HLA class II polymorphisms as prognostic biomarkers for right and left-sided colon cancer.

BACKGROUND: Colon cancer (CC) is one of the most common malignancies worldwide. Characterization of new prognostic biomarkers for right-sided CC (RCC) and left-sided CC (LCC) may contribute to improving early detection. An association of human leukocyte antigens class II (HLA-II) with the predisposition to CC was suggested. AIM OF THE STUDY: We evaluated the association of DRB1 and DQB1 with the risk of LCC and RCC. PATIENTS AND METHODS: Our study comprised 93 CC patients and 100 healthy controls. Genotyping of HLA class II alleles were performed by the Polymerase Chain Reaction Sequence-Specific Primers (PCR-SSP). RESULTS: DRB1*03 was positively associated with CC. In contrast, DRB1*11, DRB1*13, DQB1*03, and DQB1*05 were negatively linked to CC. Haplotype analysis revealed that DRB1*04-DQB1*04 and DRB1*09-DQB1*02 were positive, while DRB1*01-DQB1*05, DRB1*04-DQB1*03, DRB1*07-DQB1*02, DRB1*11-DQB1*03, DRB1*11-DQB1*05, and DRB1*13-DQB1*06 were negatively associated with CC. For sigmoid CC, DRB1*13, DRB1*11, and DQB1*05 were negative, while DRB1*04-DQB1*02, and DRB1*07-DQB1*03 were positively associated. DRB1*03 and DRB1*04-DQB1*04 were positive, while DRB1*11 and DQB1*03 were negatively linked to RCC. According to the LCC, DRB1*07, DRB1*11, DQB1*03, DQB1*05, and DRB1*07-DQB1*02 were negative. In contrast, DRB1*09-DQB1*02 was positively associated with LCC. Stratified analysis revealed that DRB1*11 is associated with higher risk of metastasis in CC and sigmoid CC, and tolerance to treatment in RCC. DQB1*03 was associated with lymph-node invasion in CC. CONCLUSION: DRB1 and DQB1 polymorphisms could be used as future biomarkers for the early detection of subjects at a higher risk of developing RCC and LCC, metastasis in sigmoid CC, and tolerance to treatment in RCC.

Obesity, Lipid Profile and Cytokines in Spondyloarthritis.

Context: Chronic rheumatic diseases seem to be associated with a higher risk of developing cardiovascular diseases. The link between cytokines and lipid profile in spondyloarthritis is not well elucidated. Aims: We aimed to assess the relationship between cytokines and obesity, lipid profile and atherogenic indexes in spondyloarthritis. Methods and Material: We conducted a cross-sectional study including 45 patients with axial radiographic spondyloarthritis. For each patient, we measured the following pro-inflammatory cytokines: interleukin (IL-) 1, IL-8, IL-6, IL-17, IL-23 and tumor necrosis factor a (TNFa), and anti-inflammatory cytokines: IL-10. We also measured total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol (LDLc). We calculated the following ratios: TC/HDLc, TG/HDLc, LDLc/HDLc and Log[TG/HDLc]. Statistical Analysis Used: SPSS. Results: The mean age was 46 ± 11.9 years. IL-8 levels were increased in obese patients (P = 0.003). IL-8 and IL-22 levels were significantly higher in patients with abdominal obesity (P = 0.024 and P = 0.042, respectively). IL-6 levels were lower in patients with hypercholesterolemia (P = 0.009). IL-1 levels correlated to TG (r = 0.413; P = 0.005). IL-1 and IL-6 were correlated to TG/HDLc (IL-1: r = 0.484, P = 0.001; IL-6; r = 0.700, P = 0.012) and Log[TG/HDLc] (IL-1: r = 0.354; P = 0.012; IL-6: r = 0.309, P = 0.041). IL-10 level was correlated to TC/HDLc (r = 0.333, P = 0.027) and LDLc/HDLc (r = 0.342, P = 0.023). Conclusions: IL-8 and IL-22 were higher in patients with abdominal obesity, highlighting the contribution of the adipocytes to the secretion of pro-inflammatory cytokines. The correlation between cytokines and atherogenic indexes suggests the role of these cytokines in the occurrence of cardiovascular diseases in spondyloarthritis.

Deciphering the balance of IL-6/IL-10 cytokines in severe to critical COVID-19 patients.

The severity of COVID-19 is largely determined by the inflammatory response, a "Cytokine storm," that involves both pro- and anti-inflammatory cytokines. In the current study we investigated the balance of pro- and anti-inflammatory status as represented by the levels of IL-6/IL-10 in severe to critical COVID-19 patients. 66 confirmed COVID-19 patients admitted to the ICU were categorized into groups according to the mortality and respiratory failure. Data were collected retrospectively in ICU, including a peripheral immune cells and infection-related biomarker CRP. The measurements of cytokine levels were performed by Immulite analyzer for IL-6 and ELISA sandwich for IL-10. In addition, longitudinal measurement of IL-6 was performed during 5 days post admission. Longitudinal assays showed that IL-6 was sustained at a medium level within 5 days post admission in severe cases who survived or not requiring mechanical ventilation, whereas it was sustained at high levels throughout the disease course in either deceased cases or who developed respiratory failure. The ratio of IL-6/lymphocytes was positively correlated with the risk of mortality, while IL-10/lymphocytes ratio could predict respiratory failure in ICU. IL-6/IL-10 profiling revealed that deceased patients have different magnitudes of both IL-6 and IL-10 cytokine release. Notably, excessive levels of IL-6 concomitant with high levels of IL-10 were more common in diseased COVID-19 patients. Taking into account the IL-6/IL-10 profiling may help clinicians to identify the right time of anti-inflammation treatment and select patients who will respond to anti-cytokine therapies and maintain an adequate inflammatory response for SARS-CoV-2 clearance.

Outcomes of treatment of severe COVID-19 pneumonia with tocilizumab: a report of two cases from Tunisia.

The SARS CoV-2 pandemic is a global health threat with high morbidity and mortality (1 to 4%) rates. COVID-19 is correlated with important immune disorders, including a "cytokine storm". A new therapeutic approach using the immunomodulatory drug, Anti-IL6 (tocilizimub), has been proposed to regulate it. We report here the first Tunisian experience using tocilizimub in two severe cases of COVID-19 pneumonia. The diagnosis was confirmed by chest scan tomography. Biological parameters showed a high level of Interleukin-6 (IL-6) that increased significantly during hospitalization. The patients developed hypoxia, so they received intravenously 8 mg/kg body weight tocilizumab. There was a resultant decrease in the level of IL6, with clinically good evolution. Blocking the cytokine IL-6 axis is a promising therapy for patients developing COVID-19 pathology.

High levels of proinflammatory cytokines IL-6, IL-8, TNF-Α, IL-23, and IFN- in Tunisian patients with type 1 autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a chronic hepatitis of unknown etiology and several cytokines have been implicated in its pathogenesis and onset. Our objective was to determine the profile of pro and anti-inflammatory cytokines, including IL-1ß, IL-6, IL-8, IL-23, IFN-, TNF-α, IL-10 in autoimmune hepatitis and their association with HLA gene polymorphisms. Serum cytokine levels were determined in 50 autoimmune hepatitis patients and one hundred fifty controls using chemiluminescence and ELISA techniques and HLA genotyping performed by PCR SSP. The levels of IL-6 (12 pg/mL vs. 5.5 pg/mL, p = 0.017), IL-8 (24.1 pg/mL vs. 7.8 pg/mL, p = 0.006), and TNF-α (61.1 pg/mL vs. <4.00 pg/mL, p = 0.002) were significantly higher in AIH patients in pretreatment phase compared to levels after remission and in controls. HLA*DRB15 was significantly associated with higher levels of IL-8. IL-6, IL-8, and TNF-α may be biomarkers of AIH activity. HLA gene expression may play a role in higher cytokine production and could allow an earlier diagnosis and better management of the disease.

Association of STAT4, TGFß1, SH2B3 and PTPN22 polymorphisms with autoimmune hepatitis.

The physiopathology of autoimmune hepatitis (AIH) is complex and still not fully elucidated. The genes localized outside the histocompatibility complex involved in regulation and signal transduction of the immune system SH2B3, TGFß1, STAT4 and PTPN22 could be associated to the susceptibility and hepatocyte lysis mechanism of this lethal autoimmune disorder. PATIENTS AND METHODS: We investigated four polymorphic sites in SH2B3 (rs3184504), TGFß1 (rs1800471), STAT4 (rs7574865) and PTPN22 (rs2476601) in 45 AIH patients and 150 healthy controls from Tunisia using real-time PCR. RESULTS: Significant associations were found for SH2B3 T allele (OR = 1.861; p = 0.015, pc = 0.366) and PTPN22 A allele (OR = 7.070; p = 0.026; pc = 1.00) and AIH with opposite homozygous being protective against the disease (CC genotype with OR = 0.420, p = 0.025; GG genotype with OR = 0.136, p = 0.025, respectively). No statistically significant associations were found for the TGFß1 and STAT4 polymorphisms with AIH susceptibility. CONCLUSION: Our work enlarges information on non-HLA genes that are associated with AIH by focusing in a region of the world that was poorly molecularly characterized for this disease.

The relationship between TNF alpha gene polymorphisms (-238/-308), TNF RII VNTR (p75) and outcomes of hepatitis B virus infection in Tunisian population.

The present study was undertaken to investigate the association between Hepatitis B Virus (HBV) infection and polymorphisms of tumour necrosis factor alpha TNF-α -308 G>A, TNF-α -238 G>A and TNF RII VNTR (p75) gene promoter in a Tunisian population. Blood samples were collected from 100 Tunisian patients with HBV infection, 45 with Chronic Hepatitis (CH), 36 with Liver Cirrhosis (LC), 15 with Hepatocellular Carcinoma (HCC) and 200 healthy individuals of similar ethnicity. Genomic DNA was extracted from peripheral blood leukocytes. Genotyping of the analysed polymorphisms was performed using Amplified Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR), Restriction Fragment Length Polymorphism (RFLP) and Variable Number Tandem Repeat PCR (PCR-VNTR). The variant homozygotes -308 GG were associated with 50% decreased risk of HBV chronic infection (GG vs AA+GA; p=0.010; OR=0.50; 95%CI=0.29-0.85). However, the carriers of minor allele -308 A have higher risk (1.5 times) to develop a chronic infection than other patients (p=0.027; OR=1.46; 95%CI=1.04-2.06). The minor allele of -238 polymorphism was positively associated with virus resistance and the development of chronic infection (p=0.043; OR=1.42; 95%CI =1.01 1.99). The distribution of -308, -238 and TNF RII VNTR (p75) among the three groups differed significantly. For HCC groups, there were statistically significant differences in allele distribution in -308, -238 respectively in which A allele remains a risk factor for HBV evolution to HCC (p=0.008 and p=0.026). Haplotype analysis revealed that TNF-α (-308A; -238A) was significantly associated to HBV chronic infection and moreover to disease aggravation to HCC stage. Our findings imply that variations in the genes governing the levels of constitutive and inducible TNF-α and TNF RII might be an important risk factor, which could explain the variable outcomes of HBV infection.