CD8+T cell activation associated with viral replication in chronic infection

PD-1 expression is controlled during T-cell activation. PD-1 has an important role in regulating immune response as well as tolerance. During chronic hepatitis C virus [HCV] infection there is high level of PD-1 expression on exhausted CD8+T cells. There is also reduced expression of T-bet. T-bet is identified as a transcriptional repressor of Pdcd1. The study will attempt to find out the level of expression of PD-1 on peripheral CD8 + T-cells, associated with chronic HCV infection. Fifty patients with chronic hepatitis C virus infection [CHCV], whose age ranged between [16-59] years, were selected from the National Hepatology and Tropical Medicine Research Institute were included in this study, before Interferon and ribavirin therapy, and fifteen healthy individuals were included to serve as controls. All the patients and controls were subjected to the following: history, clinical examination, abdominal ultrasonography and collection of blood samples for routine laboratory investigations. CBCs and analysis of the expression of surface markers on CD8+T cells and PD-1. Our results suggested that increased expression of PD-1 cells was an additional inhibitory mechanism that contributed to virus-specific CD8 + T cell exhaustion in chronic hepatitis C virus [CHCV] infected patients. Our study concluded that there's significant increase in PD-1 expression of circulating HCV-specific CD8 + T cells in CHCV patients. The blockade of the inhibitory receptors [PD-1] programmed cell death is considered as a novel strategy for the treatment of chronic HCV infection

role of interleukin-18 promoter polymorphisms [-607 C/A and 137 G/C ] in determining HCV clearance or persistence

Two interleukin [IL-18] Polymorphisms [- 607 C/A and -137 G/C] and their haplotypes are known to affect the IL-18 expression. A number of SNPs [single nucleotide polymorphisms] that influence IL- 18 production are found in the gene promoter region. The study will determine HCV clearance or persistence as a result of IL-18 promoter polymorphisms [-607 C/A and 137 G/C] in chronic hepatitis C virus infected patients during interferon and ribavirin treatment. Eighty patients with chronic hepatitis C virus infection, their age ranges between [23-57] years, selected from the National Hepatology and Tropical Medicine Research Institute were included in this study, during interferon and ribavirin therapy and fifteen healthy individuals were included to serve as controls. All the patients and controls were subjected to the following history, clinical examination, abdominal ultrasonography and collection of blood samples for routine laboratory investigation, CBCs and serological assay and specific sequence primer polymerase chain reaction [PCR] IL-18-137, 607 SNP. There was no significant difference in the frequencies of -137 allelic distribution in CHCV infection patients and healthy controls. The -607 AA allele was higher among controls than in patients with CHCV infection. The -607 CC allele was higher among the CHCV patients than in the healthy controls. 87.5% of the studied CHCV patients had response to IFN therapy, the majority of cases had A1F1 biopsy results. IL-18 promoter polymorphism at -607 position with AA allele is a potential protective marker, as it is higher among healthy controls than the CHCV patients. That IL-18 could be considered as a target for therapeutics

Tumour necrosis factor-alpha gene expression in chronic Hepatitis C virus infection

Objective: Tumour necrosis factor [TNF]-alpha, a prototype proinflammatory cytokine, has been implicated as an important pathogenic mediator in a variety of liver conditions. Some genetic polymorphisms in the human TNF-alpha promoter region, such as the G-A transitions -308 and - 238, have been shown to influence TNF-alpha expression in chronic hepatitis C virus infection

Aim of the work: The present study was to investigate the influence that the- 308and- 238 TNF- alpha promoter polymorphisms have on the response to interferon and ribavirin therapy in chronic hepatitis C virus infection

Patients and methods: One hundred forty patients with chronic hepatitis C virus infection, their age ranges between [20-56] years, selected from the National Hepatology and Tropical Medicine Research Institute were included in this study, during interferon and ribavirin therapy and thirty five healthy individuals were included to serve as controls, the patients and controls were divided into two groups the first group forty patients and fifteen controls for the detection of TNF-alpha -308, -238 genotypes polymorphisms, the second group were one hundred patients and twenty healthy controls for the detection of serum levels of TNF-alpha. All the patients and controls were subjected to the following history, clinical examination, abdominal ultrasonography and collection of blood samples for routine laboratory investigation, CBCs and serological assay, genotyping of 308, 238 TNF-alpha promoter polymorphism and serum levels of TNF-alpha

Results: There was no statistically significant difference between chronic HCV patients and healthy controls as regarding TNF-alpha -238 different alleles. The frequencies of TNF-alpha gene polymorphism with A/G and G/G mutation at – 308 were significantly higher in chronic HCV patients than those in the controls. The serum level of TNF-alpha was markedly higher in the chronic HCV patients than in the healthy controls. There were significant association between TNF-alpha gene polymorphism in the- 308 A/G, G/G alleles and increased serum TNF- alpha in CHCV infection

Conclusion: The results indicate that the TNF-alpha gene polymorphism at position -308 is associated with susceptibility of chronic HCV infection

Recommendations: Our major concern was to improve the response to treatment in patients with chronic HCV infection, whether the disadvantage of having the TNF-alpha -308 allele became more apparent after interferon and ribavirin therapy is unclear and needs further study that detecting the polymorphism of the -308 TNF-alpha allele before administering interferon therapy may be valuable for predicting the treatment response, especially in difficult- to treat patients

Decreased level of soluble receptors of advanced glycated end products [sRAGE] and Glycine 82 Serine [G82S] polymorphism in patients with RA

The receptor for advanced glycated end products [RAGE] is a multi-ligand receptor expressed as a cell surface molecule, interacting with diverse ligands. Since soluble RAGE [sRAGE] acts as a competitive receptor for cellular RAGE, the balance between these two types of receptors might be of importance in the pathogenesis of RA. To evaluate the levels of sRAGE in patients with RA compared with healthy controls and to assess the relationship between sRAGE levels and disease characteristics. Also, we assessed the association between the gene variants and the sRAGE level and disease activity. The study included 33 patients with RA and 16 healthy normal controls. All patients and controls are subjected to full clinical assessment, joint examination including tender joint count [TJC], swollen joint count [STC] and estimation of DAS 28 and laboratory investigations including CBC, ESR, urine analysis, kidney function tests, liver function tests, RF and C-reactive protein [CRP]. Soluble RAGE was determined by enzymatic immunoassay and molecular study was done for single nucleotide polymorphisms [SNP] in the glycine 82 serine [G82S] of the RAGE gene. RF was positive in 72.7% of patients and was negative in all controls. CRP was significantly higher in RA patients as compared with controls [p < 0.01]. Serum levels of sRAGE were significantly lower in RA patients than controls. RA: Rheumatoid arthritis. AGEs: Advanced glycation endproducts. sRAGE: Soluble receptor for advanced glycation end products. NF-KB: Nuclear factor-kappaB. DAS28: Disease activity score. MS: Morning stiffness. TJC: Tender joint count. SJC: Swollen joint count. CRP: C-reactive protein. SNP: Single nucleotide polymorphisms. G82S: Glycine 82 serine gene polymorphism. HMGB1: High mobility group box I or amphoterin. MMPs: Matrix metalloproteinases. [840.11 +/- 230.32 versus 1111.59 +/- 143.20, p < 0.05]. Genotyping of the RAGE gene showed G82S in 22 out of 33 RA patients, 5 of them were homozygous for the RAGE serine 82 allele, while genotyping in the control subjects showed polymorphisms in the G82S in 5 out of 16, only one of them was homozygous for the RAGE G82S allele, indicating significantly increased G82S allele in RA patients as compared with controls [p < 0.05]. The G82S allele was related to the MS, CRP and sRAGE in RA patients. The sRAGE levels were significantly lower in RA patients with more disease activity as indicated by MS, TJC and CRP. The sRAGE levels were significantly lower in RA patients with cardiac disease than those without cardiac disease. Linear regression analysis detected CRP and gene polymorphism as significant predictors for sRAGE. The levels of sRAGE were significantly lower in patients with RA and this reduction was correlated with the disease activity and glycine 82 serine gene polymorphism. Thus, the sRAGE may be an important marker of disease activity and can be used as a therapeutic target in these conditions