The allele 4 of neck region liver-lymph node-specific ICAM-3-grabbing integrin variant is associated with spontaneous clearance of hepatitis C virus and decrease of viral loads

L-SIGN is a C-type lectin expressed on liver sinusoidal endothelial cells involved in the capture of hepatitis C virus and trans-infection of adjacent hepatocyte cells. The neck region of L-SIGN is highly polymorphic, with three to nine tandem repeats of 23 residues. This polymorphism is associated with a number of infectious diseases, but has not been explored in HCV. We therefore investigated the impact of L-SIGN neck region length variation on the outcome of HCV infection. We studied 322 subjects, 150 patients with persistent HCV infection, 63 individuals with spontaneous clearance and 109 healthy controls. In healthy subjects, we found a total of nine genotypes, with the 7/7 genotype being the most frequent (33%) followed by the 7/6 (22.9%) and the 7/5 (18.3%). The frequencies of the alleles were as follows: 7-LSIGN (56.4%), 6-LSIGN (20.2%), 5-L-SIGN (18.3%) and 4-L-SIGN (5%). The frequency of the 7/4 genotype was higher in spontaneous resolvers (14.3%) as compared with the persistent group (4%) (OR = 0.25, 95% CI = 0.07–0.82, p 0.022). In addition, we found that 4-L-SIGN was associated with spontaneous resolution of HCV infection (OR = 0.30, 95%CI, 0.12–0.74, p 0.005). Interestingly, patients with 4-L-SIGN had lower viral loads when compared with carriers of the 5 (p 0.001), 6 (p 0.021) and 7-alleles (p 0.048). The results indicate that neck region polymorphism of L-SIGN can influence the outcome of HCV infection and the four-tandem repeat is associated with clearance of HCV infection

Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis

The host genetic basis of mixed cryoglobulin vasculitis is not well understood and has not been studied in large cohorts. A genome-wide association study was conducted among 356 hepatitis C virus (HCV) RNA-positive individuals with cryoglobulin-related vasculitis and 447 ethnically matched, HCV RNA-positive controls. All cases had both serum cryoglobulins and a vasculitis syndrome. A total of 899 641 markers from the Illumina HumanOmni1-Quad chip were analyzed using logistic regression adjusted for sex, as well as genetically determined ancestry. Replication of select single-nucleotide polymorphisms (SNPs) was conducted using 91 cases and 180 controls, adjusting for sex and country of origin. The most significant associations were identified on chromosome 6 near the NOTCH4 and MHC class II genes. A genome-wide significant association was detected on chromosome 6 at SNP rs9461776 (odds ratio=2.16, P=1.16E-07) between HLA-DRB1 and DQA1: this association was further replicated in additional independent samples (meta-analysis P=7.1 × 10(-9)). A genome-wide significant association with cryoglobulin-related vasculitis was identified with SNPs near NOTCH4 and MHC Class II genes. The two regions are correlated and it is difficult to disentangle which gene is responsible for the association with mixed cryoglobulinemia vasculitis in this extended major histocompatibility complex region

UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis

Background & Aims: Thirty-to-forty percent of patients with primary biliary cholangitis inadequately respond to ursodeoxycholic acid. Our aim was to assemble national, real-world data on the effectiveness of obeticholic acid (OCA) as a second-line treatment, alongside non-licensed therapy with fibric acid derivatives (bezafibrate or fenofibrate). Methods: This was a nationwide observational cohort study conducted from August 2017 until June 2021. Results: We accrued data from 457 patients; 349 treated with OCA and 108 with fibric acid derivatives. At baseline/pre-treatment, individuals in the OCA group manifest higher risk features compared with those taking fibric acid derivatives, evidenced by more elevated alkaline phosphatase values, and a larger proportion of individuals with cirrhosis, abnormal bilirubin, prior non-response to ursodeoxycholic acid, and elastography readings >9.6kPa (P <.05 for all). Overall, 259 patients (OCA) and 80 patients (fibric acid derivatives) completed 12 months of second-line therapy, yielding a dropout rate of 25.7% and 25.9%, respectively. At 12 months, the magnitude of alkaline phosphatase reduction was 29.5% and 56.7% in OCA and fibric acid groups (P <.001). Conversely, 55.9% and 36.4% of patients normalized serum alanine transaminase and bilirubin in the OCA group (P <.001). The proportion with normal alanine transaminase or bilirubin values in the fibric acid group was no different at 12 months compared with baseline. Twelve-month biochemical response rates were 70.6% with OCA and 80% under fibric acid treatment (P =.121). Response rates between treatment groups were no different on propensity-score matching or on sub-analysis of high-risk groups defined at baseline. Conclusion: Across the population of patients with primary biliary cholangitis in the United Kingdom, rates of biochemical response and drug discontinuation appear similar under fibric acid and OCA treatment

STAT4-associated natural killer cell tolerance following liver transplantation

OBJECTIVE: Natural killer (NK) cells are important mediators of liver inflammation in chronic liver disease. The aim of this study was to investigate why liver transplants (LTs) are not rejected by NK cells in the absence of human leukocyte antigen (HLA) matching, and to identify a tolerogenic NK cell phenotype. DESIGN: Phenotypic and functional analyses on NK cells from 54 LT recipients were performed, and comparisons made with healthy controls. Further investigation was performed using gene expression analysis and donor:recipient HLA typing. RESULTS: NK cells from non-HCV LT recipients were hypofunctional, with reduced expression of NKp46 (p<0.05) and NKp30 (p<0.001), reduced cytotoxicity (p<0.001) and interferon (IFN)-γ secretion (p<0.025). There was no segregation of this effect with HLA-C, and these functional changes were not observed in individuals with HCV. Microarray and RT-qPCR analysis demonstrated downregulation of STAT4 in NK cells from LT recipients (p<0.0001). Changes in the expression levels of the transcription factors Helios (p=0.06) and Hobit (p=0.07), which control NKp46 and IFNγ expression, respectively, were also detected. Hypofunctionality of NK cells was associated with impaired STAT4 phosphorylation and downregulation of the STAT4 target microRNA-155. Conversely in HCV-LT NK cell tolerance was reversed, consistent with the more aggressive outcome of LT for HCV. CONCLUSIONS: LT is associated with transcriptional and functional changes in NK cells, resulting in reduced activation. NK cell tolerance occurs upstream of major histocompatibility complex (MHC) class I mediated education, and is associated with deficient STAT4 phosphorylation. STAT4 therefore represents a potential therapeutic target to induce NK cell tolerance in liver disease.This work was supported by grants from the Wellcome Trust to KMJ and SIK (092675/Z/10/Z)

The mosaic of KIR haplotypes in rhesus macaques

To further refine and improve biomedical research in rhesus macaques, it is necessary to increase our knowledge concerning both the degree of allelic variation (polymorphism) and diversity (gene copy number variation) in the killer cell immunoglobulin-like receptor (KIR) gene cluster. Pedigreed animals in particular should be studied, as segregation data will provide clues to the linkage of particular KIR genes/alleles segregating on a haplotype and to its gene content as well. A dual strategy allowed us to screen the presence and absence of genes and the corresponding transcripts, as well as to track differences in transcription levels. On the basis of this approach, 14 diverse KIR haplotypes have been described. These haplotypes consist of multiple inhibitory and activating Mamu-KIR genes, and any gene present on one haplotype may be absent on another. This suggests that the cost of accelerated evolution by recombination may be the loss of certain framework genes on a haplotype

Fine-mapping of genetic loci driving spontaneous clearance of hepatitis C virus infection

Approximately three quarters of acute hepatitis C (HCV) infections evolve to a chronic state, while one quarter are spontaneously cleared. Genetic predispositions strongly contribute to the development of chronicity. We have conducted a genome-wide association study to identify genomic variants underlying HCV spontaneous clearance using ImmunoChip in European and African ancestries. We confrmed two previously reported signifcant associations, in the IL28B/IFNL4 and the major histocompatibility complex (MHC) regions, with spontaneous clearance in the European population. We further fne-mapped the association in the MHC to a region of about 50 kilo base pairs, down from 1 mega base pairs in the previous study. Additional analyses suggested that the association in MHC is stronger in samples from North America than those from Europe

Serum IP-10 Levels Correlate with the Severity of Liver Histopathology in Patients Infected with Genotype-1 HCV

Background/Aims: Interferon-gamma-inducible protein 10 (IP-10) plays important roles in the pathogenesis of hepatitis C virus (HCV) infection. We investigated the association between serum IP-10 levels and liver pathology in patients with chronic HCV infection. Methods: The serum IP-10 concentration was assessed in 85 patients with chronic HCV infection using a solid phase sandwich enzyme-linked immunosorbent assay, and a liver biopsy specimen was obtained. The pathology was scored using the Knodell histologic activity index (HAI). Results: Of the 85 patients, 58 had genotype 1 HCV infection, 21 had genotype non-1, and 6 were undetermined. The serum IP-10 levels did not differ between patients infected with genotype 1 and genotype non-1 (p=0.472). In patients with genotype 1 infection, the total HAI score and the stage of fibrosis were highly correlated with the serum IP-10 level (r=0.555, r=0.578, p<0.001). Furthermore, the serum IP-10 concentrations of patients with severe fibrosis (stages 3, 4) were higher than those of patients with mild fibrosis (stages 0 to 2; 214.4 vs. 72.3 pg/mL, p=0.002) among patients with genotype 1 infection. However, in patients without genotype 1 infection, the histopathology was not associated with the serum IP-10 level. A multivariate analysis showed that serum IP-10 was an independent predictor of fibrosis (stages 3, 4) in patients with genotype 1 infection (odds ratio, 1.034; 95% confidence interval, 1.006 to 1.064; p=0.018). Conclusions: Serum IP-10 concentration was significantly correlated with the severity of liver histology in genotype 1 HCV infection. (Gut Liver 2011;5:506-512)X1116sciescopuskciothe

Association of KIR2DS1 and KIR2DS3 with fatal outcome in Ebola virus infection

Zaïre ebolavirus (ZEBOV) infection rapidly outruns the host's immunity and leads to death within a week. Fatal cases have been associated with an aberrant innate, proinflammatory immune response followed by a suppressed adaptive response leading to the rapid depletion of peripheral NK cells and lymphocytes. A critical role for NK cells has been suggested but not elucidated. In this genetic study, we investigated the association of KIR genotype with disease outcome by comparing genotypes of a Gabonese control population, IgG+ contacts, survivors, and fatalities of ZEBOV infection. We showed that the activating KIR2DS1 and KIR2DS3 genes associate with fatal outcome in Ebola virus infection. In addition, this study brings supplemental evidence in favor of the specificity of the IgG+ contact population. The outcome of fulminating Ebola virus infection could depend in part on the host's inherited KIR gene repertoire. This supports a key role for KIRs in disease susceptibility to infections

Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1

Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection

KIR Polymorphisms Modulate Peptide-Dependent Binding to an MHC Class I Ligand with a Bw6 Motif

Molecular interactions between killer immunoglobulin-like receptors (KIRs) and their MHC class I ligands play a central role in the regulation of natural killer (NK) cell responses to viral pathogens and tumors. Here we identify Mamu-A1*00201 (Mamu-A*02), a common MHC class I molecule in the rhesus macaque with a canonical Bw6 motif, as a ligand for Mamu-KIR3DL05. Mamu-A1*00201 tetramers folded with certain SIV peptides, but not others, directly stained primary NK cells and Jurkat cells expressing multiple allotypes of Mamu-KIR3DL05. Differences in binding avidity were associated with polymorphisms in the D0 and D1 domains of Mamu-KIR3DL05, whereas differences in peptide-selectivity mapped to the D1 domain. The reciprocal exchange of the third predicted MHC class I-contact loop of the D1 domain switched the specificity of two Mamu-KIR3DL05 allotypes for different Mamu-A1*00201-peptide complexes. Consistent with the function of an inhibitory KIR, incubation of lymphocytes from Mamu-KIR3DL05+ macaques with target cells expressing Mamu-A1*00201 suppressed the degranulation of tetramer-positive NK cells. These observations reveal a previously unappreciated role for D1 polymorphisms in determining the selectivity of KIRs for MHC class I-bound peptides, and identify the first functional KIR-MHC class I interaction in the rhesus macaque. The modulation of KIR-MHC class I interactions by viral peptides has important implications to pathogenesis, since it suggests that the immunodeficiency viruses, and potentially other types of viruses and tumors, may acquire changes in epitopes that increase the affinity of certain MHC class I ligands for inhibitory KIRs to prevent the activation of specific NK cell subsets