Impact of IL-10 gene promoter polymorphisms on treatment response in HCV patients: A systematic review, a meta-analysis, and a meta-regression.

The impact of interleukin-10 (IL-10) gene promoter polymorphisms (SNPs) on treatment response in HCV patients was dissimilarly estimated. Hence, the aim of this meta-analysis was to robustly assess the effect of IL-10 SNPs on treatment response in HCV patients. An electronic literature search was carried out through PubMed, EMBASE, Web of science, and Scopus databases. Studies assessing the association between IL-10 polymorphisms and treatment response in HCV patients were included. Studies were excluded if genotype frequencies are not consistent with the Hardy-Weinberg Equilibrium (HWE) or in case of including patients with hepatitis B virus coinfection. Risk of bias in included studies was assessed using the Newcastle-Ottawa Scale. Meta-analyses were performed for the influence of IL-10 gene promoter SNPs (rs1800896 (-1082 A/G), rs1800871 (-819 C/T), and rs1800872 (-592 C/T)) and haplotypes on treatment response in HCV patients. Subgroup analyses, meta-regressions, publication bias assessment, and sensitivity analyses were also conducted. Overall, 32 studies with a total of 5943 HCV cases and 2697 controls were included in the present study. The -1082*G allele was significantly associated with increased risk of non-response (NR) to treatment, OR [95% CI] = 1.29 [1.1-1.51], p = .002. Besides, the rs1800872 -592*C allele was significantly associated with increased NR risk, OR [95% CI] = 1.22 [1.02-1.46], p = .03. Subgroup analysis showed that this association remained significant only in patients treated with PEG-IFN alone, p = .01. The -1082*G/-819*C/-592*C (GCC) haplotype was significantly associated with increased NR risk, OR [95% CI] = 1.62 [1.13-2.23], p = .009. Our results suggest that the IL-10 rs1800896 was associated with NR risk especially in North-African and Asian populations. Moreover, the IL-10 gene promoter -1082*G/-819*C/-592*C (GCC) haplotype which has been associated with higher production of IL-10, was significantly associated with increased NR risk.

Pre- and Post-treatment Serum BAFF Levels and BAFF Gene Polymorphisms in Patients with Graves' Disease.

BACKGROUND: B cell activating factor (BAFF), a crucial factor for B cell survival and differentiation, has been linked to several autoimmune conditions. The aim of this study was to evaluate the association of BAFF gene's polymorphisms with its serum levels and to assess their effect on Graves' disease (GD) susceptibility and presentation. METHODS: Sixty-two GD patients and 152 healthy controls have been enrolled to investigate BAFF rs9514827 (-2841 T/C), rs1041569 (-2701 T/A) and rs9514828 (-871 C/T) gene's polymorphism by PCR-RFLP and serum BAFF level's kinetics under medical treatment by ELISA. RESULTS: Median serum BAFF level at baseline was significantly higher in GD patients (841.7 pg/ml [685.23-1058.32]) comparatively to controls (495.75 pg/ml [383.17-595.7]), p = 7.29 E-25. A ROC curve was used to assess BAFF performances in GD diagnosis and revealed an AUC of 94.9% [0.919-0.979], p = 7.29 E-25. At a cutoff value of 654.9 pg/ml of BAFF at baseline, the sensitivity and the specificity were, respectively, 83.9% and 90.8%. BAFF level was significantly increased in smoking patients (1079.55 pg/ml [875.35-1203]) comparatively to nonsmokers (746.95 pg/ml [643.2-915.7]), p = 3.1 E-5. While -2841 T/C and -2701 T/A genotypes and alleles frequencies were similar between patients and controls, the -871*T allele was significantly more prevalent in patients (0.613) than in controls (0.477); p = .01, OR [95% CI] = 1.73 [1.13-2.65]. The three studied polymorphisms were not associated with serum BAFF level at baseline. CONCLUSION: Serum BAFF level is significantly increased in GD especially in smoking patients. rs9514828 - 871*T allele might be a susceptibility variant for GD.

Comparative study of six SARS-CoV-2 serology assays: Diagnostic performance and antibody dynamics in a cohort of hospitalized patients for moderate to critical COVID-19.

BACKGROUND: To overcome the COVID-19 pandemic, serology assays are needed to identify past and ongoing infections. In this context, we evaluated the diagnostic performance of 6 immunoassays on samples from hospitalized patients for moderate to critical COVID-19. METHODS: 701 serum samples obtained from 443 COVID-19 patients (G1: 356 positive RT-PCR patients and G2: 87 negative RT-PCR cases) and 108 pre-pandemic sera from blood donors were tested with 6 commercial immunoassays: (1) Elecsys Anti-SARS-CoV-2, Roche (Nucleocapsid, N), (2) Elecsys Anti-SARS-CoV-2 S, Roche (Spike, S), (3) Vidas SARS-COV-2 IgM/IgG, BioMérieux (S), (4) SARS-CoV-2 IgG, Abbott (N), (5) Access SARS-CoV-2 IgG, Beckman Coulter (Receptor Binding Domain), and (6) Standard F COVID-19 IgM/IgG Combo FIA, SD Biosensor (N). RESULTS: Global sensitivities of the evaluated assays were as follows: (1) Roche anti-N = 74.5% [69.6-79.3], (2) Roche anti-S = 92.7% [84.7-100], (3) Vidas IgM = 74.9% [68.6-81.2], (4) Vidas IgG = 73.9% [67.6-80.1], (5) Abbott = 78.6% [63.4-93.8], (6) Beckman Coulter = 74.5% [62-86.9], (7) SD Biosensor IgM = 73.1% [61-85.1], and (8) SD Biosensor IgG = 76.9% [65.4-88.4]. Sensitivities increased gradually from week 1 to week 3 as follow: (1) Roche anti-N: 63.3%, 81% and 82.1%; (2) Vidas IgM: 68.2%, 83.2% and 85.9%; and (3) Vidas IgG: 66.7%, 79.1% and 86.6%. All immunoassays showed a specificity of 100%. Seropositivity was significantly associated with a higher frequency of critical COVID-19 (50.8% vs. 38.2%), p = 0.018, OR [95% CI] = 1.668 [1.09-2.553]. Inversely, death occurred more frequently in seronegative patients (28.7% vs. 13.6%), p=3.02 E-4, OR [95% CI] = 0.392 [0.233-0.658]. CONCLUSION: Evaluated serology assays exhibited good sensitivities and excellent specificities. Sensitivities increased gradually after symptoms onset. Even if seropositivity is more frequent in patients with critical COVID-19, it may predict a recovery outcome.

PLA2R antibody, PLA2R rs4664308 polymorphism and PLA2R mRNA levels in Tunisian patients with primary membranous nephritis.

BACKGROUND: Primary membranous nephritis (PMN) is an autoimmune disease induced by the deposit of antibodies (Ab) to the phospholipase receptor A2 receptor (PLA2R) on podocytes. In this context, we aimed to assess the relationships between anti-PLA2R Ab, PLA2R rs4664308 SNP, PLA2R mRNA levels and PMN susceptibility and outcome. METHODS: Sixty-eight PMN patients, 30 systemic lupus erythematosus (SLE) patients with secondary MN and 30 healthy control subjects served for anti-PLA2R Ab measurement by ELISA and PLA2R rs4664308 SNP genotyping by a commercial real-time PCR. Twenty patients with tubulo-interstitial nephritis (TIN) were used as controls for renal PLA2R mRNA quantification in PMN patients from kidney biopsies. PLA2R mRNA quantification was carried-out by real-time PCR after RNA extraction. RESULTS: Forty-three (63.2%) PMN patients received initial therapy consisting of alternating monthly cycles of corticosteroids and cyclophosphamide. Twelve (17.6%) patients had resistant PMN to initial therapy and were consecutively treated by cyclosporine or tacrolimus. Anti-PLA2R Ab were positive in 54 (79.4%) PMN patients, while all SLE patients and controls were negative, p<0.0001. Moreover, anti-PLA2R Ab levels were significantly higher in PMN patients (134.85 [41.25-256.97] RU/ml) than in SLE patients (3.35 [2.3-4.35] RU/ml) and controls (2 [2-2.3]), p<0.0001. Consequently, a ROC curve showed for 100% specificity a sensitivity of 94.1% at a threshold of 2.6 RU/ml. Besides, Anti-PLA2R antibodies levels were significantly associated to non-remission; p = 0.002. The rs4664308*A wild-type allele was significantly more frequent in PMN patients (0.809) than in controls (0.633) and SLE patients (0.65); p = 0.008, OR [95% CI] = 2.44 [1.24-4.82] and p = 0.016, OR [95% CI] = 2.27 [1.15-4.5], respectively. Renal PLA2R mRNA levels were significantly higher in PMN patients (218.29 [66.05-486.07]) than in TIN patients (22.09 [13.62-43.34]), p<0.0001. Moreover, PLA2R mRNA levels were significantly higher in non-remission patients (fold-factor vs. partial remission = 2.46 and fold-factor vs. complete remission = 12.25); p = 1.56 10E-8. In addition, PLA2R mRNA and anti-PLA2R Ab levels were significantly correlated, Spearman Rho = 0.958, p<0.0001. CONCLUSION: Anti-PLA2R Ab and renal PLA2R mRNA could be useful markers for PMN outcome predicting. The PLA2R rs6446308 SNP is associated with PMN susceptibility in Tunisians.

Association of Autoantibody to Rods and Rings with Hepatitis C Outcome and Viral Load.

Despite the current availability of more potent drugs, hepatitis C virus (HCV) infection is still treated with a combination of IFN-α and ribavirin in many countries. Interferon/ribavirin therapy can induce the appearance of autoantibodies to Rods and Rings (anti-RR), which have been associated to a poorer prognosis. The aim of this study was to investigate the prevalence of anti-RR antibodies before and after ribavirin therapy and to look for a possible association with HCV infection outcome. In this context, anti-RR antibodies were detected by IFI on HEp-2 cells in 142 patients under ribavirin therapy (G1: 74 patients with a positive posttreatment HCV-PCR and G2: 68 patients with a negative posttreatment HCV-PCR, matched in age and gender), 84 kidney transplant recipients (KTRs) under mycophenolate and 158 controls (30 with systemic lupus erythematosus, 37 with rheumatoid arthritis, and 91 healthy blood donors). No patient had anti-RR antibody before IFN-α/ribavirin therapy, while 27 (19%) developed the anti-RR pattern under treatment. The anti-RR antibody was absent in all KTRs and the 158 controls. The frequency of anti-RR antibody was significantly higher in G1 (27; 36.48%) than in G2 (0), p < 0.001. Moreover, and in G1, anti-RR antibody was more frequent in nonresponders (NR) patients (23, 56.1%) than in relapsers (REL) (4, 12.1%); p < 0.001, OR [95%CI] = 9.26 [2.75-31.18]. Moreover, anti-RR antibody titer was significantly higher in NR patients (3,200 [1,600-6,400]) comparatively to REL patients (800 [500-1,400]), p = 0.002. Likewise, log of viral load postribavirin therapy was significantly higher in anti-RR positive patients (6.24 ± 0.64) than in anti-RR negative (4.69 ± 1.06), p < 0.001. Based on these findings, ribavirin-induced anti-RR autoantibody seems to be associated with a more frequent nonresponse to IFN-α/ribavirin therapy with a significant higher HCV viral load.

The role of IL-23/IL-17 axis in human kidney allograft rejection.

Th17 cell subset has been implicated in autoimmune diseases, tumor immunity and, transplant rejection. In order to investigate the role of IL-17/IL-23 pathway in allograft outcome, intragraft expression of IL-17 mRNA and single nucleotide polymorphisms (SNPs) of IL-17A, IL-17F, IL-17RC, and IL23R genes were evaluated with a quantification of IL-17A, IL-17F, and IL-23 plasma levels. This study revealed that recipients with acute rejection (AR) had a significant increase in IL-17A mRNA expression levels after transplantation compared to controls (P = 0.037). Moreover, IL-17A plasma levels were significantly higher in AR group; pretransplantation (Day-1 [D-1]): P = 0.00022 and posttransplantation (Day 7 [D7]): P < 10-14 . IL-17F and IL-23 plasma levels were significantly higher in AR at D7 only (47.86 vs. 22.99 pg/ml; and 33.82 vs. 18.811 pg/ml; P = 0.015 and P < 10-17 , respectively). Using receiver-operating characteristic curves, D7 IL-17A and IL-23 plasma levels exhibited excellent sensitivities and specificities for predicting AR. Genetic study revealed no association between IL-17A, IL-17F, IL-17RC, and IL23R studied SNPs and AR. Nevertheless, a significant improvement of graft survival was found in kidney transplant recipients carrying IL-17F-rs763780*A/A, IL-17RC*G/G, and *G/A genotypes. Besides, IL-17A mRNA levels were significantly higher in patients carrying the IL-23R*G/G genotype comparatively to those with *G/A genotype. Based on these findings, significant increase of IL-17A mRNA and protein levels in AR recipients that are genetically controlled highlights the role of this cytokine that can be a useful clinical biomarker to predict early acute renal allograft rejection.

IL-17A, IL-17RC polymorphisms and IL17 plasma levels in Tunisian patients with rheumatoid arthritis.

BACKGROUND: Interleukin-17 (IL-17), a cytokine mainly secreted by Th17 cells, seems to play a significant role in the pathogenesis of rheumatoid arthritis (RA). Functional genetic polymorphisms in IL-17 and its receptor genes can influence either qualitatively or quantitatively their functions. Therefore, we aimed to study the impact of IL17-A and IL17RC polymorphisms on plasma level of IL-17 and RA susceptibility and severity. METHODS: In this context, IL-17A*rs2275913 and IL-17RC*rs708567 polymorphisms were investigated together with the quantification of IL17 plasma level in 115 RA patients and 91 healthy control subjects matched in age, sex and ethnic origin. RESULTS: There were no statistically significant associations between IL-17A and IL-17RC studied polymorphisms and RA susceptibility. In contrast, IL-17A plasma levels were significantly higher in patients (55.07 pg/ml) comparatively to controls (4.75 pg/ml), p<10E-12. A ROC curve was used to evaluate the performance of plasma IL-17 in detecting RA. Given 100% specificity, the highest sensitivity of plasma IL-17A was 61.7% at a cut-off value of 18.25 pg/ml; p < 10E-21, CI = [0.849-0.939]. Analytic results showed that the IgM-rheumatoid factor and anti-CCP antibodies were significantly less frequent in patients with the IL-17RC*A/A genotype than those carrying *G/G and *G/A genotypes; p = 0.013 and p = 0.015, respectively. Otherwise, IL-17 plasma levels' analysis showed a significant association with the activity of RA (DAS28≥5.1 = 74.71 pg/ml vs. DAS28<5.1 = 11.96 pg/ml), p<10E-6. CONCLUSION: IL-17A*rs2275913 (G/A) and IL-17RC*rs708567 (G/A) polymorphisms did not seem to influence RA susceptibility in Tunisian population. This result agrees with those reported previously. Plasma IL-17A level seems to be predictive of severe RA occurrence.

Polymorphisms of Toll-like receptor-4 and CD14 in systemic lupus erythematosus and rheumatoid arthritis.

BACKGROUND: Toll-like receptor 4 (TLR4) and its co-receptor CD14 play a major role in innate immunity by recognizing PAMPs and signal the activation of adaptive responses. These receptors can recognize endogenous ligands mainly auto-antigens. In addition, TLR4 (Asp299Gly) and CD14 (C/T -159) polymorphisms (SNPs) may modify qualitatively and/or quantitatively their expression. Therefore, they could be implied in autoimmune diseases and can influence both susceptibility and severity of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). PATIENTS AND METHODS: TLR4 (Asp299Gly) and CD14 (C/T -159) SNPs were genotyped using polymerase chain reaction (PCR)-RFLP in 127 SLE patients, 100 RA patients, and 114 healthy controls matched in age and gender. RESULTS: CD14*T allele was significantly more frequent in SLE patients (0.456) comparatively to controls (0.355), p = 0.02 OR (95% CI) = 1.53 [1.04-2.24]. In RA patients, the higher frequency of CD14*T allele (0.405) failed to reach significance, p = 0.28. Investigation of the TLR4 (Asp299Gly) SNP showed no significant association neither with SLE nor with RA.Analysis of these SNPs according to clinical and biological features showed a significant higher frequency of arthritis in SLE patients carrying CD14*T/T genotype (92%) comparatively to those with C/C and C/T genotypes (72.5%), p = 0.04. Moreover, SLE patients carrying CD14*T/T/TLR4*A/A haplotype had significantly more arthritis (91.3%) than the rest of SLE group (73%), p = 0,044 and confirmed by multivariable analysis after adjustment according to age and gender, p = 0.01. CONCLUSION: The CD14 (-159)*T allele seems to be associated with susceptibility to SLE and arthritis occurrence.

MCP-1, CCR2 and CCR5 polymorphisms in Tunisian patients with atopic asthma.

Chemokines and their receptors play an important role in the late inflammatory stage of asthma. In this study, we aimed to investigate polymorphisms of MCP-1 (CCL2), CCR2 and CCR5 which can affect qualitatively and/or quantitatively their production and thus influence both susceptibility and severity of asthma and its clinical and biological features.MCP-1 (A/G -2518), CCR2 (+/64I), CCR5 (G/A -59029) and CCR5 (∆32) polymorphisms were evaluated by PCR in 107 Tunisian patients with asthma and 169 healthy controls.No significant association was found between the four investigated polymorphisms and asthma. Nevertheless the haplotype MCP1*AG/CCR2*+/+ was significantly l ess frequent in patients (20.5%) compared to controls (32.5%) (p=0.03; OR=0.54; 95% CI: 0.29-0.98). Whereas no difference was observed in CCR2/CCR5 haplotypes between patients and controls. Analysis of polymorphisms with clinical and biological features showed that the concomitant presence of MCP-1*G/CCR2*64I alleles was less frequent in severe forms (4.34%) compared to moderate disease (12%) but the difference was not significant (p=0.27). No association was observed between the four polymorphisms and the presence of atopic rhinitis or atopic conjunctivitis and an elevated rate of serum IgE over 200 IU/ml.Additional effects of MCP-1 and its receptor CCR2 polymorphisms seem to be involved in disease susceptibility to asthma in Tunisian patients; nevertheless they could be protective against its severe forms.

Role of immune system, apoptosis and angiogenesis in pathogenesis of rheumatoid arthritis and joint destruction, a systematic review.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disorder of unknown cause that is notorious for the chronic polyarticular synovial inflammation and progressive destruction of affected joints. Understanding the pathogenesis of RA provides the basis for optimal management of that disease in patients. The pathogenesis of RA was largely explored in many studies in human as much as in mice models with collagen II induced arthritis, nevertheless the pathogenesis puzzle is still incomplete. AIM: The aim of this systematic review was to collect the results of many observations and to put them down into an original story of RA set up. METHODS: An exhaustive electronic and library search of the relevant literature was carried out through "science direct" and "interscience wiley" web sites. The key words used for the search were "rheumatoid arthritis", "pathogenesis", "apoptosis", "angiogenesis", "immune response" and "joint destruction". RESULTS: The suspected responsible antigen isn't yet determined although the great specificity of anti-CCP antibodies suggests that this antigen carries probably many citrullinated residues. The immuno-pathogenesis of RA involves both the innate and the adaptive immune system. In the other hand, apoptosis defect contribute to hyperplasia of rheumatoid synovium and in extended half life of fibroblast like synoviocytes (FLS), neutrophils and many other cells implied in rheumatoid synovitis. Hyperplasia of synovium leads to ischemia and that results in neo-angiogenesis with increase of proangiogenic factors such as VEGF. The last part of the pathogenesis of RA is the joint destruction resulting from increased MMP production and activation of osteoclasts which leads to the breakup of cartilage and to bone damage.