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Arthritis & Rheumatology (Hoboken, N.J.) Feb 2022In this study, we sought a comprehensive understanding of myeloid cell types driving fibrosis in diffuse cutaneous systemic sclerosis (dcSSc) skin.
Expansion of Fcγ Receptor IIIa-Positive Macrophages, Ficolin 1-Positive Monocyte-Derived Dendritic Cells, and Plasmacytoid Dendritic Cells Associated With Severe Skin Disease in Systemic Sclerosis.
OBJECTIVE
In this study, we sought a comprehensive understanding of myeloid cell types driving fibrosis in diffuse cutaneous systemic sclerosis (dcSSc) skin.
METHODS
We analyzed the transcriptomes of 2,465 myeloid cells from skin biopsy specimens from 12 dcSSc patients and 10 healthy control subjects using single-cell RNA sequencing. Monocyte-derived dendritic cells (mo-DCs) were assessed using immunohistochemical staining and immunofluorescence analyses targeting ficolin-1 (FCN-1).
RESULTS
A t-distributed stochastic neighbor embedding analysis of single-cell transcriptome data revealed 12 myeloid cell clusters, 9 of which paralleled previously described healthy control macrophage/DC clusters, and 3 of which were dcSSc-specific myeloid cell clusters. One SSc-associated macrophage cluster, highly expressing Fcγ receptor IIIA, was suggested on pseudotime analysis to be derived from normal CCR1+ and MARCO+ macrophages. A second SSc-associated myeloid population highly expressed monocyte markers FCN-1, epiregulin, S100A8, and S100A9, but was closely related to type 2 conventional DCs on pseudotime analysis and identified as mo-DCs. Mo-DCs were associated with more severe skin disease. Proliferating macrophages and plasmacytoid DCs were detected almost exclusively in dcSSc skin, the latter clustering with B cells and apparently derived from lymphoid progenitors.
CONCLUSION
Transcriptional signatures in these and other myeloid populations indicate innate immune system activation, possibly through Toll-like receptors and highly up-regulated chemokines. However, the appearance and activation of myeloid cells varies between patients, indicating potential differences in the underlying pathogenesis and/or temporal disease activity in dcSSc.
Topics: Dendritic Cells; Humans; Lectins; Macrophages; Monocytes; Receptors, IgG; Scleroderma, Diffuse; Severity of Illness Index; Ficolins
PubMed: 34042322
DOI: 10.1002/art.41813 -
Rheumatology (Oxford, England) Jun 2023Scleroderma is a rare, potentially fatal, clinically heterogeneous, systemic autoimmune connective tissue disorder that is characterized by progressive fibrosis of the... (Review)
Review
Scleroderma is a rare, potentially fatal, clinically heterogeneous, systemic autoimmune connective tissue disorder that is characterized by progressive fibrosis of the skin and visceral organs, vasculopathy and immune dysregulation. The more severe form of the disease, diffuse cutaneous scleroderma (dcSSc), has no cure and limited treatment options. Haematopoietic stem cell transplantation has emerged as a potentially disease-modifying treatment but faces challenges such as toxicity associated with fully myeloablative conditioning and recurrence of autoimmunity. Novel cell therapies-such as mesenchymal stem cells, chimeric antigen receptor-based therapy, tolerogenic dendritic cells and facilitating cells-that may restore self-tolerance with more favourable safety and tolerability profiles are being explored for the treatment of dcSSc and other autoimmune diseases. This narrative review examines these evolving cell therapies.
Topics: Humans; Skin; Hematopoietic Stem Cell Transplantation; Scleroderma, Localized; Immune Tolerance; Autoimmunity; Scleroderma, Diffuse; Scleroderma, Systemic
PubMed: 36355455
DOI: 10.1093/rheumatology/keac628 -
Biomolecules Jan 2020Avocado and soybean unsaponifiables (ASU) constitute vegetable extracts made from fruits and seeds of avocado and soybean oil. Characterized by its potent... (Review)
Review
Avocado and soybean unsaponifiables (ASU) constitute vegetable extracts made from fruits and seeds of avocado and soybean oil. Characterized by its potent anti-inflammatory effects, this ASU mixture is recommended to act as an adjuvant treatment for osteoarthritic pain and slow-acting symptomatic treatment of hip and knee osteoarthritis; autoimmune diseases; diffuse scleroderma and scleroderma-like states (e.g., morphea, sclerodactyly, scleroderma in bands). Besides, it was reported that it can improve the mood and quality of life of postmenopausal women in reducing menopause-related symptoms. This article aims to summarize the studies on biological effects of the avocado-soybean unsaponifiable, its chemical composition, pharmacotherapy as well as applications in auto-immune, osteoarticular and menopausal disorders. Finally, we will also discuss on its safety, toxicological and regulatory practices.
Topics: Animals; Autoimmune Diseases; Humans; Osteoarthritis; Persea; Plant Extracts; Postmenopause; Soybean Oil; Glycine max
PubMed: 31940989
DOI: 10.3390/biom10010130 -
Reumatologia Clinica Oct 2023Keloidal or nodular scleroderma (NS) is a variant of localized scleroderma (LS) frequently seen in patients with limited or diffuse systemic sclerosis (SSc). It presents...
Keloidal or nodular scleroderma (NS) is a variant of localized scleroderma (LS) frequently seen in patients with limited or diffuse systemic sclerosis (SSc). It presents as raised, firm plaques or nodules with extensive dermal fibrosis and hyalinized collagen bundles. We present a patient with SSc who presented with this rare entity.
Topics: Humans; Scleroderma, Localized; Scleroderma, Systemic; Keloid
PubMed: 37805259
DOI: 10.1016/j.reumae.2023.02.009 -
European Respiratory Review : An... Jun 2017Between September 2015 and August 2016 there were >1500 publications in the field of diffuse parenchymal lung diseases (DPLDs). For the Clinical Year in Review session... (Review)
Review
Between September 2015 and August 2016 there were >1500 publications in the field of diffuse parenchymal lung diseases (DPLDs). For the Clinical Year in Review session at the European Respiratory Society Congress that was held in London, UK, in September 2016, we selected only five articles. This selection, made from the enormous number of published papers, does not include all the relevant studies that will significantly impact our knowledge in the field of DPLDs in the near future. This review article provides our personal view on the following topics: early diagnosis of idiopathic pulmonary fibrosis, current knowledge on the multidisciplinary team diagnosis of DPLDs and the diagnostic role of transbronchial cryobiopsy in this diagnostic setting, insights on the new entity of interstitial pneumonia with autoimmune features, and new therapeutic approaches for scleroderma-related interstitial lung disease.
Topics: Animals; Autoimmunity; Biopsy; Early Diagnosis; Humans; Interdisciplinary Communication; Lung Diseases, Interstitial; Patient Care Team; Predictive Value of Tests; Prognosis; Risk Factors; Scleroderma, Systemic; Tomography, X-Ray Computed
PubMed: 28446601
DOI: 10.1183/16000617.0004-2017 -
Annals of the Rheumatic Diseases Aug 2018Recent studies demonstrate autoantibodies are powerful tools to interrogate molecular events linking cancer and the development of autoimmunity in scleroderma.... (Observational Study)
Observational Study
OBJECTIVES
Recent studies demonstrate autoantibodies are powerful tools to interrogate molecular events linking cancer and the development of autoimmunity in scleroderma. Investigating cancer risk in these biologically relevant subsets may provide an opportunity to develop personalised cancer screening guidelines. In this study, we examined cancer risk in distinct serologic and phenotypic scleroderma subsets and compared estimates with the general population.
METHODS
Patients in the Johns Hopkins Scleroderma Center observational cohort were studied. Overall and site-specific cancer incidence was calculated in distinct autoantibody and scleroderma phenotypic subsets, and compared with the Surveillance, Epidemiology and End Results registry, a representative sample of the US population.
RESULTS
2383 patients with scleroderma contributing 37 686 person-years were studied. 205 patients (8.6%) had a diagnosis of cancer. Within 3 years of scleroderma onset, cancer risk was increased in patients with RNA polymerase III autoantibodies (antipol; standardised incidence ratio (SIR) 2.84, 95% CI 1.89 to 4.10) and those lacking centromere, topoisomerase-1 and pol antibodies (SIR 1.83, 95% CI 1.10 to 2.86). Among antipol-positive patients, cancer-specific risk may vary by scleroderma subtype; those with diffuse scleroderma had an increased breast cancer risk, whereas those with limited scleroderma had high lung cancer risk. In contrast, patients with anticentromere antibodies had a lower risk of cancer during follow-up (SIR 0.59, 95% CI 0.44 to 0.76).
CONCLUSIONS
Autoantibody specificity and disease subtype are biologically meaningful filters that may inform cancer risk stratification in patients with scleroderma. Future research testing the value of targeted cancer screening strategies in patients with scleroderma is needed.
Topics: Adult; Antibodies, Antinuclear; Autoantibodies; Breast Neoplasms; Female; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Neoplasms; Phenotype; Registries; Risk Assessment; Scleroderma, Diffuse; Scleroderma, Localized; United States
PubMed: 29678941
DOI: 10.1136/annrheumdis-2018-212999 -
Nature Communications Nov 2022Centromere defects in Systemic Sclerosis (SSc) have remained unexplored despite the fact that many centromere proteins were discovered in patients with SSc. Here we...
Centromere defects in Systemic Sclerosis (SSc) have remained unexplored despite the fact that many centromere proteins were discovered in patients with SSc. Here we report that lesion skin fibroblasts from SSc patients show marked alterations in centromeric DNA. SSc fibroblasts also show DNA damage, abnormal chromosome segregation, aneuploidy (only in diffuse cutaneous (dcSSc)) and micronuclei (in all types of SSc), some of which lose centromere identity while retaining centromere DNA sequences. Strikingly, we find cytoplasmic "leaking" of centromere proteins in limited cutaneous SSc (lcSSc) fibroblasts. Cytoplasmic centromere proteins co-localize with antigen presenting MHC Class II molecules, which correlate precisely with the presence of anti-centromere antibodies. CENPA expression and micronuclei formation correlate highly with activation of the cGAS-STING/IFN-β pathway as well as markers of reactive oxygen species (ROS) and fibrosis, ultimately suggesting a link between centromere alterations, chromosome instability, SSc autoimmunity, and fibrosis.
Topics: Humans; Scleroderma, Systemic; Scleroderma, Diffuse; Chromosomal Instability; Fibrosis; Nucleotidyltransferases
PubMed: 36400785
DOI: 10.1038/s41467-022-34775-8 -
Current Rheumatology Reports Apr 2009Described as an autoimmune collagen vascular disease, the most striking feature of scleroderma may be a systemic vasculopathy. This vasculopathy includes characteristic... (Review)
Review
Described as an autoimmune collagen vascular disease, the most striking feature of scleroderma may be a systemic vasculopathy. This vasculopathy includes characteristic noninflammatory macrovascular and microvascular changes with dramatic and possibly occlusive formation of a thickened neointima. Scleroderma vessels also have an unusual endothelial phenotype, with loss of normal markers including vascular endothelial (VE)-cadherin. These endothelial cells express type 1 interferon and regulator of G protein signaling 5 (RGS5), two molecules associated with vascular rarefaction. These genes may be important because tissue is hypoxic with high levels of vascular endothelial growth factor (VEGF), especially early in the disease. The combination of VEGF and rarefaction is not necessarily paradoxical. VEGF-mediated angiogenesis creates labile vessels that may not survive unless the vessel acquires a smooth muscle coat. The combination of interferon and RGS5 is consistent with an antiangiogenic phenotype. We offer a hypothesis that places vascular injury at the center of this disease and also suggest possible clinical approaches for arresting and/or reversing the disease.
Topics: Animals; Biomarkers; Disease Models, Animal; Endothelium, Vascular; Humans; Scleroderma, Diffuse; Scleroderma, Limited; Skin; Vascular Diseases
PubMed: 19296882
DOI: 10.1007/s11926-009-0015-3 -
Journal of Cellular and Molecular... Jul 2018Systemic sclerosis (SSc) is a rare disorder of the connective tissue characterized by fibrosis of the skin, skeletal muscles and visceral organs. Additional... (Review)
Review
Systemic sclerosis (SSc) is a rare disorder of the connective tissue characterized by fibrosis of the skin, skeletal muscles and visceral organs. Additional manifestations include activation of the immune system and vascular injury. SSc causes disability and death as the result of end-stage organ failure. Two clinical subsets of the SSc are accepted: limited cutaneous SSc (lc-SSc) and diffuse cutaneous SSc (dc-SSc). At present, the aetiology and pathogenesis of SSc remain obscure, and consequently, disease outcome is unpredictable. Numerous studies suggest that reactive oxidizing species (ROS) play an important role in the pathogenesis of scleroderma. Over the years, several reports have supported this hypothesis for both lc-SSc and dc-SSc, although the specific role of oxidative stress in the pathogenesis of vascular injury and fibrosis remains to be clarified. The aim of the present review was to report and comment the recent findings regarding the involvement and role of oxidative stress in SSc pathogenesis. Biomarkers proving the link between ROS and the main pathological features of SSc have been summarized.
Topics: Antioxidants; Biomarkers; Humans; Oxidative Stress; Reactive Oxygen Species; Scleroderma, Systemic
PubMed: 29664231
DOI: 10.1111/jcmm.13630 -
Acta Reumatologica Portuguesa 2008Juvenile scleroderma is a rare childhood condition characterized by fibrosis of the skin and internal organs. Clinical manifestations of childhood scleroderma are... (Review)
Review
Juvenile scleroderma is a rare childhood condition characterized by fibrosis of the skin and internal organs. Clinical manifestations of childhood scleroderma are different from adult disease and early recognition, correct classification and treatment can improve long-term outcome. This review explores the most recent actualizations on clinical manifestations, classification criteria, treatment options and prognosis of juvenile scleroderma. There are two main forms of the disease: localized scleroderma and systemic sclerosis. Localized scleroderma is the most common form in children and mostly restricted to the skin. Juvenile diffuse systemic sclerosis is related to visceral involvement and cardiac disease which is the main cause of death in these patients. The outcome of juvenile systemic sclerosis is better compared with the adult form. Treatment remains a medical challenge and the EULAR task force proposed an approach to juvenile scleroderma treatment based on expert's opinion and guidelines used for the treatment of adults. Larger studies on childhood scleroderma are warranted.
Topics: Child; Humans; Scleroderma, Localized; Scleroderma, Systemic
PubMed: 18846006
DOI: No ID Found