title: Limited loss of tolerance to islet autoantigens in ICA+ first degree relatives of patients with type I diabetes expressing the HLA dqb1*0602 allele.
abstract: The DQB1*0602 allele confers dominant protection from Type I diabetes even among islet cell antibody positive (ICA+) first degree relatives of affected individuals. Lack of progression to diabetes in these subjects, despite ICA positivity, could be explained by a loss of tolerance limited to fewer islet autoantigens than in ICA+ relatives progressing to the disease. To test this hypothesis we have determined autoantibodies by radioassay to three islet autoantigens, glutamic acid decarboxylase (GAD), insulin and the novel neuroendocrine antigen ICA512/IA-2 in 84 HLA-typed ICA+ first degree relatives of patients with Type I diabetes. Among the eleven relatives expressing the 0602 allele (0602+) only two were positive for more than one antibody as determined by radioassay. In contrast, 55/73 ICA+ relatives lacking this allele (non-0602) expressed more than one autoantibody (P < 0.01). The prevalence of antibodies to GAD (GAA) was not significantly different in ICA+ relatives with and without the 0602 allele (7/11 in 0602+ versus 60/73 in non-0602). In contrast, anti-insulin antibodies (IAA) were present in only 2/11 0602+ ICA+ relatives versus 47/70 in non-0602 ICA+ relatives (P < 0.01). Similarly, only one individual carrying the 0602 allele was positive for ICA512 autoantibodies versus 33/70 in the non-0602 group (P < 0.01). These data indicate that even among ICA+ relatives the 0602 allele is associated with a limited immune response to islet antigens and amongst 0602+ relatives this response is mostly directed against GAD.
authors.affiliation: Department of Neuropharmacology, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gianani
authors.forename: C F
authors.initials: CF
authors.lastname: Verge
authors.forename: R I
authors.initials: RI
authors.lastname: Moromisato-Gianani
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.forename: Y J
authors.initials: YJ
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Pugliese
authors.forename: G S
authors.initials: GS
authors.lastname: Eisenbarth
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005192:Family Health; D005968:Glutamate Decarboxylase / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics*; D006801:Humans; D007108:Immune Tolerance; D007328:Insulin / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D008875:Middle Aged; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000276:immunology; D011863:Radioimmunoassay
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D006683:HLA-DQ Antigens; D007328:Insulin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D005968:Glutamate Decarboxylase