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Journal of Clinical Medicine May 2024Depressive disorders are a growing problem worldwide. They are also characterized by high comorbidity, including from the circle of dermatological diseases. Autoimmune... (Review)
Review
Depressive disorders are a growing problem worldwide. They are also characterized by high comorbidity, including from the circle of dermatological diseases. Autoimmune diseases seem to be particularly correlated with depressive comorbidity, raising the question of their possible common pathomechanism. The PubMed database was searched, focusing on results published after 2016. A particular reciprocal correlation of depressive disorders with psoriasis, atopic dermatitis, alopecia areata, impetigo, lupus and systemic scleroderma was found. One possible explanation for the co-occurrence of the above diseases is that the inflammatory theory may be applicable to depression, the various elements of which also apply to autoimmune diseases.
PubMed: 38892934
DOI: 10.3390/jcm13113224 -
Journal of Clinical Medicine May 2024Systemic sclerosis (SSc) represents a rare and intricate autoimmune connective tissue disease, the pathophysiology of which has not been fully understood. Its key... (Review)
Review
Systemic sclerosis (SSc) represents a rare and intricate autoimmune connective tissue disease, the pathophysiology of which has not been fully understood. Its key features include progressive fibrosis of the skin and internal organs, vasculopathy and aberrant immune activation. While various anti-nuclear antibodies can serve as biomarkers for the classification and prognosis of SSc, their direct role in organ dysfunction remains unclear. Anti-Th/To antibodies are present in approximately 5% of SSc patients, and are particularly prevalent among those with the limited subtype of the disease. Although the presence of these autoantibodies is associated with a mild course of the disease, there is a strong connection between them and severe clinical manifestations of SSc, including interstitial lung disease, pulmonary arterial hypertension and gastrointestinal involvement. Also, the additional clinical correlations, particularly with malignancies, need further research. Moreover, the disease's course seems to be influenced by antibodies, specific serum cytokines and TLR signaling pathways. Understanding the relationships between presence of anti-Th/To, its molecular aspects and response to treatment options is crucial for the development of novel, personalized therapeutic techniques and should undergo profound analysis in future studies.
PubMed: 38892733
DOI: 10.3390/jcm13113022 -
International Journal of Molecular... Jun 2024The bleomycin-induced scleroderma model is a well-established and dependable method for creating a mouse model of SSc (systemic sclerosis). In the field of skin...
The bleomycin-induced scleroderma model is a well-established and dependable method for creating a mouse model of SSc (systemic sclerosis). In the field of skin connective tissue diseases, increasing evidence from clinical and animal experiments suggests that TLRs (Toll-like receptors) play an important role in several diseases. This study aimed to determine the role of TLR7 (Toll-like receptor 7) and TLR9 (Toll-like receptor 9) in the mechanisms of immune abnormalities and fibrosis in SSc. This study used TLR7-KO mice (TLR7-knockout mice with a balb/c background) and TLR9-KO mice (TLR9-knockout mice with a balb/c background) as well as WT mice (wild-type balb/c mice). All three kinds of mice were induced by BLM (bleomycin) in a scleroderma model as the experimental group; meanwhile, WT mice treated with PBS (phosphate-buffered saline) were used as the control group. We analyzed the fibrotic phenotype and the immunological abnormality phenotype of TLR7-deficient and TLR9-deficient mice in the SSc disease model using flow cytometry, RT-PCR (reverse transcription-polymerase chain reaction), a histological examination, and IHC (immunohistochemical staining). In a mouse model of SSc disease, the deletion of TLR7 attenuated skin and lung fibrosis, while the deletion of TLR9 exacerbated skin and lung fibrosis. The deletion of TLR7 resulted in a relative decrease in the infiltration and expression of various pro-inflammatory and fibrotic cells and cytokines in the skin. On the other hand, the deletion of TLR9 resulted in a relative increase in the infiltration and expression of various pro-inflammatory and cytokine-inhibiting cells and cytokines in the skin. Under the influence of pDCs (plasmacytoid dendritic cells), the balances of Beff/Breg (IL-6 + CD19 + B cell/IL-10 + CD19 + B cell), Th17/Treg (IL-17A + CD4 + T cell/Foxp3 + CD25 + CD4 + T cell), M1/M2 (CD86 + macrophage/CD206 + macrophage), and Th1/Th2 (TNFα + CD3 + CD4 + T cell/IL-4 + CD3 + CD4 + T cell) were biased towards the suppression of inflammation and fibrosis as a result of the TLR7 deletion. Comparatively, the balance was biased towards promoting inflammation and fibrosis due to the TLR9 deletion. In the SSc model, TLR7 promoted inflammation and fibrosis progression, while TLR9 played a protective role. These results suggest that TLR7 and TLR9 play opposite roles in triggering SSc to produce immune system abnormalities and skin fibrosis.
Topics: Animals; Toll-Like Receptor 7; Scleroderma, Systemic; Toll-Like Receptor 9; Mice; Mice, Knockout; Disease Models, Animal; Bleomycin; Mice, Inbred BALB C; Cytokines; Skin; Fibrosis; Pulmonary Fibrosis; Membrane Glycoproteins
PubMed: 38892317
DOI: 10.3390/ijms25116133 -
Frontiers in Immunology 2024Systemic sclerosis is a systemic connective tissue disease whose main pathophysiological mechanism is a progressive fibrosis of internal organs and skin leading to... (Review)
Review
Systemic sclerosis is a systemic connective tissue disease whose main pathophysiological mechanism is a progressive fibrosis of internal organs and skin leading to thickening and induration. Blood vessels may also be involved. However, systemic scleroderma is not the only disease causing cutaneous sclerosis. There is a group of diseases that mimic scleroderma in their clinical presentation - these are scleroderma-like syndromes. A distinction can be made between syndromes of inflammatory/autoimmune, genetic, metabolic, toxic, drug-induced, occupational, paraneoplastic and syndromes caused by deposition disorders. In the following paper, we have reviewed the literature on scleroderma-like syndromes. We have outlined the factors predisposing to the development of each disease, its pathogenesis, clinical presentation, diagnostic and treatment process and the differences between each syndrome and systemic scleroderma.
Topics: Humans; Scleroderma, Systemic; Diagnosis, Differential; Skin; Syndrome
PubMed: 38887288
DOI: 10.3389/fimmu.2024.1351675 -
Stem Cell Research & Therapy Jun 2024Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is... (Review)
Review
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
Topics: Humans; Fibrosis; Stem Cell Transplantation; Scleroderma, Systemic; Animals; COVID-19
PubMed: 38886859
DOI: 10.1186/s13287-024-03782-5 -
Reumatologia Clinica May 2024Pulmonary hypertension (PH) associated with systemic sclerosis (SSc) increases morbidity and mortality. Cardiopulmonary comorbidities, as per the 2021 PH consensus, play...
INTRODUCTION
Pulmonary hypertension (PH) associated with systemic sclerosis (SSc) increases morbidity and mortality. Cardiopulmonary comorbidities, as per the 2021 PH consensus, play a role in the choice of therapy between monotherapy and combination therapy.
METHODS
A cross-sectional study was conducted in patients with SSc based on the 2013 ACR/EULAR criteria or very early disease (VEDOSS 2011). PH was considered if they met the following criteria: pulmonary artery systolic pressure (PASP)>39mmHg or peak tricuspid regurgitation velocity (PTRV)>3.4m/s, PASP between 33 and 39mmHg or PTRV between 2.9 and 3.4m/s plus two additional findings suggestive of PH. PH was classified as type 2 if LVEF<50% or moderate to severe diastolic dysfunction was present; type 3 if extensive interstitial disease on tomography>20% or forced vital capacity (FVC)<75%; type 4 if abnormalities related to embolism were detected on scintigraphy or tomography. If patients did not meet these criteria, they were classified as type 1 PH. Complete data on cardiopulmonary risk factors and other factors were required. The frequency of these factors in the population and differences between groups based on risk factors were estimated.
RESULTS
A total of 228 patients were selected. Three had type 2 PH, 24 had type 3, and 40 had type 1 PH, with the majority (75%) having at least one cardiopulmonary risk factor, and 47.5% having more than one. Mild diastolic dysfunction (25%) and hypertension (35%) were the most prevalent. In the type 1 PH group, those with risk factors experienced an increase in the number of years with Raynaud's phenomenon, anticentromere antibodies, and gastrointestinal symptoms (p<0.05).
CONCLUSION
In patients with PH, 75% have one, and 45% have two or more risk factors.
Topics: Humans; Scleroderma, Systemic; Cross-Sectional Studies; Female; Hypertension, Pulmonary; Male; Middle Aged; Phenotype; Adult; Aged; Risk Factors
PubMed: 38880552
DOI: 10.1016/j.reumae.2024.01.006 -
Reumatologia Clinica May 2024Autoimmune diseases are known to be associated with an elevated risk of cardiovascular diseases; however, there exists a lack of awareness regarding this increased risk...
INTRODUCTION
Autoimmune diseases are known to be associated with an elevated risk of cardiovascular diseases; however, there exists a lack of awareness regarding this increased risk among patients.
OBJECTIVE
This study aimed to assess the prevalence of cardiovascular risk factors and events in various systemic autoimmune diseases, including Systemic Sclerosis (SSc), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Sjögren's syndrome (SS), matched by age, sex, and disease duration. Additionally, the study aimed to evaluate the perceived and actual risks of cardiovascular disease among patients.
METHODS
A cross-sectional self-reported survey on the patient's perspective of cardiovascular risk was conducted between January and June 2023. Sociodemographic and clinical data, including disease activity, were collected through medical records and questionnaires. Traditional cardiovascular risk factors and events were assessed, alongside the perceived cardiovascular risk. The SCORE calculation and Charlson Comorbidity Index (CCI) were employed for cardiovascular risk assessment.
RESULTS
Survey responses from 180 patients (45 patients each with SSc, SLE, RA, and SS) with systemic autoimmune diseases revealed that 20% perceived a low risk, 23% perceived neither lower nor higher, and 56% perceived a higher risk of developing cardiovascular diseases in the next ten years. Only 45% agreed that their autoimmune disease could increase the risk of a heart attack, even in the absence of other risk factors, and 46.7% were unaware that NSAIDs pose a cardiovascular risk. An association between cardiovascular risk measured by SCORE, comorbidities, and risk perception was observed in RA, SSc, and SS patients, with no association found in SLE patients (p=0.27). Except for SS patients (p=0.02), no association between CCI and disease activity level was found. Regarding the influence of age, working status, and education in CVD risk perception, an association between CVD risk perception and age was observed (p=0.01), with patients over 40 years exhibiting a higher perception of CVD risk. No differences were found regarding working status (p=0.19) nor education level (p=0.06).
CONCLUSIONS
Patients with SS, RA, and SSc displayed a heightened perception of cardiovascular risk, correlating with their actual risk and preexisting comorbidities. However, patients exhibited unawareness of certain cardiovascular risk behaviors. This underscores the need for tailored education programs on cardiovascular risk for autoimmune disease patients, to be implemented at the time of diagnosis and during follow-up in outpatient clinics.
Topics: Humans; Male; Female; Cross-Sectional Studies; Autoimmune Diseases; Cardiovascular Diseases; Middle Aged; Adult; Aged; Heart Disease Risk Factors; Self Report; Arthritis, Rheumatoid; Lupus Erythematosus, Systemic; Sjogren's Syndrome; Scleroderma, Systemic; Risk Assessment; Prevalence; Self Concept; Risk Factors
PubMed: 38880551
DOI: 10.1016/j.reumae.2024.05.002 -
Scientific Reports Jun 2024Systemic sclerosis (SSc) is a multifaceted disease, and its diagnosis triggers substantial anxiety and uncertainty for those affected. Currently, there are no valid data... (Randomized Controlled Trial)
Randomized Controlled Trial
Systemic sclerosis (SSc) is a multifaceted disease, and its diagnosis triggers substantial anxiety and uncertainty for those affected. Currently, there are no valid data describing the impact of disease-specific patient education on the disease knowledge available. We created a two-day, online educational seminar to provide SSc patients with disease-specific information. The primary objective of the study was to observe the change in the disease-specific knowledge of the patients. A total of 118 patients were randomized into an intervention group and a waiting list control group. The change in knowledge was assessed using a multiple-choice test. The intervention group completed the questionnaire before, directly after, and 3 months after the seminar, while the waiting list control group also took the test 3 months before the seminar to rule out nonspecific learning. The primary outcome measure was the score difference between baseline and 3 months after baseline. The study was registered in the German Clinical Trials Register (protocol code DRKS00024915). The educational seminar resulted in a small, but measurable, increase in knowledge. While the two tests in the waiting list control group prior to the seminar did not show a nonspecific increase in disease knowledge, the intervention led to a numerical increase in knowledge (mean ± sd score difference 0.34 ± 1.31, 95% CI (- 0.23; 0.86), p = 0.26) that did not reach statistical significance. Multiple linear regression analysis showed that being a member of a self-help group (β = 1.12; p = 0.03) is a positive predictor of a higher disease knowledge. Although highly appreciated by participants, a two-day online seminar may not be the most appropriate format to generate measurable disease-specific knowledge. Self-help group membership was a positive predictor of a higher level of disease-specific knowledge prior to the educational seminar and should be recommended to every affected person.
Topics: Humans; Scleroderma, Systemic; Female; Male; Middle Aged; Patient Education as Topic; Health Knowledge, Attitudes, Practice; Surveys and Questionnaires; Adult; Aged; Internet
PubMed: 38877137
DOI: 10.1038/s41598-024-64532-4 -
Frontiers in Immunology 2024Integrin-dependent cell adhesion and migration play important roles in systemic sclerosis (SSc). The roles of integrin activating molecules including talins and...
BACKGROUND
Integrin-dependent cell adhesion and migration play important roles in systemic sclerosis (SSc). The roles of integrin activating molecules including talins and kindlins, however, are unclear in SSc.
OBJECTIVES
We aimed to explore the function of integrin activating molecules in SSc.
METHODS
Transcriptome analysis of skin datasets of SSc patients was performed to explore the function of integrin-activating molecules including talin1, talin2, kindlin1, kindlin2 and kindlin3 in SSc. Expression of talin1 in skin tissue was assessed by multiplex immunohistochemistry staining. Levels of talin1 in serum were determined by ELISA. The effects of talin1 inhibition were analyzed in human dermal fibroblasts by real-time PCR, western blot and flow cytometry.
RESULTS
We identified that talin1 appeared to be the primary integrin activating molecule involved in skin fibrosis of SSc. Talin1 was significantly upregulated and positively correlates with the modified Rodnan skin thickness score (mRSS) and the expression of pro-fibrotic biomarkers in the skin lesions of SSc patients. Further analyses revealed that talin1 is predominantly expressed in the dermal fibroblasts of SSc skin and promotes fibroblast activation and collagen production. Additionally, talin1 primarily exerts its effects through integrin β1 and β5 in SSc.
CONCLUSIONS
Overexpressed talin1 is participated in skin fibrosis of SSc, and talin1 appears to be a potential new therapeutic target for SSc.
Topics: Humans; Scleroderma, Systemic; Talin; Fibrosis; Skin; Fibroblasts; Female; Male; Middle Aged; Adult; Cells, Cultured
PubMed: 38863696
DOI: 10.3389/fimmu.2024.1400819 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... May 2024To establish a diagnostic model for scleroderma by combining machine learning and artificial neural network based on mitochondria-related genes.
OBJECTIVE
To establish a diagnostic model for scleroderma by combining machine learning and artificial neural network based on mitochondria-related genes.
METHODS
The GSE95065 and GSE59785 datasets of scleroderma from GEO database were used for analyzing expressions of mitochondria-related genes, and the differential genes were identified by Random forest, LASSO regression and SVM algorithms. Based on these differential genes, an artificial neural network model was constructed, and its diagnostic accuracy was evaluated by 10-fold crossover verification and ROC curve analysis using the verification dataset GSE76807. The mRNA expressions of the key genes were verified by RT-qPCR in a mouse model of scleroderma. The CIBERSORT algorithm was used to estimate the bioinformatic association between scleroderma and the screened biomarkers.
RESULTS
A total of 24 differential genes were obtained, including 11 up-regulated and 13 down-regulated genes. Seven most relevant mitochondria-related genes (POLB, GSR, KRAS, NT5DC2, NOX4, IGF1, and TGM2) were screened using 3 machine learning algorithms, and the artificial neural network diagnostic model was constructed. The model showed an area under the ROC curves of 0.984 for scleroderma diagnosis (0.740 for the verification dataset and 0.980 for cross-over validation). RT-qPCR detected significant up-regulation of POLB, GSR, KRAS, NOX4, IGF1 and TGM2 mRNAs and significant down-regulation of NT5DC2 in the mouse models of scleroderma. Immune cell infiltration analysis showed that the differential genes in scleroderma were associated with follicular helper T cells, immature B cells, resting dendritic cells, memory activated CD4T cells, M0 macrophages, monocytes, resting memory CD4T cells and mast cell activation.
CONCLUSION
The artificial neural network diagnostic model for scleroderma established in this study provides a new perspective for exploring the pathogenesis of scleroderma.
Topics: Mice; Animals; Neural Networks, Computer; Mitochondria; Machine Learning; Algorithms; Scleroderma, Systemic; Humans; Biomarkers; Gene Expression Profiling; Computational Biology; ROC Curve; Disease Models, Animal
PubMed: 38862450
DOI: 10.12122/j.issn.1673-4254.2024.05.14