High-Density SNP Mapping of the HLA Region Identifies Multiple Independent Susceptibility Loci Associated with Selective IgA Deficiency

Selective IgA deficiency (IgAD; serum IgA<0.07 g/l) is the most common form of human primary immune deficiency, affecting approximately 1∶600 individuals in populations of Northern European ancestry. The polygenic nature of IgAD is underscored by the recent identification of several new risk genes in a genome-wide association study. Among the characterized susceptibility loci, the association with specific HLA haplotypes represents the major genetic risk factor for IgAD. Despite the robust association, the nature and location of the causal variants in the HLA region remains unknown. To better characterize the association signal in this region, we performed a high-density SNP mapping of the HLA locus and imputed the genotypes of common HLA-B, -DRB1, and -DQB1 alleles in a combined sample of 772 IgAD patients and 1,976 matched controls from 3 independent European populations. We confirmed the complex nature of the association with the HLA locus, which is the result of multiple effects spanning the entire HLA region. The primary association signal mapped to the HLA-DQB1*02 allele in the HLA Class II region (combined P = 7.69×10−57; OR = 2.80) resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*02 and -DRB1*0701-DQB1*02 haplotypes, while additional secondary signals were associated with the DRB1*0102 (combined P = 5.86×10−17; OR = 4.28) and the DRB1*1501 (combined P = 2.24×10−35; OR = 0.13) alleles. Despite the strong population-specific frequencies of HLA alleles, we found a remarkable conservation of these effects regardless of the ethnic background, which supports the use of large multi-ethnic populations to characterize shared genetic association signals in the HLA region. We also provide evidence for the location of association signals within the specific extended haplotypes, which will guide future sequencing studies aimed at characterizing the precise functional variants contributing to disease pathogenesis

Anti-CD28-induced co-stimulation and TCR avidity regulates the differential effect of TGF-beta1 on CD4+ and CD8+ naïve human T-cells

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldTGF-beta1 is a powerful regulator of various T-cell functions. However, it has been unclear how the T-cell responsiveness towards TGF-beta1 is affected by its phenotype or signaling intensity. In the present study, we demonstrate that the phenotype and the TCR-signaling intensity of the responding T-cell as well as the presence of anti-CD28 co-stimulation markedly affects how naïve human cord blood T-cells respond to TGF-beta1. In this report we demonstrate that the strength of the stimulatory signal modifies the T-cell response towards TGF-beta1. Thus, the greatest anti-proliferative effect of TGF-beta1 was observed during weak stimulatory conditions (low dose of anti-CD3 with no co-stimulatory signal). However, such anti-proliferative effect was reduced during strong stimulatory signal (high dose of anti-CD3 with a CD28-directed co-stimulatory signal). In addition, our results indicate that CD8+ T-cells are generally more responsive towards TGF-beta1 than CD4+ T-cells. To our surprise, naïve T-cells had a skewed Th1/Tc1 cytokine secretion pattern with high amounts of IL-2, IFNgamma and TNFalpha, but low amounts of IL-4, IL-5 and IL-10. TGFbeta1 significantly reduced the secretion of IL-2 and IFNgamma, but such suppression was partially prevented by anti-CD28-induced co-stimulation. In contrast, the inhibitory effect on IL-5 secretion was unaffected by anti-CD28 co-stimulation. Interestingly, TGF-beta1 induced IL-10 and TNFalpha secretion. However, the induction of IL-10 secretion was reduced during optimal stimulatory conditions while TGF-beta1 further induced TNFalpha secretion. These data demonstrate that the duration, intensity and type of signaling alters the sensitivity of T-cells to powerful immunological modifying agents like TGF-beta1

Wally and the Major [picture] : joy-ride /

Part of the Stan Cross Archive of cartoons and drawings, 1912-1974.; Inscription: "Stan Cross 2/57"--In ink, lower right. "6742 Thur Mar 8"--In ink, right margin; "6742"--In pencil, upper right corner; "Joy-Ride"--In pencil, upper margin.; Also available in an electronic version via the internet at: http://nla.gov.au/nla.pic-vn4303561

The epidemiology and natural history of primary biliary cirrhosis: a nationwide population-based study.

Very few population-based studies exist on the epidemiology of primary biliary cirrhosis (PBC), and none have been conducted in the last decade. We aimed to determine the epidemiology and prognosis of PBC over the past two decades. Patients were identified by multiple case finding strategies, covering the total population of Iceland. A search was conducted in the centralized database of antimitochondrial antibody (AMA) measurements and computerized diagnosis and pathological registries. All AMA measurements taken in Iceland between 1991 and 2010 were analyzed. Relevant clinical information was gathered from medical records, pathology reports, and death certificates. Incidence was compared between two periods, 1991-2000 versus 2001-2010. A total of 168 patients were identified, of which 138 were female (82%), with a median age 62 years (range 13-92). Prevalence at the end of the study period was 38.3 cases per 100 000 person-years. Age-standardized incidence for female patients during the first period was 3.4 versus 4.1 during the second (NS) and that for male patients was 0.6 during the first period versus 1.0 per 100 000 during the second (NS). Overall incidence in the first period was 2.0 and that in the second was 2.5 per 100 000 (NS). Stage III-IV liver fibrosis was present in 28% of patients at diagnosis with no significant differences between the two decades. Median survival after diagnosis was 15 years. Five patients underwent liver transplantation. The incidence and prevalence figures of PBC in Iceland are among the highest reported and have been stable over the last two decades. The prognosis of patients in this population-based cohort is better than that previously reported

Resolution of Th/Tc17‐driven inflammation during anti‐TNFα treatment of rheumatoid arthritis reveals a unique immune biomarker profiling pattern

To access publisher's full text version of this article click on the hyperlink belowRheumatoid arthritis (RA) is a chronic multisystem disease with a complex immunopathology. Its inflammatory state is dominated by pro-inflammatory cytokines such as TNF alpha and activated Th1/Th17. Only proportion of patients achieve clinical remission despite potent biologics targeting these pathways. This study investigated the resolution of inflammation in RA patients (naive for biologics) receiving TNF alpha inhibitors (TNFi) and evaluated the biological mechanisms behind treatment response and assessed them using clinical scoring systems. The majority showed a good clinical response after six months (6M) and a significant drop in DAS28-CRP (P = 90%. Thus, the immunological complexity in RA is driven by a complex interplay of pro-inflammatory cytokines and effector T-cell response dominated by Th17/Tc17. In addition, the resolution of inflammation could be linked to a partially Treg-driven homeostatic innate immune response. Therefore, a more complex therapeutic approach against the above markers might be of value to obtain full clinical remission in the future.Celltrion Healthcar

Secondary association signals in the HLA locus.

<p>Combined <i>P</i> values are shown for all SNPs and imputed HLA alleles, following conditioning on the HLA-B*0801-DRB1*0301-DQB1*02 (red diamonds), the HLA-B*0801-DRB1*0301-DQB1*02+HLA-DRB1*0701-DQB1*02 (yellow triangles) and the HLA-B*0801-DRB1*0301-DQB1*02+HLA-DRB1*0701-DQB1*02+HLA-DRB1*0102 (green circles) haplotypes. All association results are represented as the −log₁₀ of the combined <i>P</i> values (left y-axis). The most associated SNP and HLA allele in each step of the stepwise conditional logistic regression analysis are indicated by squares. Recombination rates from the HapMap CEU are depicted in blue (right y-axis). Genomic positions on the x-axis are based on the NCBI Build 36 (hg 18) assembly. Mb, megabase pairs.</p

Representation of the haplotypes carrying the <i>HLA-DRB1</i> alleles most associated with IgAD.

<p>Reconstructed extended haplotypes using the final set of 49 SNPs spanning the classical HLA region were aligned to the respective extended haplotype. Shown here are the reconstructed haplotypes carrying the HLA-DRB1*03 (a), -DRB1*07 (b), -DRB1*0102 (c) and -DRB1*15 (d) alleles. Recombinant haplotypes represent all haplotypes containing the same <i>HLA-DRB1</i> allele in association with a different <i>HLA-B</i> allele, as compared to the respective extended haplotype. Vertical bars delimit the HLA Class III region. N, Number of haplotypes. Haplotype frequencies in the Swedish/Icelandic, Spanish and Icelandic cohorts are detailed in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002476#pgen-1002476-t001" target="_blank">Table 1</a>.</p

Primary association signal of the HLA locus with IgAD.

<p>Allele-based association tests were performed for all 1,686 genotyped SNPs and imputed HLA alleles (represented by yellow diamonds) and for the 9,905 SNPs imputed with high confidence using the HapMap2 reference set (represented by light blue circles). All association results are represented as the −log₁₀ of the combined <i>P</i> values (left y-axis). The most associated SNP and HLA allele are indicated by yellow squares. Recombination rates from the HapMap CEU are depicted in dark blue (right y-axis). Genomic positions on the x-axis are based on the NCBI Build 36 (hg 18) assembly. CI, confidence interval; Mb, megabase pairs.</p