The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

Diversity within the innate and adaptive immune response to hepatitis C is important in determining spontaneous resolution (SR) and treatment response. The aim of this study was to analyze how these variables interact in combination; furthering our understanding of the mechanisms that drive successful immunological clearance. Multivariate analysis was performed on retrospectively collected data for 357 patients previously genotyped for interferon (IFN)-?3/4, killer cell immunoglobulin (KIR), human leukocyte antigen (HLA) class I and II and tapasin. High resolution KIR genotyping was performed for individuals with chronic infection and haplotypes determined. Outcomes for SR, IFN response and cirrhosis were examined. Statistical analysis included univariate methods, ?2 test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA-C1C1 (P = 0.027), IFN-?3/4 rs12979860 CC (P = 0.027), tapasin G in individuals with aspartate at residue 114 of HLA-B (TapG:HLA-B114D) (P = 0.007) and HLA-DRB1*04:01 (P = 0.014) were associated with SR with a strong additive influence (?2 test for trend P < 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN-?3/4 rs12979860 CC was protective in hepatitis C virus (HCV) G1 infection and KIR2DL3:HLA-C1 in HCV G2/3. In common with SR, variables did not interact synergistically. Polymorphisms predictive of viral clearance did not predict disease progression. In summary, different individuals resolve HCV infection using discrete and non-interacting immunological pathways. These pathways are influenced by viral genotype. This work provides novel insights into the complexity of the interaction between host and viral factors in determining the outcome of HCV infection

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&lt;0.05) and NKp30 (p&lt;0.001), reduced cytotoxicity (p&lt;0.001) and interferon (IFN)-? secretion (p&lt;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&lt;0.0001). Changes in the expression levels of the transcription factors Helios (p=0.06) and Hobit (p=0.07), which control NKp46 and IFN? 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.<br/

Epistasis associated to inflammatory bowel disease (IBD) in humans

Gene-gene interactions underlie biochemical pathways and have been well demonstrated in model organisms. Very few examples exist on replicated epistasis in humans. Here, we performed genome-wide scans to detect epistasis associated to Crohn’s disease (CD) and ulcerative colitis (UC). We used extensive data of the IIBDGC consisting of 18277 and 14224 CD and UC patients, respectively, and ~34050 healthy controls from 15 European countries typed on the Immunochip. At first, we removed rare variants at MAF0.75. To limit our results to independent effects, SNPs on chromosome 6 (which contains the HLA locus), were furthermore pruned to ensure an LD of r2<0.35. We adjusted the binary traits, CD and UC, for population stratification by regressing out the first 5 principal components in R-3.0.1. The study cohorts were randomly stratified into two subgroups (referred as discovery and replication). We then performed screenings for epistatic interactions with new adjusted trait values in the two subgroups using multidimensional reduction tool MB-MDR with permutation-based (step-down MaxT) multiple testing correction and significance assessment at 0.05. We identified 14 and 6 SNP-pairs associated to CD and UC, respectively, which were concordant between the discovery and replication groups. All SNP-pairs involved concomitant variants located on the same chromosomes (for CD at 1p31.3, 5p13.1, 16q12.1 and for UC at 1p31.3, 6p21.3). A more detailed investigation of these findings, as well as the implementation of different analysis protocols, will further increase our understanding of possible epistatic mechanisms underpinning IBD

KILLER IMMUNOGLOBULIN-LIKE RECEPTOR (KIR)-LIGAND MISMATCHES DO NOT AFFECT THE DURATION OF PERIPHERAL BLOOD DONOR CD4 T CELL CHIMERISM FOLLOWING LUNG TRANSPLANTATION

Transplantation and autoimmunit