleroderma, Systemic
PubMed: 34467524
DOI: 10.1111/all.15073 -
Pediatric Rheumatology Online Journal Sep 2022Limited joint mobility (LJM), previously known as cheiroarthropathy, refers to the presence of reduced extension at the finger joints in people with diabetes and may be...
BACKGROUND
Limited joint mobility (LJM), previously known as cheiroarthropathy, refers to the presence of reduced extension at the finger joints in people with diabetes and may be associated with scleroderma-like syndromes such as diabetic sclerodactyly. While scleroderma-like syndromes and LJM have been observed in patients with long-term diabetes and associated complications, the coexistence of diabetes with Juvenile systemic sclerosis (jSSc) is rarely described.
CASE PRESENTATION
We describe the case of a 14-year-old boy with long-lasting type 1 diabetes (T1D) and suspected LJM associated with Raynaud phenomenon, sclerodactyly and tapering of the fingertips. A comprehensive work-up showed positive autoantibodies (ANA, anti-Ro-52, anti-Mi-2b), abnormal nailfold capillaroscopy with a scleroderma pattern, interstitial lung disease and cardiac involvement. The overall clinical picture was consistent with the diagnosis of jSSc.
CONCLUSIONS
LJM can be the initial sign of underlying systemic sclerosis. Nailfold capillaroscopy may help differentiate jSSc from classical LJM in pediatric patients with T1D and finger contractures or skin induration of no clear origin. This case report provides a starting point for a novel hypothesis regarding the pathogenesis of jSSc. The association between T1D and jSSc may be more than a coincidence and could suggest a relationship between glucose metabolism, fibrosis and microangiopathy.
Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Humans; Male; Microscopic Angioscopy; Scleroderma, Localized; Scleroderma, Systemic
PubMed: 36089600
DOI: 10.1186/s12969-022-00741-3 -
International Journal of Molecular... Sep 2019Systemic sclerosis (SSc) is a rare autoimmune disease, characterized by vasculopathy and fibrosis of the skin and internal organs. This disease is still considered... (Review)
Review
Systemic sclerosis (SSc) is a rare autoimmune disease, characterized by vasculopathy and fibrosis of the skin and internal organs. This disease is still considered incurable and is associated with a high risk of mortality, which is related to fibrotic events. An early diagnosis is useful for preventing complications, and targeted therapies reduce disease progression and ameliorate patients' quality of life. Nevertheless, there are no validated biomarkers for early diagnosis with predictive prognostic value. Exosomes are membrane vesicles, transporting proteins and nucleic acids that may be delivered to target cells, which influences cellular behavior. They play important roles in cell-cell communication, both in physiological and pathological conditions, and may be useful as circulating biomarkers. Recent evidences suggest a role for these microvesicles in the three main aspects related to the pathogenesis of SSc (immunity, vascular damage, and fibrosis). Moreover, exosomes are of particular interest in the field of nano-delivery and are used as biological carriers. In this review, we report the latest information concerning SSc pathogenesis, clinical aspects of SSc, and current approaches to the treatment of SSc. Furthermore, we indicate a possible role of exosomes in SSc pathogenesis and suggest their potential use as diagnostic and prognostic biomarkers, as well as therapeutic tools.
Topics: Animals; Exosomes; Fibroblasts; Humans; Lymphocytes; MicroRNAs; Scleroderma, Systemic; Signal Transduction
PubMed: 31487964
DOI: 10.3390/ijms20184337 -
Current Opinion in Rheumatology Jan 2024Tissue fibrosis is an increasingly prevalent condition associated with various diseases and heavily impacting on global morbidity and mortality rates. Growing evidence... (Review)
Review
PURPOSE OF REVIEW
Tissue fibrosis is an increasingly prevalent condition associated with various diseases and heavily impacting on global morbidity and mortality rates. Growing evidence indicates that common cellular and molecular mechanisms may drive fibrosis of diverse cause and affecting different organs. The scope of this review is to highlight recent findings in support for an important role of vascular endothelial cells in the pathogenesis of fibrosis, with a special focus on systemic sclerosis as a prototypic multisystem fibrotic disorder.
RECENT FINDINGS
Although transition of fibroblasts to chronically activated myofibroblasts is widely considered the central profibrotic switch, the endothelial cell involvement in development and progression of fibrosis has been increasingly recognized over the last few years. Endothelial cells can contribute to the fibrotic process either directly by acting as source of myofibroblasts through endothelial-to-myofibroblast transition (EndMT) and concomitant microvascular rarefaction, or indirectly by becoming senescent and/or secreting a variety of profibrotic and proinflammatory mediators with consequent fibroblast activation and recruitment of inflammatory/immune cells that further promote fibrosis.
SUMMARY
An in-depth understanding of the mechanisms underlying EndMT or the acquisition of a profibrotic secretory phenotype by endothelial cells will provide the rationale for novel endothelial cell reprogramming-based therapeutic approaches to prevent and/or treat fibrosis.
Topics: Humans; Endothelial Cells; Fibrosis; Scleroderma, Systemic; Fibroblasts; Myofibroblasts
PubMed: 37582200
DOI: 10.1097/BOR.0000000000000963 -
European Respiratory Review : An... Jun 2018Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in systemic sclerosis (SSc). We performed a systematic review to characterise the use and... (Review)
Review
Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in systemic sclerosis (SSc). We performed a systematic review to characterise the use and validation of pulmonary function tests (PFTs) as surrogate markers for systemic sclerosis-associated interstitial lung disease (SSc-ILD) progression.Five electronic databases were searched to identify all relevant studies. Included studies either used at least one PFT measure as a longitudinal outcome for SSc-ILD progression ( outcome studies) and/or reported at least one classical measure of validity for the PFTs in SSc-ILD ( validation studies).This systematic review included 169 outcome studies and 50 validation studies. Diffusing capacity of the lung for carbon monoxide () was cumulatively the most commonly used outcome until 2010 when it was surpassed by forced vital capacity (FVC). FVC (% predicted) was the primary endpoint in 70.4% of studies, compared to 11.3% for % predicted Only five studies specifically aimed to validate the PFTs: two concluded that was the best measure of SSc-ILD extent, while the others did not favour any PFT. These studies also showed respectable validity measures for total lung capacity (TLC).Despite the current preference for FVC, available evidence suggests that and TLC should not yet be discounted as potential surrogate markers for SSc-ILD progression.
Topics: Biopsy; Disease Progression; Humans; Lung; Lung Diseases, Interstitial; Predictive Value of Tests; Prognosis; Pulmonary Diffusing Capacity; Reproducibility of Results; Respiratory Function Tests; Scleroderma, Systemic; Time Factors; Tomography, X-Ray Computed; Total Lung Capacity; Vital Capacity
PubMed: 29769294
DOI: 10.1183/16000617.0102-2017 -
Current Opinion in Rheumatology Nov 2022Activation of the type 1 interferon (T1 IFN) pathway has been implicated in the pathogenesis of systemic sclerosis (SSc) by an increasing number of studies, most of... (Review)
Review
PURPOSE OF REVIEW
Activation of the type 1 interferon (T1 IFN) pathway has been implicated in the pathogenesis of systemic sclerosis (SSc) by an increasing number of studies, most of which share key findings with similar studies in systemic lupus erythematosus (SLE). Here we will focus on the evidence for T1 IFN activation and dysregulation in SSc, and the rationale behind targeting the pathway going forward.
RECENT FINDINGS
An increased expression and activation of T1 IFN-regulated genes has been shown to be present in a significant proportion of SSc patients. TI IFN activation markers have been found to predict and correlate with response to immunosuppressive treatment as well as severity of organ involvement. As inhibition of the IFN-α receptor has been proven to be effective in active SLE, benefit may be seen in targeting the IFN pathway in SSc.
SUMMARY
The role played by T1 IFN and its regulatory genes in SSc is becoming increasingly evident and strikingly similar to the role observed in SLE. This observation, together with the benefit of type 1 IFN targeting in SLE, supports the notion of a potential therapeutic benefit in targeting T1 IFN in SSc.
Topics: Biomarkers; Humans; Interferon Type I; Interferon-alpha; Lupus Erythematosus, Systemic; Scleroderma, Systemic
PubMed: 36125916
DOI: 10.1097/BOR.0000000000000907 -
Autoimmunity Reviews Oct 2017The pathophysiology of SSc-mediated organ damage is complex and not well understood. Hallmarks of the disease include skin thickening, vasculopathy and gastrointestinal... (Review)
Review
The pathophysiology of SSc-mediated organ damage is complex and not well understood. Hallmarks of the disease include skin thickening, vasculopathy and gastrointestinal dysmotility. Diverse anti-nuclear antibodies can be used as biomarkers for classification and prognosis, but their role in producing tissue pathology/organ dysfunction is not established. In contrast, antibodies against cell surface receptors for platelet derived growth factor, angiotensin II, endothelin A, ICAM-1, and type 3 muscarinic acetyl choline receptors may play a major role in skin thickening, vasoconstriction/pulmonary and renal hypertension, ischemia and gastrointestinal dysmotility, respectively. In addition, antibodies to an inhibitory B-lymphocyte surface molecule, CD 22, may allow increased production of other autoantibodies. Each of these types of antibodies have been reported in some SSc patients, and laboratory studies suggest signaling pathways and mechanisms by which they may contribute to disease activity. However, we are far from a consensus on their importance. Additional epidemiologic, mechanistic and physiologic studies are needed. Confirmation of the roles of anti-receptor antibodies and identification of the signaling pathways by which they alter cellular functions would have major implications for treatment of SSc, both in terms of targeting autoantibodies and the cells that produce them, and in the use of small molecules which inhibit their pernicious effects.
Topics: Autoantibodies; Humans; Scleroderma, Systemic
PubMed: 28778706
DOI: 10.1016/j.autrev.2017.07.019 -
Translational Research : the Journal of... Aug 2018The present review aims to summarize available knowledge on the role of the ubiquitin-proteasome system (UPS) in the pathogenesis of scleroderma and scleroderma-related... (Review)
Review
The present review aims to summarize available knowledge on the role of the ubiquitin-proteasome system (UPS) in the pathogenesis of scleroderma and scleroderma-related disease mechanisms. This will provide the reader with a more mechanistic understanding of disease pathogenesis and help to identify putative novel targets within the UPS for potential therapeutic intervention. Because of the heterogenous manifestations of scleroderma, we will primarily focus on conserved mechanisms that are involved in the development of lung scleroderma phenotypes.
Topics: Autoimmunity; Fibrosis; Humans; Immunity, Innate; Proteasome Endopeptidase Complex; Scleroderma, Systemic; Ubiquitin
PubMed: 29702079
DOI: 10.1016/j.trsl.2018.03.003 -
Genes Aug 2021Epigenetic factors are heritable and ultimately play a role in modulating gene expression and, thus, in regulating cell functions. Non-coding RNAs have growing... (Review)
Review
Epigenetic factors are heritable and ultimately play a role in modulating gene expression and, thus, in regulating cell functions. Non-coding RNAs have growing recognition as novel biomarkers and crucial regulators of pathological conditions in humans. Their characteristic feature is being transcribed in a tissue-specific pattern. Now, there is emerging evidence that lncRNAs have been identified to be involved in the differentiation of human skin, wound healing, fibrosis, inflammation, and immunological response. Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by fibrosis, vascular abnormalities, and immune system activation. The pathogenesis remains elusive, but clinical manifestations reveal autoimmunity with the presence of specific autoantibodies, activation of innate and adaptive immunity, vascular changes, and active deposition of extracellular matrix components leading to fibrosis. The use of multi-omics studies, including NGS, RNA-seq, or GWAS, has proposed that the non-coding genome may be a significant player in its pathogenesis. Moreover, it may unravel new therapeutic targets in the future. The aim of this review is to show the pathogenic role of long non-coding RNAs in systemic sclerosis. Investigation of these transcripts' functions has the potential to elucidate the molecular pathology of SSc and provide new opportunities for drug-targeted therapy for this disorder.
Topics: Animals; Biomarkers; Genetic Therapy; Humans; Precision Medicine; RNA, Long Noncoding; Scleroderma, Systemic; Translational Research, Biomedical
PubMed: 34573278
DOI: 10.3390/genes12091296 -
Arthritis Research & Therapy 2007The precise aetiology of systemic sclerosis (SSc) remains elusive, but significant advances over the past few years have improved our understanding of the underlying... (Review)
Review
The precise aetiology of systemic sclerosis (SSc) remains elusive, but significant advances over the past few years have improved our understanding of the underlying pathogenic processes and identified key pathways and mediators that are potential therapeutic targets. The situation is complicated by the clinical heterogeneity of SSc and the differential pathogenesis that underlies the two commonest subsets, namely diffuse and limited cutaneous disease. However, there are common mediators that could be targeted to provide clinical benefit in both types of disease. To date, clinical success with therapies directed against logical profibrotic mediators, such as connective tissue growth factor and transforming growth factor-beta, is yet to be reported, although studies are ongoing. More promising clinical results have been obtained with the dual endothelin receptor antagonist bosentan, which has been shown to manage two vascular complications of SSc effectively: pulmonary arterial hypertension and digital ulceration. It remains to be determined whether the identification of additional mediators merely furthers our knowledge of the natural history of SSc or presents targets that can be manipulated to manage SSc patients effectively.
Topics: Animals; Drug Delivery Systems; Humans; Scleroderma, Systemic
PubMed: 17767744
DOI: 10.1186/ar2190