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.

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.

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-38 promoter variants and risk of COVID-19 among Iraqis.

Coronavirus disease-19 (COVID-19) has recently emerged as a respiratory infection with a significant impact on health and society. The pathogenesis is primarily attributed to a dysregulation of cytokines, especially those with pro-inflammatory and anti-inflammatory effects. Interleukin-38 (IL-38) is a recently identified anti-inflammatory cytokine with a proposed involvement in mediating COVID-19 pathogenesis, while the association between IL38 gene variants and disease susceptibility has not been explored. Therefore, a pilot study was designed to evaluate the association of three gene variants in the promoter region of IL38 gene (rs7599662 T/A/C/G, rs28992497 T/C and rs28992498 C/A/T) with COVID-19 risk. DNA sequencing was performed to identify these variants. The study included 148 Iraqi patients with COVID-19 and 113 healthy controls (HC). Only rs7599662 showed a significant negative association with susceptibility to COVID-19. The mutant T allele was presented at a significantly lower frequency in patients compared to HC. Analysis of recessive, dominant and codominant models demonstrated that rs7599662 TT genotype frequency was significantly lower in patients than in HC. In terms of haplotypes (in order: rs7599662, rs28992497 and rs28992498), frequency of CTC haplotype was significantly increased in patients compared to HC, while TTC haplotype showed significantly lower frequency in patients. The three SNPs influenced serum IL-38 levels and homozygous genotypes of mutant alleles were associated with elevated levels. In conclusion, this study indicated that IL38 gene in terms of promoter variants and haplotypes may have important implications for COVID-19 risk.

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.

HLA-G 14-bp insertion/deletion polymorphism and risk of coronavirus disease 2019 (COVID-19) among Iraqi patients.

Human leukocyte antigen (HLA)-G molecules are proposed to influence susceptibility to coronavirus disease 2019 (COVID-19). A case-control study was conducted on 209 patients with COVID-19 and198 controls to assess soluble HLA-G (sHLA-G) levels and HLA-G 14-bp insertion [Ins]/deletion [Del] polymorphism. Results revealed that median levels of sHLA-G were significantly higher in serum of COVID-19 patients than in controls (17.92 [interquartile range: 14.86-21.15] vs. 13.42 [9.95-17.38] ng/mL; probability <0.001). sHLA-G levels showed no significant differences between patients with moderate, severe or critical disease. Del allele was significantly associated with the risk of COVID-19 (odds ratio = 1.89; 95% confidence interval = 1.44-2.48; corrected probability = 0.001), while a higher risk was associated with Del/Del genotype (odds ratio = 2.39; 95% confidence interval = 1.25-4.58; corrected probability = 0.048). Allele and genotype frequencies of HLA-G 14-bp Ins/Del polymorphism stratified by gender or disease severity showed no significant differences in each stratum. Further, there was no significant impact of genotypes on sHLA-G levels. In conclusion, sHLA-G levels were up-regulated in COVID-19 patients regardless of disease severity. Further, it is suggested that HLA-G 14-bp Ins/Del polymorphism is associated with COVID-19 risk.

Severity of coronavirus disease 19: Profile of inflammatory markers and ACE (rs4646994) and ACE2 (rs2285666) gene polymorphisms in Iraqi patients.

Susceptibility to coronavirus disease 2019 (COVID-19) and disease severity has recently been associated with inflammatory markers and genetic polymorphisms of ACE (angiotensin-converting enzyme) and ACE2 genes, but the evidence has been inconclusive. This case-control study (99 COVID-19 patients and 96 controls) sought to assess the significance of age, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR) and SARS-CoV-2 RT-PCR cycle threshold (Ct) in severity of COVID-19. Besides, two variants of ACE and ACE2 genes (rs4646994 and rs2285666, respectively) were analyzed to determine their role in COVID-19 susceptibility and/or disease severity. Results revealed that age, CRP and NLR were significantly elevated in severe cases compared to moderate cases, while RT-PCR Ct value was significantly decreased. Allele and genotypes of both variants were not associated with COVID-19 risk, with the exception of rs2285666 A allele. It showed a significantly higher frequency in female patients than in female controls (probability = 0.041). In conclusion, the study indicated the role of age, CRP, NLR and SARS-CoV-2 RT-PCR Ct in susceptibility to COVID-19 severity. However, analysis of the ACE and ACE2 gene variants (rs4646994 and rs2285666, respectively) showed that the two variants were not associated with the risk of developing COVID-19.

Interleukin-37 gene polymorphism and susceptibility to coronavirus disease 19 among Iraqi patients.

Coronavirus disease 19 (COVID-19) is a highly contagious respiratory viral infection. Dysregulated immune response is an important feature of disease, and cytokines are among the most important mediators of dysregulated immunity. Interleukin-37 (IL-37) is one such cytokine and studies have indicated its role in pathogenesis of COVID-19. However, IL37 gene polymorphisms have not been identified in patients with COVID-19. Therefore, this case-control study (100 patients and 100 controls) was performed to understand the role six single nucleotide polymorphisms of IL37 gene (SNPs: rs3811042, rs3811043, rs2466449, rs3811045, rs3811046 and rs3811047) in susceptibility to COVID-19 among cases with severe disease. These polymorphisms were identified by Sanger DNA sequencing. Results revealed that TG genotype of rs3811046 showed a significantly increased frequency in patients compared to controls (61.0 vs. 38.0%; odds ratio [OR] = 2.55; 95% confidence interval [CI] = 1.45-4.50; probability [p] = 0.002; corrected p [pc] = 0.01). GA genotype of rs3811047 also showed an increased frequency in patients but the pc-value was not significant (39.0 vs. 24.0%; OR = 2.02; 95% CI = 1.10-3.71; p = 0.033; pc = 0.165). Haplotype analysis revealed a significantly increased frequency of the haplotype G-C-A-T-T-A (in the order: rs3811042, rs3811043, rs2466449, rs3811045, rs3811046 and rs3811047) in COVID-19 patients compared to controls (0.055 vs. 0.006; OR = 10.23; 95% CI = 1.53-68.14; p = 0.003; pc = 0.03). In conclusion, the study indicated that two variants of IL37 gene (rs3811046 and rs3811047) may be associated with susceptibility to COVID-19 among Iraqi population.

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.

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.

Soluble HLA-G is upregulated in serum of patients with severe COVID-19.

Soluble HLA-G (sHLA-G) molecules are considered potent immunomodulators, and their dysregulated expression has been implicated in several pathological conditions, including coronavirus disease 19 (COVID-19). Therefore, a case-control study (103 COVID-19 patients and 105 controls) was performed to determine sHLA-G role in severity of COVID-19. Results revealed that median levels of sHLA-G were significantly increased in serum of patients compared to controls (19.3 vs. 12.7 ng/mL; p <0.001). When patients and controls were stratified by age group, gender, body mass index, chronic disease, or ABO and Rh blood groups, the sHLA-G level did not show a significant difference in each stratum. Logistic regression analysis demonstrated that the up-regulated expression of sHLA-G was associated with an elevated risk of developing COVID-19. Receiver operating characteristic curve analysis showed that sHLA-G was a very good predictor of COVID-19, and at a cut-off value of 15.4 ng/mL, the sensitivity and specificity of sHLA-G were 79.6 and 79.0%, respectively. Spearman rank correlation analysis revealed that sHLA-G was positively correlated with age, erythrocyte sedimentation rate, white blood cell count, and random blood glucose, while a negative correlation was recorded with vitamin D. In conclusion, up-regulated expression of sHLA-G was indicated in patients with severe COVID-19.