The 5' untranslated region variant rs3811050 C/T of the interleukin-38 encoding gene is associated with susceptibility to rheumatoid arthritis in Iraqi women.

BACKGROUND: Interleukin (IL)-38, the latest member of the IL-1 cytokine family, is proposed to have a pathogenic role in rheumatoid arthritis (RA). It is encoded by the IL1F10 gene, which harbors single nucleotide polymorphisms (SNPs) that may predict the risk of autoimmune diseases. Among them are 5' untranslated region (UTR) SNPs, which play a key role in post-transcriptional control, but have not been studied in Iraqi RA patients. METHODS: Two novel IL1F10 5'UTR SNPs (rs3811050 C/T and rs3811051 T/G) were explored in RA and control women (n = 120 and 110, respectively). SNPs were genotyped using TaqMan assay. An ELISA kit was used to measure serum IL-38 concentrations. RESULTS: A reduced risk of RA was associated with rs3811050 T allele and CT genotype (corrected probability [pc] = 0.01 and < 0.001, respectively), while there was no significant association with rs3811051. Haplotype analysis demonstrated that C-T haplotype was associated with a 1.65-fold greater risk of RA, whereas a reduced risk was linked to T-G haplotype. IL-38 concentrations were higher in patients than in controls (p < 0.001). In addition, IL-38 showed acceptable performance in distinguishing between RA and control women (p < 0.001). When IL-38 concentrations were stratified according to SNP genotypes, no significant differences were found. CONCLUSIONS: The rs3811050 variant was more likely to affect RA susceptibility in Iraqi women, and the T allele may play a role in reducing disease risk. IL-38 concentrations were elevated in RA patients, but were not affected by the rs3811050 and rs3811051 genotypes.

Evaluation of interleukins (IL-1α, IL-1Ra, IL-12, IL-17A, IL-31, and IL-33) and chemokines (CXCL10 and CXCL16) in the serum of male patients with ankylosing spondylitis.

BACKGROUND: A case-control study was performed to explore eight pro-inflammatory and anti-inflammatory cytokines, namely interleukin (IL)-1α, IL-1Ra (IL-1 receptor antagonist), IL-12, IL-17A, IL-31, IL-33, CXCL10 (C-X-C motif chemokine ligand 10), and CXCL16, with the aim to understand their role in ankylosing spondylitis (AS) pathogenesis and evaluate their utility as markers to differentiate between diseased and healthy individuals. Among these cytokines, IL-31 and CXCL16 have not been well studied in AS. PATIENTS AND METHODS: The study included 94 male patients with AS and 91 age-matched control males. Interleukin and chemokine levels were measured using ELISA kits. RESULTS: Serum levels of IL-17A, CXCL10, and CXCL16 were significantly elevated in patients compared to controls, while IL-31 levels were significantly decreased in patients. IL-17A, CXCL10, and CXCL16 were associated with an increased risk of AS, while IL-31 was associated with a decreased risk of disease (odds ratio = 1.22, 1.78, 1.14, and 0.89, respectively). As indicated by the area under the curve (AUC), IL-17A, IL-31, CXCL10, and CXCL16 were potential markers to differentiate between AS patients and controls (AUC = 0.877, 0.735, 0.8, and 0.7, respectively). IL-1α, IL-1Ra, IL-12, and IL-33 levels showed no significant variations between patients and controls. CONCLUSIONS: Among the eight cytokines examined, IL-17A, CXCL10, and CXCL16 were up-regulated in the serum of AS patients, while IL-31 was down-regulated. The levels of IL-1α, IL-1Ra, IL-12, and IL-33 showed no significant differences between patients and controls. Serum levels of all cytokines were not affected by disease duration, HLA-B27 positivity, or disease activity.

Molecular landscape of the interleukin-40 encoding gene, C17orf99, in patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant hematological disorder in which aberrant cytokine signaling and inflammation play a role in disease initiation and progression. Interleukin-40 (IL-40) is a novel cytokine encoded by the chromosome 17 open reading frame 99 (C17orf99) gene. This cytokine is involved in mediating inflammation but its biological significance in the pathogenesis of AML has not been investigated. In this case-control and observational study, mRNA expression and DNA methylation of the C17orf99 gene were evaluated in the peripheral blood of AML patients. In addition, the polymorphism of two novel intergenic variants of the C17orf99 gene, rs2004339 A/G and rs2310998 G/A, were explored using a real-time polymerase chain reaction assay. The study was conducted on 131 patients with AML and 106 controls and gene expression and DNA methylation were expressed as fold-change (2-ΔΔCt). Results revealed that mRNA expression of the C17orf99 gene was down-regulated in AML patients, particularly in females, while up-regulated expression was found in patients with hypoalbuminemia. For DNA methylation, it was up-regulated in AML patients, particularly in females, AML M5 subtype, and CD4-negative and CD14-positive peripheral blood cells. The mutant A allele and the corresponding homozygous AA genotype of rs2004339 was significantly associated with an increased risk of AML. The AA genotype was also associated with significantly up-regulated C17orf99 mRNA expression and DNA methylation of compared to the wild-type GG genotype. In conclusions, C17orf99 mRNA expression showed down-regulated levels in the peripheral blood of AML patients, while DNA methylation was up-regulated. The intergenic variant rs2004339 was associated with susceptibility to AML and had an effect on mRNA expression and DNA methylation.

A novel intergenic variant, rs2004339 A/G, of the gene encoding interleukin-40, C17orf99, is associated with risk of rheumatoid arthritis in Iraqi women.

Interleukin-40 (IL-40) is a novel cytokine encoded by the chromosome 17 open reading frame 99 (C17orf99) gene. Recent studies have shown that IL-40 levels are significantly up-regulated in patients with rheumatoid arthritis (RA). However, the association of genetic variants of the C17orf99 gene with the risk of RA has not been investigated. In this case-control study, two intergenic variants, rs2004339 A/G and rs2310998 G/A, were genotyped for the first time in 120 Iraqi women with RA (30 newly diagnosed [ND] and 90 medicated [MD; treated with the tumor necrosis inhibitor etanercept plus methotrexate]) and 110 control women using TaqMan 5'-allele discrimination method. Serum IL-40 levels were also determined using an enzyme-linked immunosorbent assay kit. Multinomial logistic regression analysis was used to analyze rs2004339 and rs2310998 under five genetic models (allele, recessive, dominant, over-dominant, and co-dominant). Results revealed that the mutant A allele (allele model) and the homozygous AA genotype (co-dominant model) of rs2004339 were significantly associated with an increased risk of RA (odds ratio [OR] = 3.37 and 7.44, respectively; corrected probability [pc] < 0.001), while rs2310998 showed no association with RA risk. When comparing the allele and genotype frequencies of rs2004339 and rs2310998 between ND and MD patients, there were no statistically significant differences. Haplotype analysis of the two variants (in the order rs2004339-rs2310998) revealed that haplotypes A-A (OR = 1.72; pc = 0.024) and A-G (OR = 2.85; pc < 0.001) were associated with an increased risk of RA. IL-40 levels (median and interquartile range) were significantly elevated in RA patients compared to controls (29.3 [15.5-41.5] vs. 12.6 [7.4-18.8] pg/mL; p < 0.001). IL-40 levels were not influence by disease duration or disease activity, but the rs2310998 genotypes had an effect; IL-40 levels were significantly higher in women with the AA genotype than in women with the GG genotype (20.1 [12.9-37.1] vs. 15.8 [8.3-22.6] pg/mL; p = 0.006). Regarding medication, IL-40 tended to show elevated levels in ND cases compared to MD cases but without a significant difference. In conclusion, the mutant A allele and the mutant-type AA genotype of the intergenic variant rs2004339 were associated with an increased risk of RA among Iraqi women. Serum IL-40 levels were also elevated in patients, particularly ND patients, and were positively affected by the mutant-type AA genotype. Accordingly, the role of IL-40 in the pathogenesis of RA has been indicated.

Interleukin-37 gene expression is down-regulated in patients with acute myeloid leukemia and shown to be affected by CD14 and HLA-DR immunophenotypes.

Recent evidence has indicated that interleukin 37 (IL-37) shows down-regulated expression in patients with acute myeloid leukemia (AML), but its association with immunophenotypic markers has not been explored. In the current study, IL37 mRNA expression was analyzed in the peripheral blood of 131 AML patients and 100 controls using the 2-ΔΔCt method (fold change), which was based on the principles of quantitative real-time polymerase chain reaction. AML patients were characterized in terms of gender, therapy, fms-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) and nucleophosmin 1 (NPM1) mutations, French-American-British classification (FAB), World Health Organization (WHO) classification, and immunophenotypes of 25 cytoplasmic and surface markers. IL37 mRNA expression was given as median and interquartile range. Low expression of IL37 mRNA (0.273 [0.062-0.456]) was found in AML patients. This reduced expression was more pronounced in females than in males but the difference was significant before the Bonferroni correction (0.196 [0.045-0.411] vs. 0.4 [0.153-0.466]; probability [p] = 0.008; corrected p = 0.064). In addition, the FAB M4 type (0.109 [0.031-0.269]) and the WHO PML-RARA type (0.171 [0.061-0.482]) had the lowest expression of IL37 mRNA among the other types. For immunophenotypes, only two significant differences were found. First, CD14-positive patients showed a lower level of expression than CD14-negative patients (0.146 [0.033-0.413] vs. 0.323 [0.108-0.468]; p = 0.02). Second, HLA-DR-positive patients showed a higher level of expression than HLA-DR-negative patients (0.325 [0.163-0.474] vs. 0.214 [0.045-0.42]; p = 0.04). However, the corrected p-value was not significant in both cases (p > 0.05). In conclusion, IL37 mRNA expression was down-regulated in AML patients, especially females, and those with the FAB M4 type and the WHO PML-RARA type. This expression may be affected by the immunophenotypic markers CD14 and HLA-DR.

Serum profiles of pro-inflammatory and anti-inflammatory cytokines in non-hospitalized patients with mild/moderate COVID-19 infection.

This study attempted to explore pro-inflammatory and anti-inflammatory responses in patients with mild/moderate coronavirus disease 19 (COVID-19). Eight pro-inflammatory (IL-1α, IL-1ß, IL-12, IL-17A, IL-17E, IL-31, IFN-γ and TNF-α) and three anti-inflammatory (IL-1Ra, IL-10 and IL-13) cytokines, as well as two chemokines (CXCL9 and CXCL10), were analyzed in the serum from ninety COVID-19 patients and healthy controls. Cytokine/chemokine levels were measured using enzyme-linked immunosorbent assay kits. Results revealed that IL-1α, IL-1ß, IL-10, IL-12, IL-13, IL-17A, IL-31, IFN-γ, TNF-α and CXCL10 were significantly higher in patients than in controls, while IL-1Ra levels were significantly lower in patients. IL-17E and CXCL9 levels showed no significant differences between patients and controls. Seven cytokines/chemokines recorded an area under the curve greater than 0.8: IL-12 (0.945), IL-17A (0.926), CXCL10 (0.909), IFN-γ (0.904), IL-1α (0.869), TNF-α (0.825) and IL-10 (0.821). As indicated by the odds ratio, elevated levels of nine cytokines/chemokines were associated with an increased risk of COVID-19: IL-1α (19.04), IL-10 (5.01), IL-12 (43.66), IL-13 (4.25), IL-17A (16.62), IL-31 (7.38), IFN-γ (13.55), TNF-α (12.00) and CXCL10 (11.18). Only one positive (IL-17E with TNF-α) and six negative (IL-1ß, IL-17A and IL-17E with CXCL9, IL-10 with IL-17A, and IL-1ß and IL-17A with CXCL10) correlations were found between these cytokines/chemokines. In conclusion, pro-inflammatory (IL-1α, IL-1ß, IL-12, IL-13, IL-17A, IL-31, IFN-γ, TNF-α and CXCL10) and anti-inflammatory (IL-10 and IL-13) cytokines/chemokines were up-regulated in the serum of patients with mild/moderate COVID-19. Their potential as biomarkers for diagnosis and prognosis is suggested and the association with COVID-19 risk is indicated to give more insight on COVID-19 immunological responses among non-hospitalized patients.

Interleukin-22 and interleukin-33 show up-regulated levels in the serum of patients with mild/moderate Coronavirus disease 2019.

Background: This study analyzed serum concentrations of interleukin (IL)-22 and IL-33 (pro-inflammatory and anti-inflammatory cytokines) in 90 patients with mild/moderate coronavirus disease 2019 (COVID-19) and 90 healthy controls. Enzyme-linked immunosorbent assay kits were used to measure IL-22 and IL-33 concentrations. Results: Median (interquartile range) concentrations of IL-22 and IL-33 were significantly higher in patients than in controls (IL-22: 18.6 [18.0-19.3] vs. 13.9 [12.1-14.9] pg/mL, probability [p] < 0.001; IL-33: 37.8 [35.3-43.0] vs. 24.1 [23.0-26.2] pg/mL, p < 0.001). As indicated by the area under the curve (AUC), IL-22 and IL-33 were excellent predictors of COVID-19 (AUC = 0.95 and 0.892, respectively). Multinomial logistic regression analysis demonstrated that individuals with high production (> control median) of IL-22 (odds ratio = 17.80 [95% CI: 6.48-48.90]; p = 0.001) and IL-33 (odds ratio = 19.0 [95% CI: 7.4-48.6]; p = 0.001) were more likely to develop COVID-19. A positive correlation was found between IL-22 and IL-33 and both cytokines also showed positive correlations with granulocyte-to-lymphocyte ratio and erythrocyte sedimentation rate in all participants. Conclusions: IL-22 and IL-33 showed up-regulated concentrations in the serum of patients with mild/moderate COVID-19. Both cytokines may have prognostic value for COVID-19 along with their association with disease risk.

Toll-like receptor 10 is down-regulated in serum of patients with relapsing-remitting multiple sclerosis but not associated with Epstein-Barr virus.

In this study, toll-like receptor 10 (TLR10) and Epstein-Barr virus (EBV) were determined in the peripheral blood of 43 patients with relapsing-remitting multiple sclerosis and 41 age- and gender-matched controls. Serum TLR10 levels were assessed using an enzyme-linked immunosorbent assay kit. EBV DNA and viral load were detected using a real-time polymerase chain reaction assay kit. Results revealed that median TLR10 levels were significantly lower in patients than in controls (318 vs. 574 pg/mL; p < 0.001). Most patients were classified as low producers of TLR10 (≤ median of controls) compared to controls (84.0 vs. 51.0%; p < 0.001). Logistic regression analysis revealed that participants with low TLR10 production had an odds ratio of 4.52. Receiver operating characteristic curve analysis indicated that TLR10 is a good predictor of multiple sclerosis (area under the curve = 0.778; p < 0.001). Prevalence of EBV was less frequent in patients than in controls but the difference was not significant (23.3 vs. 41.5%; p = 0.102), while median EBV load was significantly higher in patients compared to controls (8.55 vs. 1.29 DNA copy/100 cells). When TLR10 levels were stratified according to age group, gender, EBV positivity, Expanded Disability Status Scale (EDSS), or therapy, no significant differences were found in each stratum. Further, no significant correlation was found between TLR10 levels and EDSS or EBV load. In conclusions, TLR10 was down-regulated in serum of multiple sclerosis patients, and this down-regulation was not affected by age, gender, EBV load, EDSS, or therapy.