Peripheral loss of CD8(+) CD161(++) TCRVα7·2(+) mucosal-associated invariant T cells in chronic hepatitis C virus-infected patients.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells play an important role in innate host defence. MAIT cells appear to undergo exhaustion and are functionally weakened in chronic viral infections. However, their role in chronic hepatitis C virus (HCV) infection remains unclear. MATERIALS AND METHODS: We investigated the frequency of CD8(+) CD161(++) TCR Vα7.2(+) MAIT cells in a cross-sectional cohort of chronic HCV-infected patients (n = 25) and healthy controls (n = 25). Peripheral blood mononuclear cells were investigated for circulating MAIT cell frequency, liver-homing (CCR5 and CD103), biomarkers of immune exhaustion (PD-1, TIM-3 and CTLA-4), chronic immune activation (CD38 and HLA-DR), and immunosenescence (CD57) by flow cytometry. RESULTS: The frequency of MAIT cells was significantly decreased, and increased signs of immune exhaustion and chronic immune activation were clearly evident on MAIT cells of HCV-infected patients. Decrease of CCR5 on circulating MAIT cells is suggestive of their peripheral loss in chronic HCV-infected patients. MAIT cells also showed significantly increased levels of HLA-DR, CD38, PD-1, TIM-3 and CTLA-4, besides CD57 in chronic HCV disease. CONCLUSIONS: Immune exhaustion and senescence of CD8(+) CD161(++) TCR Vα7.2(+) MAIT cells could contribute to diminished innate defence attributes likely facilitating viral persistence and HCV disease progression.

Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes.

Persistent hepatitis C virus (HCV) infection appears to trigger the onset of immune exhaustion to potentially assist viral persistence in the host, eventually leading to hepatocellular carcinoma. The role of HCV on the spontaneous expression of markers suggestive of immune exhaustion and spontaneous apoptosis in immune cells of chronic HCV (CHC) disease largely remain elusive. We investigated the peripheral blood mononuclear cells of CHC patients to determine the spontaneous recruitment of cellular reactive oxygen species (cROS), immunoregulatory and exhaustion markers relative to healthy controls. Using a commercial QuantiGenePlex(®) 2.0 assay, we determined the spontaneous expression profile of 80 different pro- and anti-apoptotic genes in persistent HCV disease. Onset of spontaneous apoptosis significantly correlated with the up-regulation of cROS, indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2/prostaglandin H synthase (COX-2/PGHS), Foxp3, Dtx1, Blimp1, Lag3 and Cd160. Besides, spontaneous differential surface protein expression suggestive of T cell inhibition viz., TRAIL, TIM-3, PD-1 and BTLA on CD4+ and CD8+ T cells, and CTLA-4 on CD4+ T cells was also evident. Increased up-regulation of Tnf, Tp73, Casp14, Tnfrsf11b, Bik and Birc8 was observed, whereas FasLG, Fas, Ripk2, Casp3, Dapk1, Tnfrsf21, and Cflar were moderately up-regulated in HCV-infected subjects. Our observation suggests the spontaneous onset of apoptosis signaling and T cell exhaustion in chronic HCV disease.

Analysis of structure, function, and evolutionary origin of the ob gene product--leptin.

Leptin, the ob gene product, is a 167 amino acid polypeptide known to play a key role in regulating the fat stores of the body and is found in all eukaryotes, including mammals, aves, and also in invertebrates. To gain insight into the structure-function relation and origin of leptin, we have analyzed the amino acid sequence of leptin from 23 species by computing the frequency of occurrence of amino acids, their secondary structure, sequence homology, et cetera. Extensive conservation is observed within the leptin sequences of all the species, suggesting an evolutionary relatedness among them. It is interesting to note that human leptin shares a very high degree of homology with gorilla, chimpanzee, and orangutan indicative of a common function of leptin in them. Analysis of the codon bias in leptin from 11 species reveals that sminthopsis shows highest variation compared to human while less variation is observed in chimpanzee and orangutan, possibly reflecting the closeness in their evolution. Thus, understanding leptin's three-dimensional structure along with primary and secondary structure might enable us to understand the functional role played by this multifaceted adipocyte derived protein.

Monoterpenes: Novel insights into their biological effects and roles on glucose uptake and lipid metabolism in 3T3-L1 adipocytes.

Various strategies have been adopted to combat complications caused by Type 2 diabetes mellitus and controlled diet is one of them. Monoterpenes, major constituents of essential oils, are synthesized and widely used as artificial food flavors. A series of twelve monoterpenes were assessed in the present study. Monoterpenes, exhibited low 2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH) and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity even at high concentrations. Some monoterpenes inhibited α-amylase and α-glucosidase activity and stimulated glucose uptake and lipolysis. Monoterpenes such as (R)-(+)-limonene stimulated both glucose uptake (17.4%) and lipolysis (17.7%); the mRNA expression of glucose transporter 1 (GLUT1) was upregulated but glucose transporter 4 (GLUT4) was unaffected, and adipose triglyceride lipase (ATGL) was suppressed. Taken together, the selected monoterpenes may not confer strong protection against free radicals but nevertheless, their positive influence on lipid and glucose metabolism may have potential in the control of obesity and Type 2 diabetes mellitus.

Polymorphisms at Locus 4p14 of Toll-Like Receptors TLR-1 and TLR-10 Confer Susceptibility to Gastric Carcinoma in Helicobacter pylori Infection.

Helicobacter pylori (H. pylori) -induced gastric inflammation impacts the functions of leptin- and ghrelin-producing cells in the gastroduodenum. Inflammation resulting from H. pylori sensing via Toll-like receptors (TLRs) and the associated downstream signaling largely remain ambiguous. Here, we investigated the role of gut hormones, pro-inflammatory cytokines and single nucleotide polymorphisms (SNPs) associated with TLR 4p14 in H. pylori disease in 30 subjects with non-ulcer dyspepsia (NUD), 40 with peptic ulcer disease (PUD) and 15 with gastric cancer (GC) subjects positive and negative for H. pylori infection. The level of pro-inflammatory cytokines was directly proportional to the severity of gastritis, and disease status influenced the levels of gut hormones and pro-inflammatory cytokines. TLR-1 SNPs rs4833095 and TLR-10 SNPs rs10004195 and were directly associated with H. pylori disease, and were up-regulated in the presence of H. pylori in a genotype-independent manner. We concluded that TLR-1 rs4833095 and TLR10 rs10004195 confer susceptibility to development of gastroduodenal disease, especially GC in H.pylori disease.