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Pathogenesis, Immunity and Therapy of Systemic Sclerosis: Molecular Aspects
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Pathogenesis, Immunity and Therapy of Systemic Sclerosis: Molecular Aspects

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 11501

Special Issue Editors

Dr. Diána Simon

E-Mail Website
Guest Editor
Department of Immunology and Biotechnology, University of Pécs Medical School, 7624 Pecs, Hungary
Interests: systemic scleroderma; autoimmunity; B cells
Dr. Tünde Minier

E-Mail Website
Guest Editor
Department of Rheumatology and Immunology, University of Pécs Medical School, 7624 Pecs, Hungary
Interests: systemic scleroderma; vasculopathy; fibrosis

Special Issue Information

Dear Colleagues,

Systemic sclerosis is a connective tissue disease with highly complex pathogenesis which comprises vascular damage, tissue fibrosis and autoimmune phenomena. Due to this complex pathomechanism, there is still an unmet need for efficient disease-modifying treatments in this disease which can affect almost all organ systems and carries the worst disease-related survival among the systemic autoimmune diseases. Ischemia–reperfusion injury, vascular dysfunction and abnormal angiogenesis represent key pathological aspects of vascular damage. Fibrosis in multiple organs is a prominent pathological finding, and is also the most characteristic and disabling clinical feature in systemic sclerosis. Innate immune signaling as well as biomechanical and oxidative stress seem to be involved in propagating the process. Dysregulation of the immune system leads to the breakage of tolerance and the activation of autoreactive T and B lymphocytes, resulting in pathological autoantibody production, inflammation and multi-organ damage. Autoantibody production as a hallmark of autoimmune processes is widely investigated in systemic sclerosis, but less attention has been devoted to the possible roles of innate immune molecules in B-cell dysfunctions. Novel observations regarding the key mechanisms in the pathogenesis of systemic sclerosis carry the potential to initiate further basic research, and may also identify new molecules for therapy. Therefore, this Special Issue aims to highlight recent advances in the cellular and molecular aspects of vascular damage, fibrosis and immune dysfunction.

Dr. Diána Simon
Dr. Tünde Minier
Guest Editors

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Keywords

  • systemic sclerosis
  • vascular damage
  • fibrosis
  • autoimmunity
  • oxidative stress
  • angiogenesis
  • immune dysfunction
  • innate immune molecules
  • biomarkers

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Published Papers (5 papers)

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Research

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12 pages, 2276 KiB  
Article
Enhanced Innate and Acquired Immune Responses in Systemic Sclerosis Primary Peripheral Blood Mononuclear Cells (PBMCs)
by Iulia Szabo, Medeea Badii, Ildikó O. Gaál, Robert Szabo, Radu A. Popp, Leo A. B. Joosten, Tania O. Crişan and Simona Rednic
Int. J. Mol. Sci. 2023, 24(19), 14438; https://doi.org/10.3390/ijms241914438 - 22 Sep 2023
Cited by 1 | Viewed by 1331
Abstract
Chronic immune activation in systemic sclerosis is supported by the production of a plethora of cytokines with proven regulatory activities of the immune responses. This study aimed to explore PBMCs’ cytokine profiles in SSc patients versus controls, as well as to investigate the [...] Read more.
Chronic immune activation in systemic sclerosis is supported by the production of a plethora of cytokines with proven regulatory activities of the immune responses. This study aimed to explore PBMCs’ cytokine profiles in SSc patients versus controls, as well as to investigate the balance between pro- and anti-inflammatory cytokines in association with disease duration. PBMCs were isolated from 18 SSc patients and 17 controls and further subjected to in vitro stimulation with lipopolysaccharide and heat-killed Candida albicans. Cytokine production was measured after 24 h and 7 days, respectively, using ELISA kits for interleukin (IL)-1β, IL-1 receptor antagonist (IL-1Ra), IL-6, tumor necrosis factor (TNF), IL-10, IL-17, and interferon-gamma (IFN-gamma). IL-1 β, IL-6, and TNF levels were increased in SSc patients compared with healthy volunteers irrespective of the stimulus used. IL-1Ra and Il-17 concentrations were not statistically different between groups, even though a trend toward higher levels in patients compared with their matched controls was also observed. Most cytokines demonstrated a stable course with disease progression, except for IL-10 levels, which declined over time. In conclusion, the results of this pilot study reveal that in patients with SSc a persistently enhanced immune response is established and maintained regardless of stimulus or disease duration. Full article
(This article belongs to the Special Issue Pathogenesis, Immunity and Therapy of Systemic Sclerosis: Molecular Aspects)
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14 pages, 866 KiB  
Article
In the Pursuit of Metabolic Markers of Systemic Sclerosis—Plasma Adiponectin and Omentin-1 in Monitoring the Course of the Disease
by Klaudia Dopytalska, Małgorzata Kalisz, Anna Litwiniuk, Irena Walecka, Wojciech Bik and Agnieszka Baranowska-Bik
Int. J. Mol. Sci. 2023, 24(12), 9988; https://doi.org/10.3390/ijms24129988 - 10 Jun 2023
Viewed by 1231
Abstract
Systemic sclerosis (SSc) is a connective tissue disease leading to cutaneous and visceral fibrosis. Pathological features of SSc include immune dysregulation, vasculopathy, and impaired angiogenesis. Adipokines act as cytokines and hormones and are involved in various pathological processes, including metabolic disorders, inflammation, vasculopathy, [...] Read more.
Systemic sclerosis (SSc) is a connective tissue disease leading to cutaneous and visceral fibrosis. Pathological features of SSc include immune dysregulation, vasculopathy, and impaired angiogenesis. Adipokines act as cytokines and hormones and are involved in various pathological processes, including metabolic disorders, inflammation, vasculopathy, and fibrosis. This study aimed to determine the level of omentin-1 and adiponectin to evaluate their potential role in the pathogenesis of SSc. We assessed serum omentin-1 and adiponectin as well as metabolic parameters in 58 patients with SSc and 30 healthy controls. The follow-up was performed in SSc individuals. Omentin-1 levels were significantly higher in SSc individuals as compared to the controls. In post-hoc analysis, omentin-1 was higher in the group with disease duration ≥7 years than in the control group. A positive correlation was noted between disease duration and both adipokines and increased with longer disease duration. However, there were no correlations between selected adipokines and metabolic parameters. Enhanced omentin-1 levels and higher levels of omentin-1 in patients with longer disease duration may suggest that omentin-1 is involved in the pathomechanisms of SSc as its concentrations are not directly related to BMI, age, and insulin resistance. Full article
(This article belongs to the Special Issue Pathogenesis, Immunity and Therapy of Systemic Sclerosis: Molecular Aspects)
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13 pages, 655 KiB  
Article
Can Pharmacogenetic Variants in TPMT, MTHFR and SLCO1B1 Genes Be Used as Potential Markers of Outcome Prediction in Systemic Sclerosis Patients?
by Marina Jelovac, Nikola Kotur, Bojan Ristivojevic, Djordje Pavlovic, Vesna Spasovski, Nemanja Damjanov, Sonja Pavlovic and Branka Zukic
Int. J. Mol. Sci. 2023, 24(10), 8538; https://doi.org/10.3390/ijms24108538 - 10 May 2023
Cited by 2 | Viewed by 2361
Abstract
Systemic sclerosis (SSc) is a rare connective tissue disorder with highest morbidity and mortality among rheumatologic diseases. Disease progression is highly heterogeneous between patients, implying a strong need for individualization of therapy. Four pharmacogenetic variants, namely TPMT rs1800460, TPMT rs1142345, MTHFR rs1801133 and [...] Read more.
Systemic sclerosis (SSc) is a rare connective tissue disorder with highest morbidity and mortality among rheumatologic diseases. Disease progression is highly heterogeneous between patients, implying a strong need for individualization of therapy. Four pharmacogenetic variants, namely TPMT rs1800460, TPMT rs1142345, MTHFR rs1801133 and SLCO1B1 rs4149056 were tested for association with severe disease outcomes in 102 patients with SSc from Serbia treated either with immunosuppressants azathioprine (AZA) and methotrexate (MTX) or with other types of medications. Genotyping was performed using PCR-RFLP and direct Sanger sequencing. R software was used for statistical analysis and development of polygenic risk score (PRS) model. Association was found between MTHFR rs1801133 and higher risk for elevated systolic pressure in all patients except those prescribed with MTX, and higher risk for kidney insufficiency in patients prescribed with other types of drugs. In patients treated with MTX, variant SLCO1B1 rs4149056 was protective against kidney insufficiency. For patients receiving MTX a trend was shown for having a higher PRS rank and elevated systolic pressure. Our results open a door wide for more extensive research on pharmacogenomics markers in patients with SSc. Altogether, pharmacogenomics markers could predict the outcome of patients with SSc and help in prevention of adverse drug reactions. Full article
(This article belongs to the Special Issue Pathogenesis, Immunity and Therapy of Systemic Sclerosis: Molecular Aspects)
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Review

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17 pages, 2069 KiB  
Review
The Pathogenesis of Systemic Sclerosis: The Origin of Fibrosis and Interlink with Vasculopathy and Autoimmunity
by Junsuk Ko, Maria Noviani, Vasuki Ranjani Chellamuthu, Salvatore Albani and Andrea Hsiu Ling Low
Int. J. Mol. Sci. 2023, 24(18), 14287; https://doi.org/10.3390/ijms241814287 - 19 Sep 2023
Cited by 15 | Viewed by 4057
Abstract
Systemic sclerosis (SSc) is an autoimmune disease associated with increased mortality and poor morbidity, impairing the quality of life in patients. Whilst we know that SSc affects multiple organs via vasculopathy, inflammation, and fibrosis, its exact pathophysiology remains elusive. Microvascular injury and vasculopathy [...] Read more.
Systemic sclerosis (SSc) is an autoimmune disease associated with increased mortality and poor morbidity, impairing the quality of life in patients. Whilst we know that SSc affects multiple organs via vasculopathy, inflammation, and fibrosis, its exact pathophysiology remains elusive. Microvascular injury and vasculopathy are the initial pathological features of the disease. Clinically, the vasculopathy in SSc is manifested as Raynaud’s phenomenon (reversible vasospasm in reaction to the cold or emotional stress) and digital ulcers due to ischemic injury. There are several reports that medications for vasculopathy, such as bosentan and soluble guanylate cyclase (sGC) modulators, improve not only vasculopathy but also dermal fibrosis, suggesting that vasculopathy is important in SSc. Although vasculopathy is an important initial step of the pathogenesis for SSc, it is still unclear how vasculopathy is related to inflammation and fibrosis. In this review, we focused on the clinical evidence for vasculopathy, the major cellular players for the pathogenesis, including pericytes, adipocytes, endothelial cells (ECs), and myofibroblasts, and their signaling pathway to elucidate the relationship among vasculopathy, inflammation, and fibrosis in SSc. Full article
(This article belongs to the Special Issue Pathogenesis, Immunity and Therapy of Systemic Sclerosis: Molecular Aspects)
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17 pages, 1710 KiB  
Review
The Role of Autophagy and Apoptosis in Affected Skin and Lungs in Patients with Systemic Sclerosis
by Vesna Spasovski, Marina Andjelkovic, Marina Parezanovic, Jovana Komazec, Milena Ugrin, Kristel Klaassen and Maja Stojiljkovic
Int. J. Mol. Sci. 2023, 24(13), 11212; https://doi.org/10.3390/ijms241311212 - 7 Jul 2023
Cited by 2 | Viewed by 1852
Abstract
Systemic sclerosis (SSc) is a complex autoimmune inflammatory disorder with multiple organ involvement. Skin changes present the hallmark of SSc and coincide with poor prognosis. Interstitial lung diseases (ILD) are the most widely reported complications in SSc patients and the primary cause of [...] Read more.
Systemic sclerosis (SSc) is a complex autoimmune inflammatory disorder with multiple organ involvement. Skin changes present the hallmark of SSc and coincide with poor prognosis. Interstitial lung diseases (ILD) are the most widely reported complications in SSc patients and the primary cause of death. It has been proposed that the processes of autophagy and apoptosis could play a significant role in the pathogenesis and clinical course of different autoimmune diseases, and accordingly in SSc. In this manuscript, we review the current knowledge of autophagy and apoptosis processes in the skin and lungs of patients with SSc. Profiling of markers involved in these processes in skin cells can be useful to recognize the stage of fibrosis and can be used in the clinical stratification of patients. Furthermore, the knowledge of the molecular mechanisms underlying these processes enables the repurposing of already known drugs and the development of new biological therapeutics that aim to reverse fibrosis by promoting apoptosis and regulate autophagy in personalized treatment approach. In SSc-ILD patients, the molecular signature of the lung tissues of each patient could be a distinctive criterion in order to establish the correct lung pattern, which directly impacts the course and prognosis of the disease. In this case, resolving the role of tissue-specific markers, which could be detected in the circulation using sensitive molecular methods, would be an important step toward development of non-invasive diagnostic procedures that enable early and precise diagnosis and preventing the high mortality of this rare disease. Full article
(This article belongs to the Special Issue Pathogenesis, Immunity and Therapy of Systemic Sclerosis: Molecular Aspects)
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