Inhibitory killer cell immunoglobulin-like receptor KIR3DL1 in combination with HLA-B Bw4iso protect against Ankylosing spondylitis

Background: The HLA class I molecules serve as ligands for both T cell receptors and killer cell immunoglobulin-like receptors (KIRs). Objective: We investigated the HLA- C and HLA-Bw4 alleles as well as KIRs expression on CD56 positive lymphocytes to evaluate whether these genes and molecules could influence Ankylosing spondylitis (AS) susceptibility, alone or in combination. Methods: We typed 40 AS patients and 40 normal controls for HLA-C asn80 (group 1) and HLA-C lys80 (group 2), HLA-B Bw4thero, HLA-B Bw4iso and HLA-A Bw4 alleles by PCR-SSP method. We also as- sessed the expression of KIR2DL1/2DS1, KIR2DL2/2DL3, KIR3DL1 and KIR2DS4 by flow cytometry. The Pearson chi-square or Fisher exact test was performed for statisti- cal analysis. Results: The frequency of HLA-B Bw4iso but not HLA-B Bw4thero and HLA-A Bw4, ligand for the inhibitory KIR3DL1, was significantly reduced in AS pa- tients as compared with controls (p<0.01). No significant differences were observed in gene carrier frequencies of HLA-C group 1 and 2 between AS and controls. Although no differences were found in the expression of KIR receptors between AS and normal subjects, we found that expression of KIR3DL1 in the presence of HLA Bw4-Biso gene was reduced in patients with AS compared to healthy controls (p<0.009). Conclusion: We conclude that HLA-B Bw4iso, the ligand of inhibitory KIR3DL1, with and without the expression of KIR3DL1 might be involved in protection against AS. Our results suggest that besides the HLA and KIR genotype, expression levels of KIRs may be in- volved in the pathogenesis of AS disease

Gene expression profiling of toll-like receptor 4 and 5 in peripheral blood mononuclear cells of patients with systemic sclerosis

The Toll-Like Receptor (TLR) family is appeared to be expressed in many cell types in the immune system and plays a role in the pathogenesis of various autoimmune diseases. The expression profile and role of TLRs in Systemic Sclerosis (SSc) have been partly explained. It is aimed through this investigation to evaluate the expression pattern of TLR 4 and 5 in Peripheral Blood Mononuclear Cells (PBMCs) from SSc patients. PBMCs were isolated from whole blood of 20 SSc patients and 50 healthy individuals. Total RNA content of leukocytes was extracted. Then, cDNA was synthesized from the mRNA of the cells. Afterward, Quantitative analysis was carried out through Real-Time PCR using the TaqMan Gene Expression Assays. An over expression of TLR5 mRNA in PBMCs from SSc patients was seen in comparison to healthy individuals. Nevertheless, the gene expression of TLR4 in SSc patients remained almost equal to controls. Our findings suggest that over expression of TLR5 in SSc patients may be involved in the pathogenesis of SSc. © 2016 Simin Almasi, Saeed Aslani, Hadi Poormoghim, Ahmadreza Jamshidi, Shiva Poursani and Mahdi Mahmoudi

Gelatinases Increase in Bleomycin-induced Systemic Sclerosis Mouse Model

Systemic sclerosis is a fibrotic autoimmune disease in which aberrant remodeling of the extracellular matrix in organs disturbs their functionalities. The aim of this study was to investigate the expression of gelatinases on systemic sclerosis. Consequently, a mouse model of systemic sclerosis was employed and the gelatinolytic activity of gelatinases was evaluated on the fibrotic tissues of this model. Two groups of ten mice were considered in this work: a group of systemic sclerosis model and control group. For the generation of systemic sclerosis model, mice received bleomycin, while the control group was subjected to phosphate buffered saline (PBS) reception. Mice were tested for fibrosis by using trichrome staining, hydroxyproline measurement and α-SMA detection in tissue sections. Additionally, the gelatinolytic activity of matrix metalloproteinase 2 and matrix metalloproteinase 9 were measured using gelatin zymography in lungs and skin tissue homogenates. The obtained results indicated that subcutaneous injection of bleomycin-induced fibrosis in skin and lung tissues of mice. Pro and active forms of matrix methaloproteinase 9 were increased in fibrotic lung tissues (p<0.05 and p<0.01, respectively), while, the gelatinolytic activity of MMP2 was unaffected in these tissues. Additionally, in skin tissues of bleomycin-treated animals, both pro and active forms of MMP9 and MMP2 were increased (p<0.05). Pro and active forms of gelatinases increase differently in skin and lung tissues of bleomycin-induced scleroderma

The role of progesterone in cellular apoptosis of skin and lung in a bleomycin-injured mouse model

Systemic sclerosis is a female predominant, a fibrotic autoimmune disease in which disturbance in tissue homeostasis and cell turnover including cell apoptosis are central events in pathogenesis. Sex hormones are known as the important players in sexual dimorphism of autoimmune diseases and in tissue homeostasis. Progesterone influences autoimmune disease via its immunomodulatory effect or by its direct action on parenchymal cell function. On the other hand, this hormone impacts tissue homeostasis by acting on cell apoptosis in a different situation. The objective of this study was to examine the effect of progesterone on cellular apoptosis of skin and lung tissues in a mouse model of scleroderma. Four group of mice were involved in this study with 10 mice in each. The fibrotic model was induced by daily subcutaneous injection of bleomycin for 28 days. One week after initiation of fibrosis induction, mice received subcutaneous progesterone alone or with bleomycin for 21 days. Control group received only Phosphate buffered saline PBS. After 28 days, under lethal anesthesia skin and lung tissues were harvested for histological assessment and hydroxyproline measurement. Apoptosis in tissue sections was detected by TUNEL assay technique. Bleomycin administration induced fibrosis in skin and lung tissues. Severe apoptosis was seen in skin and lung tissues of the bleomycin-treated group (p0.05) or in the lung (p>0.05) did not alter apoptosis in bleomycin-treated animals. Our data confirm the role of apoptosis in the pathogenesis of fibrosis in this model; however, progesterone does not affect cellular apoptosis in skin and lung tissues of bleomycin-injured animals. Copyright© February 2019, Iran J Allergy Asthma Immunol. All rights reserved

Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure Ratio and Cardiorenal Syndrome Type 2 in the Systemic Sclerosis EUSTAR Cohort

Objective The aim of the study was to evaluate the association between the tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary artery pressure (sPAP) ratio and estimated glomerular filtration rate (eGFR) and their association with mortality in the European Scleroderma Trials and Research (EUSTAR) cohort. Methods Patients with systemic sclerosis (SSc) from the EUSTAR database with TAPSE, sPAP, and parameters required to calculate eGFR were included. Logistic regression and Cox regression analysis were performed to evaluate TAPSE/sPAP as a risk factor for chronic kidney disease (CKD) and overall survival. Results A total of 2,370 patients with SSc were included; 284 (12%) patients had CKD stage 3a–5. TAPSE/sPAP (odds ratio [OR] 0.479; 95% CI 0.310–0.743; P < 0.001), arterial hypertension (OR 3.118; 95% CI 2.173–4.475; P < 0.001), diastolic dysfunction (OR 1.670; 95% CI 1.148–2.428; P < 0.01), and N-terminal pro-B-type natriuretic peptide (OR 1.165; 95% CI 1.041–1.304; P < 0.01) were associated with CKD stage 3a–5. TAPSE/sPAP ≤0.32 mm/mm Hg (hazard ratio [HR] 3.589; 95% CI 2.236–5.761; P < 0.001), eGFR <60 mL/min per 1.73 m2 (HR 2.818; 95% CI 1.777–4.468; P < 0.001), and age (HR 1.782; 95% CI 1.348–2.356; P < 0.001) were the most significant predictive factors for all-cause mortality. A total of 276 patients with SSc had pulmonary hypertension (PH) confirmed by right heart catheterization, with 69 (25%) having CKD stage 3a–5. No difference was found in eGFR between patients with PH with reduced or normal cardiac index. Conclusion Reduced TAPSE/sPAP ratio is independently associated with CKD. TAPSE/sPAP ratio ≤0.32 mm/mm Hg and eGFR <60 mL/min per 1.73 m2 are prognostic factors for all-cause mortality. In patients with SSc with PH, eGFR is independent by reduced cardiac output

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P &lt; 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P &lt; 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P &lt; 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P &lt; 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P &lt; 0.001; OR(BP) = 2.4, P &lt; 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P &lt; 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P &lt; 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Does the impact of COVID-19 on patients with systemic sclerosis change over time?

ObjectiveThe outcome of patients with COVID-19 improved over the pandemic, including patients with systemic rheumatic diseases. However, data on patients with systemic sclerosis (SSc) are lacking. This study aimed to assess the outcome of patients with both SSc and COVID-19 over several waves.MethodsPatients with both SSc and COVID-19 who were registered in the European Scleroderma Trials and Research group (EUSTAR) were collected between April 2020 and April 2021. Patients were assigned to waves 1, 2, or 3 depending on the date of their COVID-19 diagnosis. Primary endpoints were death, intensive care unit stay, or ventilatory support (severe outcome). Subgroup analyses of patients who were hospitalized or died were conducted. General and SSc-specific characteristics and treatment were compared over the waves. Descriptive statistics and multivariate logistic regression were applied.ResultsA total of 333 patients were included; 57 patients (17%) had a severe outcome, and 30 patients (9%) died. Compared to wave 1, significantly fewer patients with SSc suffered from severe COVID-19 in waves 2 and 3 (28.2% vs 9.8% and 12.7%; P P P = 0.001), and fewer patients died (15.7% vs 5.0% and 7.5%; P = 0.011). Patients were significantly younger, more often men, had less frequent arterial hypertension, and less SSc cardiac involvement over waves 1 to 3. Patients received significantly less medium to high doses of corticosteroids as they did SSc treatment.ConclusionThe outcome of patients with both SSc and COVID-19 improved significantly over time because of intrinsic and extrinsic factors.Pathophysiology and treatment of rheumatic disease

Aberrant expression of miR-138 as a novel diagnostic biomarker in systemic sclerosis

Background: MicroRNAs are short nucleotide sequences that contribute to the regulation of various biological functions and therefore their roles have been investigated in many pathologic conditions such as epithelial to mesenchymal transition in cancer and fibrosis; among them, miR-138 has been mostly studied in cancer biology and is well-known for its suppressing effect on cancer progression. Being able to suppress major pathways involved in EMT, miR-138 could be a good candidate to be investigated in fibrotic responses too. Based on our previous studies, and the capability of miR-138 to target and regulate several components of the EMT pathway; we hypothesized a role for miR-138 in systemic sclerosis. Accordingly, the gene expression of miR-138 was assessed to find any alterations in the whole blood of the SSc patients. Methods: Blood was collected from 70 patients with systemic sclerosis (equally divided between 2 groups of limited and diffuse categories) and 30 healthy individuals as controls. RNA was immediately isolated from the fresh whole blood; afterward, the resulting RNA was reverse transcribed into cDNA and then the relative expression of miR-138 was compared between the patients and the controls by the means of qPCR, and specific TaqMan primer and probes. Results: The relative expression of miR-138 was significantly lower in patients with systemic sclerosis compared to the controls. No significant difference was observed between the limited and diffuse patient groups. ROC curve analysis showed an appropriate diagnostic value of miR-138 in effectively differentiating SSc patients from the healthy controls. Conclusion: miR-138 is likely involved in the pathogenesis of SSc and with further evaluations may be utilized as a diagnostic biomarker in SSc. Also, targeting miR-138 in future studies could be promising for finding a novel treatment option for patients with SSc

Systemic sclerosis and calcinosis cutis: Response to rituximab

What is known and objective Calcinosis cutis (or cutaneous calcification) is a type of calcinosis wherein calcium deposits form in the skin and frequently encountered in limited cutaneous subtype of disease. So far, no treatment has shown an explicit beneficial effect. Medical therapy for calcinosis cutis with rituximab is limited and of variable benefit. Case summary Our patient was 54-year-old lady, a case of limited cutaneous scleroderma with widespread progressive calcinosis cutis unresponsive to current therapy. She went under treatment with rituximab with no successful outcome. What is new and conclusion Results of therapy with rituximab on regression/improvement of systemic sclerosis-related calcinosis are limited and non-conclusive. © 2015 John Wiley & Sons Ltd