The presence of abnormal septal motion on echocardiography is a predictor of abnormal cardiac magnetic resonance in systemic sclerosis.

OBJECTIVES: We aimed to perform a comprehensive analysis of the ECG, two-dimensional echocardiography (2DE) and cardiac MRI (CMR) findings in patients with systemic sclerosis (SSc), and also to investigate correlations between CMR findings and some ECG and echocardiography (ECHO) results. METHODS: We retrospectively analysed data from patients with SSc who were regularly seen at our outpatient referral centre, all assessed with ECG, Doppler ECHO and CMR. RESULTS: Ninety-three patients were included; mean (s.d.) age of 48.5 (10.3) years, 86% female, 52% diffuse SSc. Eighty-four (90%) of the patients had sinus rhythm. The most common ECG finding was the left anterior fascicular block, recorded in 26 patients (28%). The abnormal septal motion (ASM) was found in 43 (46%) patients on ECHO. Myocardial involvement (inflammation or fibrosis), as assessed by multiparametric CMR, was present in >50% of our patients. The age- and sex-adjusted model showed that ASM on ECHO increased significantly the odds of increased extracellular volume [odds ratio (OR) 4.43, 95% CI 1.73, 11.38], increased T1 Relaxation time (OR 2.67, 95% CI 1.09, 6.54), increased T2 Relaxation time (OR 2.56, 95% CI 1.05, 6.22), increased signal intensity ratio in T2-weighted imaging (OR 2.56, 95% CI 1.05, 6.22), presence of late gadolinium enhancement (OR 3.85, 95% CI 1.52, 9.76) and mid-wall fibrosis (OR 3.64, 95% CI 1.48, 8.96). CONCLUSION: This study indicates that the presence of ASM on ECHO is a predictor of abnormal CMR in SSc patients, and a precise assessment of ASM may serve as an important point for selecting the patients that should be evaluated by CMR for early detection of myocardial involvement.

Anti-inflammatory effects of PRIMA-1MET (mutant p53 reactivator) induced by inhibition of nuclear factor-κB on rheumatoid arthritis fibroblast-like synoviocytes.

Fibroblast-like synoviocytes (FLSs), the main pathological cells in rheumatoid arthritis (RA), display tumor-like phenotype, including hyper-proliferation, apoptosis resistance, and aggressive phenotype. Excessive proliferation and insufficient apoptosis of RA-FLSs can lead to hyperplastic synovial pannus tissue, excess production of inflammatory mediators, and destruction of joints. In this article, we investigate the effect of PRIMA-1MET on the apoptosis induction and inhibition of pro-inflammatory cytokines in RA-FLSs. Synovial tissue samples were obtained from 10 patients with RA. The FLSs were treated with different concentrations of PRIMA-1MET. The rate of apoptosis and cell survival was assessed by flow cytometry and MTT assay and Real-time quantitative PCR was performed to evaluate the transcription of p53, IL-6, IL-1ß, TNF-α, Noxa, p21, PUMA, Bax, Survivin, and XIAP in treated RA-FLSs. The protein level of p53, IκBα, and phospho-IκBα were measured using Western blotting. The results showed that PRIMA-1MET induced apoptosis in RA-FLSs and increased significantly the expression of Noxa, and decreased significantly IL-6, IL-1ß, p53, and phospho-IκBα expression. PRIMA-1MET can induce apoptosis in RA-FLSs through induction of Noxa expression while p53 was downregulated. Furthermore, PRIMA-1MET treatment results in the suppression of pro-inflammatory cytokine production and NF-κB inhibition. Given the role of p53 and NF-κB in RA-FLSs, PRIMA-1MET can be considered as a new therapeutic strategy for rheumatoid arthritis.

Role of the innate and adaptive immune responses in the pathogenesis of systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE), the most common form of lupus, is a multisystemic rheumatic disease with different clinical features that generally affect women of childbearing age. The common symptoms of SLE are very similar to other autoimmune and non-autoimmune disorders, thereby it is known as a thousand faces disease. In this article, we are going to discuss some of the most updated information about immune system-related factors, cells, and cytokines involved in SLE pathogenesis. METHODS: Different electronic databases, especially PubMed/MEDLINE, Scopus, and Google Scholar, were searched to review and analyze relevant literature on the role of innate and adaptive immune cells and cytokines in the pathogenesis of SLE. A search for relevant literature was accomplished using various keywords including systemic lupus erythematosus, apoptosis, autoantibodies, immunopathogenesis of SLE, adaptive and innate immune cells, inflammatory cytokines, hormones, etc. RESULTS AND CONCLUSION: The most important characteristic of SLE is the production of antibodies against different nuclear autoantigens like double-strand DNA and RNA. The depositions of the immune complexes (ICs) that are generated between autoantibodies and autoantigens, along with aberrant clearance of them, can lead to permanent inflammation and contribute to tissue or organ damage. Related mechanisms underlying the initiation and development of SLE have not been clarified yet. Although, defects in immune tolerance, enhanced antigenic load, hyperactivity of T cells, and inappropriate regulation of B cells contribute to the pathogenic autoantibodies generation. Besides, sex hormones that influence the immune system seem to act as triggers or protectors of SLE development.

A2A adenosine receptor agonist reduced MMP8 expression in healthy M2-like macrophages but not in macrophages from ankylosing spondylitis patients.

BACKGROUND: Ankylosing spondylitis (AS) is an inflammatory autoimmune disease that mostly affects different joints of the body. Macrophages are the predominant cells that mediate disease progression by secreting several pro-inflammatory mediators. Different receptors are involved in macrophages' function including the adenosine receptors (AR). Our main objective in this study was to assess the effect of applying A2A adenosine receptor agonist (CGS-21,680) on the gene expression of inflammatory mediators including bone morphogenetic proteins (BMP)-2, 4 and matrix metalloproteinases (MMP)-3, 8, 9, and 13 on the macrophages from AS patients compared to healthy macrophages. METHODS: Monocytes were isolated from the whole blood of 28 individuals (AS patients and healthy controls in a 1:1 ratio). Macrophages were differentiated using macrophage colony-stimulating factor (M-CSF), and flow cytometry was performed to confirm surface markers. CGS-21,680 was used to treat cells that had been differentiated. Using SYBR green real-time PCR, relative gene expression was determined. RESULTS: Activating A2AAR diminished MMP8 expression in healthy macrophages while it cannot reduce MMP8 expression in patients' macrophages. The effect of A2AAR activation on the expression of BMP2 and MMP9 reached statistical significance neither in healthy macrophages nor in the patients' group. We also discovered a significant positive connection between MMP8 expression and patient scores on the Bath ankylosing spondylitis functional index (BASFI). CONCLUSION: Due to the disability of A2AAR activation in the reduction of MMP8 expression in patients' macrophages and the correlation of MMP8 expression with BASFI index in patients, these results represent defects and dysregulations in the related signaling pathway in patients' macrophages.

Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis.

Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis common in Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease most common in people of Mediterranean origin. MEFV, an FMF-associated gene, is also a candidate gene for AS. We aimed to identify AS susceptibility loci and also examine the association between MEFV and AS in Turkish and Iranian cohorts. We performed genome-wide association studies in 1001 Turkish AS patients and 1011 Turkish controls, and 479 Iranian AS patients and 830 Iranian controls. Serum IL-1ß, IL-17 and IL-23 cytokine levels were quantified in Turkish samples. An association of major effect was observed with a novel rare coding variant in MEFV in the Turkish cohort (rs61752717, M694V, OR = 5.3, P = 7.63×10(-12)), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65×10(-13)). 99.6% of Turkish AS cases, and 96% of those carrying MEFV rs61752717 variants, did not have FMF. In Turkish subjects, the association of rs61752717 was particularly strong in HLA-B27-negative cases (OR = 7.8, P = 8.93×10(-15)), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69×10(-8)). Serum IL-1ß, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1ß and IL-23 levels were increased in MEFV 694V carriers compared with non-carriers. Our data suggest that FMF and AS have overlapping aetiopathogenic mechanisms. Functionally important MEFV mutations, such as M694V, lead to dysregulated inflammasome function and excessive IL-1ß function. As IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy.

Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis.

OBJECTIVE: We sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain. METHODS: PRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), HLA-B27 and sacroiliac MRI. RESULTS: In people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for HLA-B27 testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with HLA-B27 testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for HLA-B27, these values were 51.9% and 97.9%, respectively. CONCLUSIONS: PRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or HLA-B27 status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.

Downregulation of ITM2A Gene Expression in Macrophages of Patients with Ankylosing Spondylitis.

OBJECTIVES: Ankylosing spondylitis (AS) is a rheumatic disorder that is mostly determined by genetic and environmental factors. Given the known importance of macrophage in AS pathogenesis, we investigated the transcriptional profile of macrophage cells in the disease. METHODS AND RESULTS: Two approaches of differential expression and subsequently, weighted gene co-expression network analysis was utilized to analyze a publicly available microarray dataset of macrophages. Integral membrane protein 2A (ITM2A) was among the most significant genes with a decreased trend in the common results of both methods. In order to confirm the finding, the expression of ITM2A was evaluated in monocyte-derived (M2-like) and M1 macrophages obtained from 14 AS patients and 14 controls. Macrophages were differentiated from whole-blood separated monocytes by 7 days incubating with macrophage colony-stimulating factor and then macrophages specific markers were verified with the flow cytometer. M1 polarization was induced by IFN-γ and lipopolysaccharide. Finally, relative gene expression analysis by real-time polymerase chain reaction revealed a significant downregulation of the ITM2A gene in both M2 like and M1 macrophages of the AS group compared to the control. CONCLUSION: Since ITM2A plays a critical role in osteo- and chondrogenic cellular differentiation, our finding may provide new insights into AS pathogenesis.

The role of NK cells in rheumatoid arthritis.

OBJECTIVE: Natural killer (NK) cells are part of the innate immune system which not only provides a primary response to pathogenic conditions but can also play an important regulatory role in immune responses. Furthermore, these cells can influence immune responses by affecting other involved cells. Human NK cells can be classified as CD56dim and CD56bright; the former demonstrates mostly cytotoxic effects, while the latter comprises mostly tolerant or regulatory NK cells. These cells participate in the immunopathogenesis of rheumatoid arthritis (RA) and their role remains still unclear. METHODS: We searched PubMed/MEDLINE and Scopus databases to review and analyze relevant literature on the impact of NK cells in the pathogenesis of RA. RESULTS: Although the percentage of NK cells increases in peripheral blood of RA patients compared to healthy individuals, the cytotoxic function of these cells is impaired. It is demonstrated by reduced "perforin+ NK cells" and decreased per-cell lytic function. These cytotoxic NK cells may control the pathogenic bone absorptive function of osteoclasts by directly targeting these cells. CONCLUSION: Collectively, the evidence collected in the current review emphasizes the possible protective role of CD56dim NK cells in the pathogenesis of RA.

Dysregulation of ribosome-related genes in ankylosing spondylitis: a systems biology approach and experimental method.

BACKGROUND: Ankylosing spondylitis (AS) is an autoimmune rheumatic disease. Few candidate gene associations have been reported for AS and the current understanding of its pathogenesis remains still poor. Thus, the exact mechanism of AS is needed to urgently be disclosed. The purpose of this study was to identify candidate genes involving in AS disease. METHODS AND RESULTS: GSE25101 publicly available microarray and GSE117769 RNA-seq datasets of AS patients were obtained for bioinformatics analyses. Gene set enrichment analysis showed that in the microarray dataset, the ribosome pathway was significantly up-regulated in AS compared with controls. Furthermore, some ribosomal components demonstrated overexpression in patients in the RNA-seq dataset. To confirm the findings, 20 AS patients and 20 matching controls were selected from the Rheumatology Research Center clinic, Shariati Hospital. PBMCs were separated from whole blood and RNA contents were extracted. Following the results of datasets analysis, the expression level of rRNA5.8S pseudogene, rRNA18S pseudogene, RPL23, RPL7, and RPL17 genes were measured through real-time PCR. Our findings showed dysregulation of rRNA5.8S and rRNA18S pseudogenes, and also the RPL17 gene in patients. CONCLUSION: Considering that genes involved in ribosome biogenesis contributed to some AS-associated biological processes as well as diseases that have comorbidities with AS, our results might advance our understanding of the pathological mechanisms of ankylosing spondylitis.

Epigenetics in rheumatoid arthritis; fibroblast-like synoviocytes as an emerging paradigm in the pathogenesis of the disease.

Rheumatoid arthritis (RA) is characterized by immune dysfunctions and chronic inflammation that mainly affects diarthrodial joints. Genetics has long been surveyed in searching for the etiopathogenesis of the disease and partially clarified the conundrums within this context. Epigenetic alterations, such as DNA methylation, histone modifications, and noncoding RNAs, which have been considered to be involved in RA pathogenesis, likely explain the nongenetic risk factors. Epigenetic modifications may influence RA through fibroblast-like synoviocytes (FLSs). It has been shown that FLSs play an essential role in the onset and exacerbation of RA, and therefore, they may illustrate some aspects of RA pathogenesis. These cells exhibit a unique DNA methylation profile in the early stage of the disease that changes with disease progression. Histone acetylation profile in RA FLSs is disrupted through the imbalance of histone acetyltransferases and histone deacetylase activity. Furthermore, dysregulation of microRNAs (miRNAs) is immense. Most of these miRNAs have shown an aberrant expression in FLSs that are involved in proliferation and cytokine production. Besides, dysregulation of long noncoding RNAs in FLSs has been revealed and attributed to RA pathogenesis. Further investigations are needed to get a better view of epigenetic alterations and their interactions. We also discuss the role of these epigenetic alterations in RA pathogenesis and their therapeutic potential.

Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial.

INTRODUCTION: There are no determined treatment agents for severe COVID-19. It is suggested that methylprednisolone, as an immunosuppressive treatment, can reduce the inflammation of the respiratory system in COVID-19 patients. METHODS: We conducted a single-blind, randomised controlled clinical trial involving severe hospitalised patients with confirmed COVID-19 at the early pulmonary phase of the illness in Iran. The patients were randomly allocated in a 1:1 ratio by the block randomisation method to receive standard care with methylprednisolone pulse (intravenous injection, 250 mg·day-1 for 3 days) or standard care alone. The study end-point was the time of clinical improvement or death, whichever came first. Primary and safety analysis was done in the intention-to-treat (ITT) population. RESULTS: 68 eligible patients underwent randomisation (34 patients in each group) from April 20, 2020 to June 20, 2020. In the standard care group, six patients received corticosteroids by the attending physician before the treatment and were excluded from the overall analysis. The percentage of improved patients was higher in the methylprednisolone group than in the standard care group (94.1% versus 57.1%) and the mortality rate was significantly lower in the methylprednisolone group (5.9% versus 42.9%; p<0.001). We demonstrated that patients in the methylprednisolone group had a significantly increased survival time compared with patients in the standard care group (log-rank test: p<0.001; hazard ratio 0.293, 95% CI 0.154-0.556). Two patients (5.8%) in the methylprednisolone group and two patients (7.1%) in the standard care group showed severe adverse events between initiation of treatment and the end of the study. CONCLUSIONS: Our results suggest that methylprednisolone pulse could be an efficient therapeutic agent for hospitalised severe COVID-19 patients at the pulmonary phase.

Copy number variation of IL17RA gene and its association with the ankylosing spondylitis risk in Iranian patients: a case-control study.

BACKGROUND: Ankylosing spondylitis (AS) is considered as a subtype of spondyloarthritis (SpA) that mainly leads to fatigue, stiffness, spinal ankylosis, and impaired physical functions with reduced quality of life. Interleukin (IL)-17A provokes additional inflammatory mediators and recruits immune cells to the inflamed site. IL17 expression increased in various inflammatory disorders including psoriasis, rheumatoid arthritis, multiple sclerosis, crohn's disease, and ankylosing spondylitis. The current study aimed to evaluate the association of IL17RA copy number changes with the susceptibility to AS and their correlation to IL17RA expression in Iranian population. METHODS: IL17RA copy number genotyping assessments were carried out in 455 AS patients and 450 healthy controls, using custom TaqMan CNV assays. TaqMan primers and probe were located in Chr.22:17109553 based on pre-designed IL17RA Copy Number Assay ID, Hs02339506_cn. mRNA expression of IL17RA was also measured by SYBR Green real-time polymerase chain reaction (PCR). RESULTS: A IL17RA copy number loss (< 2) was associated with AS compared to 2 copies as reference (OR:2.18, 95% CI: (1.38-3.44), P-value < 0.001) and increased the risk of AS. IL17RA mRNA expression showed a significant increase in peripheral blood mononuclear cells (PBMCs) of all AS individuals than controls. The mRNA expression level of 2 copies was significantly higher in AS patients. CONCLUSIONS: Our findings revealed that a low copy number of IL17RA might confer a susceptibility risk to AS. However, it is probably not directly involved in the regulation of IL17RA mRNA expression. Epigenetic mechanisms like DNA methylation, post-transcriptional, and -translational modifications that regulate the expression of the genes may contribute in upregulation of IL17RA mRNA expression in the loss of gene copy number condition.

Activation of adenosine A2A receptor induced interleukin-23 mRNA expression in macrophages of ankylosing spondylitis patients.

BACKGROUND: Ankylosing spondylitis (AS) is an auto-inflammatory debilitating disorder with a complex pathogenesis. The adenosinergic pathway is an immunologic regulating pathway with a potential role in AS pathophysiology. In the present study, we have aimed to investigate the influence of A2A adenosine receptor (A2AAR) activation on tumor necrosis factor-α (TNF-α) and interleukin-23 (IL-23) expression and secretion by monocyte-generated macrophages of AS patients. METHODS: Whole-blood separated monocytes were extracted from 14 AS patients and 14 healthy controls. Macrophages were differentiated by macrophage colony-stimulating factor (M-CSF), and surface markers were confirmed by flow cytometer. Cells were treated with CGS-21680 as a known agonist of A2AAR. Analysis of ADORA2A, TNFA, and IL23A gene expression was performed by SYBR green real-time PCR. The concentration of secreted cytokines was also measured by ELISA kits. RESULTS: Based on our analysis, CGS-21680 significantly decreased TNF-α secretion by monocyte-derived macrophages of AS patients. Moreover, A2AAR agonist increased the IL23A mRNA expression level in monocyte-derived macrophages of AS patients considerably. Whereas, CGS-21680 did not have any influence on macrophages of healthy individuals. CONCLUSION: According to our results, it appears that A2AAR activation can increase IL-23 secretion by monocyte-derived macrophages of AS patients. Although the TNF-α reducing effect of A2AAR agonists can be a potential target in AS treatment, robust increasing of IL-23 should be considered as the undesirable effect of these agents.

microRNAs are potentially regulating the survivin gene in PBMCs from systemic sclerosis patients.

Background: Survivin is an important anti-apoptotic protein and is involved in increasing auto-reactivity during the autoimmune diseases like systemic sclerosis (SSc).Aims: In the current study, we investigate the expression level of total survivin (survivin-TS) and its three important variants alongside with evaluation of the expression level of important microRNAs (miRNAs) that are involved in survivin expression regulation.Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 50 healthy controls, 25 diffuse cutaneous SSc (DcSSc), and 25 limited cutaneous SSc (LcSSc) patients. RNA was extracted and single-strand cDNA was synthesized. Quantitative real-time PCR was used to evaluate the expression level of survivin-TS and its variants as well the miRNAs.Results: Overexpression of survivin-2B and downregulation of survivin wild-type (survivin-WT) were found in total-SSc patients; however, expression level of survivin-TS had no significant difference. The expression levels of miR-335-5p, miR-485-5p, miR-16-5p, miR-150-5p, miR-34a-5p, miR-218-5p and miR-708-5p were higher in total-SSc patients. Significantly negative correlations were found between transcript levels of miR-150-5p, miR-16-5p, and miR-485-5p with survivin-TS mRNA expression.Conclusion: Survivin variants had altered expression in total-SSc patients. In addition, miRNAs might potentially and negatively regulate the survivin-TS expression. Altered expression of survivin, regulated by miRNAs, may result in apoptosis resistance and auto-reactivity in lymphocytes from patients and have important roles in SSc pathogenicity.

Epigenetics in osteoarthritis: Novel spotlight.

Osteoarthritis (OA) is the most common type of arthritis and no longer is considered as an absolute consequence of joint mechanical use (wear and tear); rather recent data demonstrate the pivotal role of inflammatory mediators in the development and progression of this disease. This multifactorial disease results from several environmental and inherited factors. Genetic cannot solely explain all the contribution share of inheritance and, this way, it is speculated that epigenetics can play a role, too. Moreover, environmental factors can induce local epigenetic changes. The epigenetic contribution to OA pathogenesis occurs at all of its levels, DNA methylation, histone modification, microRNA, and long noncoding RNA. In fact, during early phases of OA pathogenesis, environmental factors employ epigenetic mechanisms to provide a positive feedback for the OA-related pathogenic mechanisms and pathways with an ultimate outcome of a well-established clinical OA. These epigenetic changes stay during clinical disease and prevent the body natural healing and regenerative processes to work properly, resulting in an incurable disease condition. In this review article, we aimed to have an overview on the studies performed with regard to understanding the role of epigenetics in the etiopathogenesis of OA and highlighted the importance of such kind of regulatory mechanisms within this context.

Are genetic variations in IL-21-IL-23R-IL-17A cytokine axis involved in a pathogenic pathway of rheumatoid arthritis? Bayesian hierarchical meta-analysis.

Inflammatory cytokines have been established to be involved in the pathogenesis of rheumatoid arthritis (RA). The genetic polymorphisms in the interleukin (IL) 23 receptor (IL23R), IL21, and IL17 have been associated with RA risk. However, there is no conclusive understanding of the genes encoding the immunoinflammatory IL-21-IL-23R-IL-17A pathway in RA aetiopathogenesis. This meta-analysis was conducted to attain this goal. A comprehensive literature search was conducted in Scopus and PubMed to look for the relevant case-control studies up until 2018. A Bayesian hierarchical meta-analysis was carried out to assess the association between the polymorphisms and the risk of RA. The association was estimated by calculating the logarithm of odds ratio (Log OR) and 95% credible interval (95% CI). In this meta-analysis, 37 case-control studies comprising 23,506 RA patients and 25,984 healthy individuals were found for analyzing the IL23R, IL21, and IL1A gene polymorphism and risk of RA. In the IL23R gene rs1343151 SNP, the minor A allele significantly increased the risk of RA (Log OR = 0.085, 95% CI = 0.008, 0.156). Moreover, the minor AA genotype was significantly associated with increased RA risk (Log OR = 0.176, 95% CI = 0.028, 0.321). In addition, the C allele of the IL23R gene rs2201841 SNP significantly decreased the disease risk (Log OR = -0.544, 95% CI = -1.0, -0.065). Since Bayesian meta-analysis is a powerful strategy to pool the data, it can be mentioned that genetic polymorphisms of IL23R, but not IL21 and IL17A, are involved in susceptibility to RA.

Attenuation of aquaporin-3 and epidermal growth factor receptor expression and activation in systemic sclerosis dermal fibroblasts.

OBJECTIVES: Impaired wound healing and skin dehydration are the mainstay of systemic sclerosis (SSc) cutaneous manifestations. Aquaporin-3 (AQP3) has a pivotal role in skin hydration and wound healing. Epidermal growth factor receptor (EGFR) activation is impaired in SSc fibroblasts. It is unclear whether AQP3 downregulation or epidermal growth factor (EGF) signaling are the primary points of dysregulation in SSc patients. METHODS: Skin punch biopsies were obtained from 10 SSc patients and 10 healthy subjects. The mRNA and/or protein expression levels of AQP3, EGFR/p-EGFR, matrix metalloproteinase-1/2/9 (MMP-1/2/9), and tissue inhibitors of metalloproteinase-1 (TIMP1) at baseline and after EGF and transforming growth factor-ß1 (TGF-ß1) treatment was evaluated in extracted fibroblasts using real-time polymerase chain reaction and western blot analysis. RESULTS: SSc fibroblasts expressed lower AQP3 and EGFR, compared with normal fibroblasts. Normal fibroblasts increased AQP3 expression in response to EGF whereas AQP3 expression had no change in EGF-treated-SSc fibroblasts. Likewise, EGFR was activated in response to EGF in the normal group but not SSc group. Baseline expression of MMP-1/2/9 and TIMP1 was not different between SSc and controls. EGF treatment did not result in alteration of any MMPs expression in either of the groups. Combination treatment resulted in a significant upregulation of MMP-1 in normal fibroblasts compared with SSc fibroblasts, while in SSc fibroblasts MMP-9 expression was upregulated in response to treatment with TGF-ß1 only. CONCLUSION: Downregulation of AQP3 expression in SSc fibroblasts may be related to reduced EGFR expression and activation. TGF-ß1 (alone or in combination with EGF) only can upregulate AQP3 expression in SSc fibroblasts so, TGF-ß1 affect MMP-1 and MMP-9 just in SSc fibroblasts.

Association study of copy number variation in BMP8A gene with the risk of ankylosing spondylitis in Iranian population.

BACKGROUND: Copy number variation (CNV) of DNA segments has been considered as an important component of genetic variation, affecting the quality and quantity of gene expression. Bone morphogenic protein 8A (BMP8A) has been reported to function in bone formation. With respect to the bone and joint complications in ankylosing spondylitis (AS), this investigation aimed to study the role of BMP8A gene CNV in impressing the gene expression as well as the disease risk. METHODS: A total of 900 individuals, including 450 patients with AS and 450 healthy controls were enrolled. The copy numbers of BMP8A gene were detected by TaqMan real-time polymerase chain reaction (PCR) method. BMP8A messenger RNA (mRNA) transcript level in peripheral blood mononuclear cells (PBMCs) was also measured by SYBR Green real-time gene expression PCR method. RESULTS: No significant association of BMP8A copy number was detected with the risk of AS. BMP8A mRNA expression level was significantly downregulated in patients compared with controls. mRNA expression level of BMP8A in both AS patients with and without syndesmophyte was significantly lower than the healthy control group. There was no correlation between the mRNA expression level of BMP8A and both demographic and clinical data of the patients. CONCLUSIONS: Although BMP8A gene expression was downregulated in patients with AS, its copy number could not affect the transcript level of BMP8A gene in PBMCs and was not associated with susceptibility to AS in Iranian population. BMP8a may take into account as an indicator of bone formation process in AS, but it seems that mechanisms other than CNV may regulate this protein.

Exploring the etiopathogenesis of systemic lupus erythematosus: a genetic perspective.

Systemic lupus erythematosus (SLE) is an autoimmune multi-organ disorder that presents itself in a thousand ways. Its clinical course is extremely unpredictable, which makes diagnosis and treatment a challenge for clinicians. It appears that the clinical course of SLE is determined by genetic material in combination with environmental factors. In this article, we review recent findings on the pathogenesis of SLE from the perspective of genetics, focusing on defects in the clearance of apoptotic bodies and immune complexes, on alterations in the innate immune system response, and on impaired pathways in the adaptive immune system. Furthermore, the major histocompatibility complex (MHC) and non-MHC genes discovered during genome-wide association studies (GWASs) in SLE patients are also evaluated. In addition, the effect of these polymorphisms on the function of their related transcripts and their association with the clinical manifestations of SLE and its pathophysiology are explained. Finally, the association of genetic polymorphisms with clinical responses to common medications used in the treatment of SLE is also discussed.

Association study between KIR polymorphisms and rheumatoid arthritis disease: an updated meta-analysis.

BACKGROUND: Currently published studies investigating association between the killer cell immunoglobulin-like receptor (KIR) gene polymorphisms and rheumatoid arthritis (RA) reported inconsistent and contradictory results. Hence, we aim to carry out this comprehensive meta-analysis of all eligible studies meeting the inclusion criteria to achieve precise and comprehensive relationships between genetic variations in KIR gene cluster and risk of RA. METHODS: Databases of Medline/PubMed and Scopus were searched to investigate case-control studies prior to May 2018. The associations between KIR gene polymorphisms and RA susceptibility were analyzed by computing the odds ratio (OR) and 95% confidence interval (95% CI) for each study. RESULTS: A total of 11 comparative case-control studies involving 1847 RA patients and 2409 healthy individuals were included in this meta-analysis. Four significant associations of 2DL3 (OR = 0.591, 95% CI = 0.351-0.994; P = 0.047), 2DL5 (OR = 0.716, 95% CI = 0.601-0.853; P < 0.001), 2DS5 (OR = 0.623, 95% CI = 0.393-0.988; P = 0.045), and 3DL3 (OR = 0.324, 95% CI = 0.129-0.814; P = 0.016) genes with decreased RA risk were discovered in this meta-analysis. Although, other KIR receptors including 2DL1, 2DL2, 2DL4, 3DL1, 3DL2, 3DS1, 2DS1-2DS4, and two pseudo gens of 2DP1 and 3DP1 displayed no significant association with predisposition to RA. CONCLUSIONS: These findings provide reliable evidence that 2DL3, 2DL5, 3DL3, and 2DS5 might have a potential protective role for RA.