scholarly journals Apoptosis Modulation as a Promising Target for Treatment of Systemic Sclerosis

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Stéphane Chabaud ◽  
Véronique J. Moulin
Keyword(s):  
Systemic Sclerosis ◽  
Autoimmune Disease ◽  
Therapeutic Targets ◽  
Immune Dysfunction ◽  
Vascular Damage ◽  
Loss Of Function ◽  
Internal Organs ◽  
Promising Target ◽  
New Findings ◽  
Diffuse Systemic Sclerosis

Diffuse systemic sclerosis (SSc) is a fatal autoimmune disease characterized by an excessive ECM deposition inducing a loss of function of skin and internal organs. Apoptosis is a key mechanism involved in all the stages of the disease: vascular damage, immune dysfunction, and fibrosis. The purpose of this paper is to gather new findings in apoptosis related to SSc, to highlight relations between apoptosis and fibrosis, and to identify new therapeutic targets.

scholarly journals Systemic Sclerosis Pathogenesis and Emerging Therapies, beyond the Fibroblast

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Andrea Sierra-Sepúlveda ◽  
Alexia Esquinca-González ◽  
Sergio A. Benavides-Suárez ◽  
Diego E. Sordo-Lima ◽  
Adrián E. Caballero-Islas ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Immune System ◽  
Systemic Sclerosis ◽  
Autoimmune Disease ◽  
State Of The Art ◽  
Therapeutic Targets ◽  
Organ Damage ◽  
The State ◽  
Pathogenic Mechanism ◽  
Emerging Therapies

Systemic sclerosis (SSc) is a complex rheumatologic autoimmune disease in which inflammation, fibrosis, and vasculopathy share several pathogenic pathways that lead to skin and internal organ damage. Recent findings regarding the participation and interaction of the innate and acquired immune system have led to a better understanding of the pathogenesis of the disease and to the identification of new therapeutic targets, many of which have been tested in preclinical and clinical trials with varying results. In this manuscript, we review the state of the art of the pathogenesis of this disease and discuss the main therapeutic targets related to each pathogenic mechanism that have been discovered so far.

scholarly journals Diffuse Systemic Sclerosis with Left Ventricular Diastolic Dysfunction: A Case Report

2019 ◽  
Vol 57 (220) ◽  
Author(s):  
Asmita Neupane ◽  
Prabesh Luintel ◽  
Subodh Sagar Dhakal
Keyword(s):  
Systemic Sclerosis ◽  
Diastolic Dysfunction ◽  
Vascular System ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
High Morbidity ◽  
Internal Organs ◽  
Immune Mediated ◽  
Diffuse Systemic Sclerosis ◽  
Ventricular Diastolic Dysfunction

Systemic sclerosis is a connective tissue disease characterized by wide-spread vascular lesionsand fibrosis of the skin and internal organs. It is an immune mediated rheumatic disease with thepresence of an immunological dysfunction of T lymphocytes, especially Th1 and Th17 subtypes. Itaffects gastrointestinal, pulmonary, vascular, musculoskeletal, cardiac and various other systems.This disease is rare but has high morbidity and mortality with less known effective management. Wereport a case of 70-year-old female with systemic sclerosis presented with pain along with swellingover multiple joints since 18 months which exacerbated since last 6 months and wound over fingertips since last 2 weeks. We present here other various signs, investigations and management of thisuncommon disease systemic sclerosis, also known as scleroderma. Various systems are evident tobe involved including cardiac (left ventricular diastolic dysfunction) and peripheral vascular system(Raynaud’s phenomenon).

scholarly journals A System Out of Breath: How Hypoxia Possibly Contributes to the Pathogenesis of Systemic Sclerosis

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
T. W. van Hal ◽  
L. van Bon ◽  
T. R. D. J. Radstake
Keyword(s):  
Systemic Sclerosis ◽  
Autoimmune Disease ◽  
Oxygen Tension ◽  
Vicious Circle ◽  
Low Oxygen ◽  
Internal Organs ◽  
Low Oxygen Tension

Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular alterations and immunological disturbances and fibrosis, the order of which remains to be fully determined. Clinically, patients show clear signs of hypoxia in skin and internal organs. The low oxygen tension is potentially caused by a yet to be indentified circuitry involving the three features that typify SSc. In addition, once present, the hypoxia creates a vicious circle of ongoing pathology. In this paper, we provide an overview of the evidence that points towards the mechanisms causing hypoxia in SSc. In addition, data that suggest how hypoxia itself may orchestrate worsening of symptoms is presented. Altogether, it is clear that hypoxia is an important hallmark in SSc patients. By providing an overview of the mechanisms at play and the possible therapeutic avenues that have emerged, we hope to stimulate researchers to provide novel clues into the conundrum in SSc patients.

scholarly journals Systemic Sclerosis: From Pathophysiology to Novel Therapeutic Approaches

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 163
Author(s):  
Devis Benfaremo ◽  
Silvia Svegliati ◽  
Chiara Paolini ◽  
Silvia Agarbati ◽  
Gianluca Moroncini
Keyword(s):  
Immune System ◽  
Systemic Sclerosis ◽  
Plasma Cells ◽  
Clinical Manifestations ◽  
Therapeutic Targets ◽  
Tissue Level ◽  
Internal Organs ◽  
Immune Mediated ◽  
Chronic Disorder ◽  
Substantial Progress

Systemic sclerosis (SSc) is a systemic, immune-mediated chronic disorder characterized by small vessel alterations and progressive fibrosis of the skin and internal organs. The combination of a predisposing genetic background and triggering factors that causes a persistent activation of immune system at microvascular and tissue level is thought to be the pathogenetic driver of SSc. Endothelial alterations with subsequent myofibroblast activation, excessive extracellular matrix (ECM) deposition, and unrestrained tissue fibrosis are the pathogenetic steps responsible for the clinical manifestations of this disease, which can be highly heterogeneous according to the different entity of each pathogenic step in individual subjects. Although substantial progress has been made in the management of SSc in recent years, disease-modifying therapies are still lacking. Several molecular pathways involved in SSc pathogenesis are currently under evaluation as possible therapeutic targets in clinical trials. These include drugs targeting fibrotic and metabolic pathways (e.g., TGF-β, autotaxin/LPA, melanocortin, and mTOR), as well as molecules and cells involved in the persistent activation of the immune system (e.g., IL4/IL13, IL23, JAK/STAT, B cells, and plasma cells). In this review, we provide an overview of the most promising therapeutic targets that could improve the future clinical management of SSc.

scholarly journals Genetic interactions affect lung function in patients with systemic sclerosis

2019 ◽  
Author(s):  
Anna L. Tyler ◽  
J. Matthew Mahoney ◽  
Gregory W. Carter
Keyword(s):  
Systemic Sclerosis ◽  
Autoimmune Disease ◽  
Lung Function ◽  
Lung Disease ◽  
Cause Of Death ◽  
Genetic Variants ◽  
Gene Network ◽  
Genetic Interactions ◽  
Internal Organs ◽  
Autoantibody Status

AbstractScleroderma, or systemic sclerosis (SSc), is an autoimmune disease characterized by progressive fibrosis of the skin and internal organs. The most common cause of death in people with SSc is lung disease, but the pathogenesis of lung disease in SSc is insufficiently understood to devise specific treatment strategies. Developing targeted treatments requires not only the identification of molecular processes involved in SSc-associated lung disease, but also understanding of how these processes interact to drive pathology. One potentially powerful approach is to identify alleles that interact genetically to influence lung outcomes in patients with SSc. Analysis of interactions, rather than individual allele effects, has the potential to delineate molecular interactions that are important in SSc-related lung pathology. However, detecting genetic interactions, or epistasis, in human cohorts is challenging. Large numbers of variants with low minor allele frequencies, paired with heterogeneous disease presentation, reduce power to detect epistasis. Here we present an analysis that increases power to detect epistasis in human genome-wide association studies (GWAS). We tested for genetic interactions influencing lung function and autoantibody status in a cohort of 416 SSc patients. Using Matrix Epistasis to filter SNPs followed by the Combined Analysis of Pleiotropy and Epistasis (CAPE), we identified a network of interacting alleles influencing lung function in patients with SSc. In particular, we identified a three-gene network comprisingWNT5A, RBMS3, andMSI2, which in combination influenced multiple pulmonary pathology measures. The associations of these genes with lung outcomes in SSc are novel and high-confidence. Furthermore, gene coexpression analysis suggested that the interactions we identified are tissue-specific, thus differentiating SSc-related pathogenic processes in lung from those in skin.Author summarySystemic sclerosis (SSc), or scleroderma, is a devastating autoimmune disease. Patients experience progressive fibrosis of their skin and internal organs, reduced quality of life, and increased risk of death. Lung disease associated with SSc is particularly dangerous and is currently the leading cause of death in SSc patients. There are no specific treatments for SSc or SSc-related lung disease, but promising work in the genetics of this disease has identified more than 200 genetic variants that influence SSc [1]. Piecing together how genetic variants interact with each other to influence disease may provide clues for targeted therapies. Here we present a novel analytical approach for identifying genetic interactions in a human disease cohort. In this approach we first filtered SNPs to those that are most likely to interact to influence the disease traits. We then applied the Combined Analysis of Pleiotropy and Epistasis (CAPE), which combines information across multiple traits to increase power to detect genetic interactions. Using this approach, we identified a three-gene network amongMSI2, WNT5A, andRBMS3that influenced autoantibody status and lung function in a cohort of 416 SSc patients. Gene expression data suggest that this interaction network is tissue- and disease-specific, and may thus provide a specific target for SSc therapy.

scholarly journals AB0691 ANALYSIS OF SARS-COV-2 ANTIBODIES IN NON-COVID-19 PATIENTS: COMPARISON BETWEEN SYSTEMIC SCLEROSIS PATIENTS AND HEALTHY CONTROLS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1379.1-1379
Author(s):  
L. Giardullo ◽  
C. Rotondo ◽  
A. Corrado ◽  
N. Maruotti ◽  
R. Colia ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Systemic Sclerosis ◽  
Autoimmune Disease ◽  
Reverse Transcriptase ◽  
Real Time ◽  
Polymerase Chain Reaction Assay ◽  
Nuclear Antigen ◽  
Healthy Controls ◽  
Chain Reaction ◽  
Polymerase Chain

Background:Previous study evidenced a cross-reactivity between Sars-Cov-2 antibodies and autoimmune tissue antigen involved in connective tissue diseases, as nuclear antigen (NA), extractable nuclear antigen (ENA), histone and collagen (1). No study has been published about the titer of Sars-Cov-2 antibodies in non-infected patients with autoimmune disease.Objectives:To evaluate the titer of SARS-CoV-2 antibodies in non-COVID-19 patients and compare it between systemic sclerosis (SSc) patients and healthy controls (HC).Methods:A total of 58 patients with SSc (who fulfilled ACR/EULAR 2013 SSc classification criteria) and 18 HC were enrolled. Sera of all participants were collected, and SARS-CoV-2 antibodies (IgG and IgM) were evaluated by means ELISA. In all participants swabs for SARS-CoV-2 by real-time reverse-transcriptase-polymerase-chain-reaction assay were reported negative. Demographic, clinical, and autoimmune serological characteristics of SSc patients were recorded. The normal distribution was assessed using the Shapiro–Wilk’s test. Exclusion criteria was previous or actual Sars-Cov-2 infection. Comparisons between study groups of patients were evaluated by the Student’s t-test or Mann – Whitney U-test as appropriate. The differences between categorial variables were assessed by Pearson chi-square or Fisher’s exact test, as opportune. Statistical significance was set at p ≤ 0.05.Results:We observed significant differences between SSc patients and HC in serum levels of Sars-Cov-2 antibodies (IgG: 1,4±2,1 AU/ml vs 0,36±0,19 AU/ml respectively (p=0,001); and IgM: 2,5±3,1 AU/ml vs 0,8±0,7 AU/ml (p=0,022)). In 5 SSc patients was found titer of Sars-Cov-2 antibodies (IgG) exceeding the cut-off, but the control of swabs for SARS-CoV-2 by real-time reverse-transcriptase-polymerase-chain-reaction assay were negative. No significative differences in Sars-Cov-2 autoantibodies titer were found in subgroup of SSc patients with or without ILD or PAH, limited or diffuse skin subset, and different autoantibodies profile. Furthermore, antibodies titer was not associated with different drugs (steroid, methotrexate, mofetil-mycophenolate and bosentan) in use.Conclusion:A cross mimicking between Sars-Cov-2 antibodies and antinuclear antibodies or anti ENA could be hypothesized. Further studies are necessary to unravel the reliability of Sars-Cov-2 antibodies detection in autoimmune disease.References:[1]Vojdani, A., Vojdani, E., & Kharrazian, D. (2021). Reaction of human monoclonal antibodies to SARS-CoV-2 proteins with tissue antigens: Implications for autoimmune diseases. Frontiers in Immunology, 11, 3679Disclosure of Interests:None declared

The LARGE2-APO1/APO2 regulatory module controls panicle size and grain number in rice

2021 ◽  
Author(s):  
Luojiang Huang ◽  
Kai Hua ◽  
Ran Xu ◽  
Dali Zeng ◽  
Ruci Wang ◽  
...  
Keyword(s):  
Agronomic Traits ◽  
Loss Of Function ◽  
Grain Number ◽  
Hect Domain ◽  
Regulatory Module ◽  
Promising Target ◽  
Meristematic Activity ◽  
Positive Regulators ◽  
Genetic Mechanisms ◽  
Biochemical Analyses

Abstract Panicle size and grain number are important agronomic traits and influence grain yield in rice (Oryza sativa), but the molecular and genetic mechanisms underlying panicle size and grain number control remain largely unknown in crops. Here we report that LARGE2 encodes a HECT-domain E3 ubiquitin ligase OsUPL2 and regulates panicle size and grain number in rice. The loss of function large2 mutants produce large panicles with increased grain number, wide grains and leaves, and thick culms. LARGE2 regulates panicle size and grain number by repressing meristematic activity. LARGE2 is highly expressed in young panicles and grains. Biochemical analyses show that LARGE2 physically associates with ABERRANT PANICLE ORGANIZATION1 (APO1) and APO2, two positive regulators of panicle size and grain number, and modulates their stabilities. Genetic analyses support that LARGE2 functions with APO1 and APO2 in a common pathway to regulate panicle size and grain number. These findings reveal a novel genetic and molecular mechanism of the LARGE2-APO1/APO2 module-mediated control of panicle size and grain number in rice, suggesting that this module is a promising target for improving panicle size and grain number in crops.

scholarly journals Gastric Antral Vascular Ectasia and Its Clinical Correlates in Patients with Early Diffuse Systemic Sclerosis in the SCOT Trial

2013 ◽  
Vol 40 (4) ◽  
pp. 455-460 ◽  
Author(s):  
Emily W. Hung ◽  
Maureen D. Mayes ◽  
Roozbeh Sharif ◽  
Shervin Assassi ◽  
Victor I. Machicao ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Topoisomerase I ◽  
Rna Polymerase Iii ◽  
Negative Association ◽  
Upper Gastrointestinal Endoscopy ◽  
Gastric Antral Vascular Ectasia ◽  
Clinical Correlates ◽  
Vascular Ectasia ◽  
Diffuse Systemic Sclerosis ◽  
Vascular Ectasias

Objective.To describe the prevalence and clinical correlates of endoscopic gastric antral vascular ectasia (GAVE; “watermelon stomach”) in early diffuse systemic sclerosis (SSc).Methods.Subjects with early, diffuse SSc and evidence of specific internal organ involvement were considered for the Scleroderma: Cyclophosphamide Or Transplant (SCOT) trial. In the screening procedures, all patients underwent upper gastrointestinal endoscopy. Patients were then categorized into those with or without endoscopic evidence of GAVE. Demographic data, clinical disease characteristics, and autoantibody data were compared using Pearson chi-square or Student t tests.Results.Twenty-three of 103 (22.3%) individuals were found to have GAVE on endoscopy. Although not statistically significant, anti-topoisomerase I (anti-Scl70) was detected less frequently among those with GAVE (18.8% vs 44.7%; p = 0.071). Similarly, anti-RNP antibodies (anti-U1 RNP) showed a trend to a negative association with GAVE (0 vs 18.4%; p = 0.066). There was no association between anti-RNA polymerase III and GAVE. Patients with GAVE had significantly more erythema or vascular ectasias in other parts of the stomach (26.1% vs 5.0%; p = 0.003).Conclusion.Endoscopic GAVE was present on screening in almost one-fourth of these highly selected patients with early and severe diffuse SSc. While anti-Scl70 and anti-U1 RNP trended toward a negative association with GAVE, there was no correlation between anti-RNA Pol III and GAVE. Patients with GAVE had a higher frequency of other gastric vascular ectasias outside the antrum, suggesting that GAVE may represent part of the spectrum of the vasculopathy in SSc.

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