Identification of peptides from autoantigens GAD65 and IA-2 that bind to HLA class II molecules predisposing to or protecting from type 1 diabetes.
Diabetes
; 48(10): 1937-47, 1999 Oct.
Article
em En
| MEDLINE
| ID: mdl-10512357
ABSTRACT
Type 1 diabetes is a T-cell-mediated disease in which presentation of autoantigens to CD4+ T-cells is thought to play a crucial role. Polymorphism of HLA class II genes accounts for 50% of the genetic risk of contracting type 1 diabetes. HLA-DQ and -DR molecules predisposing to or protecting from type 1 diabetes have been identified, but the molecular basis controlling these associations is as yet undefined. Apart from distinct thymic selection of autoreactive T-cells by susceptible and protective HLA molecules, exclusive presentation of autoantigenic peptides by type 1 diabetes-predisposing HLA molecules or, alternatively, induction of regulatory T-cells by protective alleles are potential mechanisms for modification of type 1 diabetes risk by HLA polymorphism. As a first step in exploring the role of HLA molecules in autoantigen-specific cellular responses in type 1 diabetes, we have screened peptides covering the sequence of two major autoantigens targeted by humoral and cellular immune responses, GAD65 and islet associated-2 (IA-2), for binding to class II molecules. We developed a sensitive novel competition binding assay allowing us to measure peptide binding on intact cells to 10 HLA-DR and 4 HLA-DQ molecules. For all tested alleles, multiple peptides binding with high affinity were identified. We report clustering of binding peptides in the COOH-terminal regions of GAD65 and IA-2, as well as highly promiscuous binding patterns of some peptides. Our results demonstrate that most peptides derived from the GAD and IA-2 autoantigens can bind to both type 1 diabetes-predisposing and type 1 diabetes-protective HLA molecules, although some exceptions were observed. The binding inventory presented here for GAD and IA-2 peptides can be useful for mapping natural epitopes and predicting peptide-specific responses induced by preventive immunization.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antígenos de Histocompatibilidade Classe II
/
Proteínas Tirosina Fosfatases
/
Diabetes Mellitus Tipo 1
/
Glutamato Descarboxilase
/
Proteínas de Membrana
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Diabetes
Ano de publicação:
1999
Tipo de documento:
Article
País de afiliação:
França