title: 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-2β, 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-2β, 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.
authors: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors: Anna E
authors: AE
authors: Long
authors: Kathleen M
authors: KM
authors: Gillespie
authors: Rachel J
authors: RJ
authors: Aitken
authors: Julia C
authors: JC
authors: Goode
authors: Polly J
authors: PJ
authors: Bingley
authors: Alistair J K
authors: AJ
authors: Williams
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D027682:Cation Transport Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics* / Q000502:physiology; D007223:Infant; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000235:genetics*; D055815:Young Adult; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; D015234:HLA-A Antigens; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8
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