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.

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.

A novel signature of interleukins 36α, 37, 38, 39 and 40 in ankylosing spondylitis.

The current study examined five cytokines, three belong to interleukin (IL)-1 family (IL-36α, IL-37 and IL-38), one belongs to IL-12 family (IL-39) and one has not been assigned to a family (IL-40), in the serum of 110 male patients with ankylosing spondylitis (AS) and 103 male controls. Studies regarding these cytokines in AS are very limited. Therefore, the significance of IL-36α, IL-37, IL-38, IL-39 and IL-40 as biomarkers of AS was evaluated. Cytokine levels were measured using enzyme-linked immunosorbent assay kits. Results revealed that serum levels (median and interquartile range) of IL-36α (90.7; 53.7-166.2 vs 39.7; 31.3-59.2 pg/mL; probability [p] < 0.001), IL-37 (161.3; 62.8-236.6 vs 58.4; 46.8-80.7 ng/mL; p < 0.001), IL-38 (135.8; 78.2-213.5 vs 65.8; 51.1-87.1 pg/mL; p < 0.001), IL-39 (57.7; 34.1-92.3 vs 29.1; 19.3-58.6 ng/L; p < 0.001) and IL-40 (3.89; 2.99-6.19 vs 2.10; 1.75-2.68 ng/L; p < 0.001) were significantly higher in AS patients than in controls. Besides, they were of value in distinguishing between AS patients and controls as evidenced by the receiver operating characteristic curve analysis: area under the curve = 0.797 (IL-36α), 0.75 (IL-37), 0.797 (IL-38), 0.728 (IL-39) and 0.886 (IL-40). Some of these cytokines were significantly correlated, but no correlation with AS activity was found. In conclusion, the levels of IL-36α, IL-37, IL-38, IL-39 and IL-40 were up-regulated in the serum of AS patients regardless of age, age at disease onset, disease duration, disease activity or HLA-B27.

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.

Evaluation of interleukin-38 levels in serum of patients with coronavirus disease 2019.

Interleukin-38 (IL-38) has recently been considered as a cytokine with anti-inflammatory properties in viral respiratory infections, particularly coronavirus disease 19 (COVID-19), but the evidence has not been well elucidated. Therefore, a case-control study was conducted to determine IL-38 serum levels in 148 patients with COVID-19 (45 moderate, 55 severe, and 48 critical) and 113 controls. Results demonstrated that IL-38 levels did not show significant differences between patients and controls (68.7 [interquartile range: 62.7-75.6] vs. 67.7 [58.0-82.6] pg/ml; probability = 0.457). Similarly, patients stratified by disease severity, age group, gender, or chronic disease showed no significant differences between IL-38 levels in each stratum. Whereas, overweight/obese patients had a significantly lower median of IL-38 compared to normal-weight patients. Further, IL-38 showed significantly higher levels in the age group ≥50 years of patients with critical illness than in the age group <50 years. Female patients with severe disease also showed significantly elevated levels of IL-38 compared to male patients. In conclusion, the study indicated that serum IL-38 levels were not affected by COVID-19 infection, but the distribution of patients according to disease severity, age, gender, and body mass index may better reveal the role of IL-38 in disease pathogenesis.

Evaluation of interleukins 37 and 38 and vitamin D status in the serum of women with Graves' disease.

BACKGROUND: Graves' disease (GD) is an autoimmune thyroid disorder and recent studies have proposed a role for interleukin (IL)-37, IL-38, and vitamin D (VitD) in the pathophysiology of disease. Therefore, this study investigated the expression of IL-37, IL-38, and VitD in the serum of GD patients and correlations of their levels with some demographic and clinical characteristics. METHODS: Serum IL-37, IL-38, and VitD levels were evaluated in 90 women with GD and 93 control women using enzyme-linked immunosorbent assay kits. Depending on therapy, six patients were newly diagnosed (ND; untreated), and 50 patients were receiving only carbimazole (CMZ), while 34 patients were also on CMZ but also received one (31 patients), two (one patient), or three (two patients) doses of radioactive iodine (RAI). RESULTS: IL-37 levels were significantly higher in GD patients than in controls, while IL-38 and VitD levels were significantly decreased. As indicated by the area under the curve (AUC), receiver operating characteristic curve analysis demonstrated the potential of IL-37, IL-38, and VitD as biomarkers to distinguish GD patients from controls (AUC = 0.953, 0.959, and 0.793, respectively). Multinomial logistic regression analysis showed that altered levels of IL-37, IL-38, and VitD were most likely associated with the pathogenesis of GD. IL-37 was negatively correlated with IL-38 and VitD, while IL-38 and VitD were positively correlated. CONCLUSION: Serum Il-37 levels were upregulated in women with GD, while IL-38 and VitD levels showed downregulated levels. The latter two were positively correlated while they showed a negative correlation with IL-37.

Interleukin-37 is down-regulated in serum of patients with severe coronavirus disease 2019 (COVID-19).

Pro-inflammatory and anti-inflammatory cytokines are indicated to play a prominent role in mediating the immunopathogenesis of coronavirus disease 19 (COVID-19). Interleukin (IL-37) is one of the anti-inflammatory cytokines that has been proposed to be involved in disease progression but the data are not overwhelming. Therefore, a case-control study was performed to analyze IL-37 levels in serum of 100 patients with severe COVID-19 and 100 blood donors (control group). Median age was significantly higher in COVID-19 cases than in controls. Stratification by gender, body mass index and ABO and Rh blood group systems showed no significant differences between patients and controls. Chronic diseases (cardiovascular and diabetes) were observed in 57.0% of patients. Serum levels of IL-37 and vitamin D were significantly decreased in patients compared to controls. The low level of IL-37 was more pronounced in males, overweight/obese cases, blood group B or AB cases, Rh-positive cases, and cases with no chronic disease. Low producers of IL-37 were more likely to develop COVID-19 (odds ratio = 2.66; 95% confidence interval = 1.51-4.70; corrected probability = 0.015). Receiver operating characteristic curve analysis demonstrated that a low serum level of IL-37 was a good predictor of COVID-19. Spearman's rank correlation analysis showed that IL-37 and vitamin D were significantly correlated. In conclusion, IL-37 was down-regulated in serum of patients with severe COVID-19 compared to controls. This down-regulation may be associated with an increased risk of disease. Gender, body mass index, blood groups and chronic disease status may also affect IL-37 levels.

Human beta-defensins 2 and 4 are dysregulated in patients with coronavirus disease 19.

Antimicrobial peptides (AMPs) have recently been proposed as significant immunological factors involved in pathogenesis of coronavirus disease 19 (COVID-19). Human ß-defensins (hBDs) are among these AMPs, but the evidence is not well detailed. Therefore, this case-control study analyzed levels of hBD1, hBD2, hBD3 and hBD4 in serum of 103 patients with severe COVID-19 and 105 healthy controls. Most patients were older than 45 years (80.6%), and more than 50% suffered from chronic diseases (cardiovascular and diabetes). Results revealed that median levels of hBD1 and hBD3 did not show significant differences between patients and controls. On the contrary, HBD2 levels were significantly decreased in patients compared to controls (1036 vs. 1289 ng/L; p < 0.001), while HBD4 levels were significantly increased (4.04 vs. 2.43 ng/L; p < 0.001). Receiver operating characteristic curve analysis demonstrated the predictive significance of hBD2 (area under the curve [AUC] = 0.795; 95% confidence interval [CI] = 0.729-0.861; p < 0.001) and hBD4 (AUC = 0.816; 95% CI = 0.756-0.876; p < 0.001) in discriminating between COVID-19 patients and controls. Logistic regression analysis (adjusted for age, gender and body mass index) confirmed the significance of hBD2 (odds ratio [OR] = 0.996; corrected p = 0.004) and hBD4 (OR = 4.948; corrected p < 0.001) in susceptibility to COVID-19. In conclusion, the study indicated that hBD2 showed low levels in serum of patients infected with severe COVID-19, while hBD4 showed elevated levels. These differences in HBDs were not influenced by age, gender, body mass index, or chronic disease.

Genetic variants in IL4RA, IL6, and IL12B genes and susceptibility to hepatitis B and C virus infections among Iraqi patients.

Hepatitis B and C viruses (HBV and HCV) are common causative pathogens of viral hepatitis. Progression of both infections is determined by virus- and host-related factors. Cytokines are important host genetic factors that may have a predisposing role in HBV and HCV infections. This case-control study evaluated the genetic association of IL4RA+1902 (rs1801275), IL6-174 (rs1800795), IL6-597 (rs1800797), and IL12B-1188 (rs3212227) variants with chronic HBV and HCV infections among Iraqi patients. A total of 220 viral hepatitis patients were enrolled in the study (113 HBV and 107 HCV), together with 141 healthy subjects. Sequence-specific primer polymerase chain reaction assay was the genotyping method. Results revealed that under a dominant genetic model, IL6-174 variant was significantly associated with HBV infection, whereas no association with the HCV risk was reported. However, the risk for both infections was markedly associated with IL6-597 variant under recessive, dominant, and codominant genetic models. Estimation of IL6-174 -IL6-597 haplotypes depicted that G-A haplotype was significantly associated with an increased risk to develop HBV infection, whereas a significantly decreased risk was associated with G-G and C-G haplotypes. For HCV, G-G and C-A haplotypes were significantly associated with risk of HCV infection. IL4RA+1902 and IL12B-1188 variants showed no association with HBV or HCV risk. Analysis of variance revealed no significant association between genotypes of the four determined single-nucleotide polymorphisms and HBV or HCV viral load. In conclusion, the study supports the concept that IL6-597 variant is associated with susceptibility to HBV and HCV infections among Iraqis. The risk of HBV infection is further associated with IL6-174 variant.

Association between interleukin-4 and interleukin-10 single nucleotide polymorphisms and multiple sclerosis among Iraqi patients.

Multiple sclerosis (MS) is a neurodegenerative autoimmune disease, in which cytokines play a prominent role. Among these cytokines are interleukin-4 (IL-4) and IL-10, which have been demonstrated to be involved in immunopathogenesis of the disease. The present case-control study inspected the association between seven single nucleotide polymorphisms (SNPs) of IL4 (IL4-1098: rs2243248, IL4-590: rs2243250, and IL4-33: rs2070874), IL4RA (IL4RA+1902: rs1801275), and IL10 (IL10-1082: rs1800896, IL10-819: rs1800871, and IL10-592: rs1800872) genes and MS in Iraqi patients. Sixty-eight clinically definite relapsing-remitting MS Iraqi patients and 158 age- and gender-matched healthy control subjects were enrolled in the study. The SNPs were detected by the PCR-SSP (polymerase chain reaction-sequence specific primer) method. Results revealed that only IL4-1098, IL4-590, IL4-33, and IL10-592 SNP allele and/or genotype frequencies showed a significant variation between MS patients and control. At the haplotype level, the estimated frequency of TCC (IL4-1098-IL4-590-IL4-33) and GCC (IL10-1082-IL10-819-IL10-592) haplotypes was significantly increased in patients compared to control (TCC: 63.2 vs. 48.0%; odds ratio = 2.81; 95% confidence interval = 1.86-4.25; pc = 5.0 × 10-6; GCC 39.0 vs. 22.2%; odds ratio = 2.24; 95% confidence interval = 1.45-3.46; pc = 0.002). In conclusion, IL4 and IL10 genes harbor important SNPs that may confer MS susceptibility. In addition, their role in reducing the risk of disease is also suggested. However, the susceptibility of the investigated role can be better evaluated in terms of haplotype frequencies.

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.

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.

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-40 is a promising biomarker associated with type 2 diabetes mellitus risk.

Interleukin (IL)-40 is a recently identified cytokine with a proposed role in the pathogenesis of inflammatory diseases. Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by low-grade inflammation. Therefore, it can be suggested that IL-40 may be involved in the pathogenesis of T2DM, but this topic has not been explored. The current study evaluated the potential of IL-40 as a biomarker for T2DM. Serum IL-40 levels were determined in 106 patients with T2DM and 109 healthy controls using an enzyme-linked immunosorbent assay kit. Median (interquartile range) IL-40 levels were significantly higher in patients than in controls (2.82 [2.58-3.25] vs. 1.22 [0.93-1.42] ng/L; probability [p] < 0.001). When IL-40 levels were stratified according to age, gender, disease duration, body mass index, diabetic neuropathy, fasting plasma glucose or glycated hemoglobin, no significant differences were found in each stratum. Receiver operating characteristic curve analysis showed that IL-40 was an excellent predictor in discriminating between T2DM patients and controls (area under the curve = 0.989; 95% confidence interval = 0.973-1.00; p < 0.001). Age- and gender-adjusted multinomial logistic regression analysis estimated an odds ratio of 53.36 (95% confidence interval = 12.52-227.45; p < 0.001) for IL-40 in T2DM. IL-40 level was negatively correlated with age (correlation coefficient = -0.274; p = 0.005) and onset age (correlation coefficient = -0.203; p = 0.037). In conclusion, IL-40 was up-regulated in the serum of T2DM patients, and can be considered as a reliable biomarker in distinguishing patients with T2DM from healthy controls.

Interleukin-39 is a novel cytokine associated with type 2 diabetes mellitus and positively correlated with body mass index.

INTRODUCTION: It is suggested that cytokines play a key role in the pathogenesis of type 2 diabetes mellitus (T2DM). Therefore, this study explored two recently discovered cytokines, interleukin (IL)-37 (anti-inflammatory) and IL-39 (pro-inflammatory), in T2DM due to limited data in this context. METHODS: Serum IL-37 and IL-39 levels were determined in 106 T2DM patients and 109 controls using enzyme-linked immunosorbent assay kits. RESULTS: Serum levels (median and interquartile range) of IL-37 (79 [47-102] vs. 60 [46-89] ng/L; probability [p] = .04) and IL-39 (66 [59-69] vs. 31 [19-42] ng/L; p < .001) were significantly elevated in T2DM patients compared to controls. As indicated by the area under the curve (AUC), IL-39 (AUC = 0.973; p < .001) was more predictable for T2DM than IL-37 (AUC = 0.582; p = .039). Elevated levels of IL-39 were significantly associated with T2DM (odds ratio = 1.30; p < .001), while IL-37 did not show this association. Classification of IL-37 and IL-39 levels by demographic and clinical characteristics of patients revealed some significant differences including gender (IL-39), body mass index (BMI; IL-37 and IL-39) and diabetic neuropathy (IL-39). BMI was positively correlated with IL-39 (correlation coefficient [rs ] = 0.27; p = .005) and glycosylated haemoglobin (rs  = 0.31; p = .001), and negatively correlated with age at onset (rs  = -0.24; p = .015). CONCLUSIONS: IL-37 and IL-39 levels were elevated in the serum of T2DM patients. Besides, IL-39 is proposed to be a novel cytokine associated with T2DM and positively correlated with BMI.

Evaluation of serum soluble HLA-G levels post-recovery from COVID-19 and post-vaccination (Sinopharm and Pfizer-BioNTech).

Serum soluble HLA-G (sHLA-G) levels have been shown to be upregulated in COVID-19 patients. In this study, sHLA-G levels were examined in COVID-19 patients 14-21 days post-recovery (100 patients) and 80 uninfected controls. In addition, individuals vaccinated with Sinopharm or Pfizer-BioNTech (50 individuals each) were followed 21 days post-first dose and 21 days post-second dose. Serum sHLA-G levels were significantly higher in recovered patients than in controls. The first and second doses of Sinopharm and Pfizer-BioNTech were associated with significantly elevated levels of sHLA-G compared to controls or recovered patients, except for the first dose of Pfizer-BioNTech where sHLA-G levels did not show significant differences compared to recovered patients. In conclusion, recovery from COVID-19, as well as vaccination with two doses of Sinopharm or Pfizer-BioNTech, were associated with up-regulated levels of sHLA-G molecules, but the first dose of Sinopharm had the greatest effect in raising sHLA-G levels.

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.

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.

Evaluation of human ß­defensins in the cerebrospinal fluid of suspected meningitis.

Human ß-defensins (HBDs) are an important class of antimicrobial peptides that have immunomodulatory functions; however, the role of HBDs have not been well explored in the pathogenesis of meningitis. A cross-sectional study was performed to explore the levels of HBD1, HBD2, HBD3, and HBD4 in the cerebrospinal fluid (CSF) of 176 suspected meningitis cases. CSF samples were first subjected to PCR analysis using a set of universal primers targeting a portion of the eubacteria 16S rRNA gene. The analysis demonstrated that 66 samples (37.5%) were PCR-positive, whilst 110 samples (62.5%) were PCR-negative. DNA sequence analysis of the PCR-positive products identified two broad categories of bacteria, Gram-negative (68.2%) and Gram-positive (31.8%). A total of 88 PCR-negative CSF samples showed abnormal leukocyte counts, glucose concentrations, and/or protein concentrations, and were considered abnormal (ABN). The remaining 22 CSF samples were considered normal (NOR). HBD1, HBD2, and HBD4 levels did not exhibit significant differences between PCR-positive, ABN, and NOR CSF samples. However, HBD3 levels were significantly higher in the ABN CSF samples than in the NOR CSF samples (P=0.005). HBD3 levels were also elevated in the PCR-positive CSF samples compared with the NOR CSF samples, but the difference was not significant (P=0.151). HBD2, HBD3, and HBD4 were correlated with leukocyte counts, glucose concentration, and protein concentration. In conclusion, HBD3 levels were significantly elevated in the CSF of suspected meningitis cases regardless of the cause of meningitis. The CSF levels of certain HBDs were affected by specific diagnostic laboratory parameters for meningitis, including leukocyte counts, glucose concentration, and protein concentration.