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Humoral responses to islet antigen-2 and zinc transporter 8 are attenuated in patients carrying HLA-A*24 alleles at the onset of type 1 diabetes.

ABSTRACT: The HLA-A*24 allele has shown negative associations with autoantibodies to islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) in patients with established type 1 diabetes. Understanding how this HLA class I allele affects humoral islet autoimmunity gives new insights into disease pathogenesis. We therefore investigated the epitope specificity of associations between HLA-A*24 and islet autoantibodies at disease onset. HLA-A*24 genotype and autoantibody responses to insulin (IAA), glutamate decarboxylase (GADA), IA-2, IA-2?, and ZnT8 were analyzed in samples collected from patients with recent-onset type 1 diabetes. After correction for age, sex, and HLA class II genotype, HLA-A*24 was shown to be a negative determinant of IA-2A and ZnT8A. These effects were epitope specific. Antibodies targeting the protein tyrosine phosphatase domains of IA-2 and IA-2?, but not the IA-2 juxtamembrane region, were less common in patients carrying HLA-A*24 alleles. The prevalence of ZnT8A specific or cross-reactive with the ZnT8 tryptophan-325 polymorphic residue, but not those specific to arginine-325, was reduced in HLA-A*24-positive patients. No associations were found between HLA-A*24 and IAA or GADA. Association of an HLA class I susceptibility allele with altered islet autoantibody phenotype at diagnosis suggests CD8 T-cell and/or natural killer cell-mediated killing modulates humoral autoimmune responses.

SUBMITTER: Long AE

PROVIDER: S-EPMC3661608 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Humoral responses to islet antigen-2 and zinc transporter 8 are attenuated in patients carrying HLA-A*24 alleles at the onset of type 1 diabetes.

Long Anna E AE Gillespie Kathleen M KM Aitken Rachel J RJ Goode Julia C JC Bingley Polly J PJ Williams Alistair J K AJ

Diabetes 20130208 6

The HLA-A*24 allele has shown negative associations with autoantibodies to islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) in patients with established type 1 diabetes. Understanding how this HLA class I allele affects humoral islet autoimmunity gives new insights into disease pathogenesis. We therefore investigated the epitope specificity of associations between HLA-A*24 and islet autoantibodies at disease onset. HLA-A*24 genotype and autoantibody responses to insulin (IAA), glutamate deca ...[more]

PMID: 23396399

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Project description:BackgroundDengue virus (DV) infection is one of the most important mosquito-borne diseases in the tropics. Recently, the severe forms, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), have become the leading cause of death among children in Southern Vietnam. Protective and/or pathogenic T cell immunity is supposed to be important in the pathogenesis of DHF and DSS.Methodology/principal findingsTo identify HLA alleles controlling T cell immunity against dengue virus (DV), we performed a hospital-based case control study at Children's Hospital No.2, Ho Chi Minh City (HCMC), and Vinh Long Province Hospital (VL) in Southern Vietnam from 2002 to 2005. A total of 211 and 418 patients with DHF and DSS, respectively, diagnosed according to the World Health Organization (WHO) criteria, were analyzed for their characteristic HLA-A, -B and -DRB1 alleles. Four hundred fifty healthy children (250 from HCMC and 200 from VL) of the same Kinh ethnicity were also analyzed as population background. In HLA class I, frequency of the HLA-A*24 showed increased tendency in both DHF and DSS patients, which reproduced a previous study. The frequency of A*24 with histidine at codon 70 (A*2402/03/10), based on main anchor binding site specificity analysis in DSS and DHF patients, was significantly higher than that in the population background groups (HCMC 02-03 DSS: OR = 1.89, P = 0.008, DHF: OR = 1.75, P = 0.033; VL 02-03 DSS: OR = 1.70, P = 0.03, DHF: OR = 1.46, P = 0.38; VL 04-05 DSS: OR = 2.09, P = 0.0075, DHF: OR = 2.02, P = 0.038). In HLA class II, the HLA-DRB1*0901 frequency was significantly decreased in secondary infection of DSS in VL 04-05 (OR = 0.35, P = 0.0025, Pc = 0.03). Moreover, the frequency of HLA-DRB1*0901 in particular was significantly decreased in DSS when compared with DHF in DEN-2 infection (P = 0.02).ConclusionThis study improves our understanding of the risk of HLA-class I for severe outcome of DV infection in the light of peptide anchor binding site and provides novel evidence that HLA-class II may control disease severity (DHF to DSS) in DV infection.

Project description:IntroductionThe human leukocyte antigen (HLA) region on chromosome 6p21 is well known to carry the most important genetic factors in susceptibility to psoriasis. Different HLA alleles and haplotypes have been reported to be associated with psoriasis in different populations. Psoriasis has a variable age of onset and, based on this, it can be classified into two types; type I with age of onset before 40 years of age and type II with age of onset after 40 years of age. The objective of this study was to determine the association of HLA class I and class II alleles and haplotypes with disease and stratification using age of onset in Pakistani psoriatic patients.MethodsA group of 603 individuals (326 cases and 277 controls) were analyzed for HLA class I and II alleles and haplotype association by sequence specific PCR. The association was further analyzed according to the age of onset of the patients.ResultsWe found that HLA alleles B*57 and Cw*06:02, DQB1*03:03:02 are strongly associated with early onset psoriasis, while alleles B*15, DRB1*13:02 and DQB1*03:03:02 are associated with late-onset psoriasis. Cw*06:02 allele was not associated with late-onset psoriasis patients. Allele DQB1*03:03:02 had the highest odds ratio in all patients. We found a novel association specifically with late-onset psoriasis samples with the haplotype HLA-A*11; B*15; Cw*04; DRB1*15; DQB1*05 (Pc = 3.60 × 10-7). We also found strong association with previously reported extended haplotype EH-57.1: HLA-B*57; Cw*06:02; DRB1*07:01; DQB1*03:03:02 in all our patients (Pc = 8.34 × 10-07).ConclusionOur results show that different HLA class I and II alleles and haplotypes are associated with psoriasis at different age of onset. In this study, we have reported novel alleles and haplotype association with late-onset psoriasis. Our data confirm the previous strong associations with HLA alleles and haplotypes and also reports novel alleles and haplotype association in Pakistani psoriasis patients.

Dataset Information

Humoral responses to islet antigen-2 and zinc transporter 8 are attenuated in patients carrying HLA-A*24 alleles at the onset of type 1 diabetes.

Publications

Humoral responses to islet antigen-2 and zinc transporter 8 are attenuated in patients carrying HLA-A*24 alleles at the onset of type 1 diabetes.

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