title: Association between IA-2 autoantibody epitope specificities and age of onset in Japanese patients with autoimmune diabetes.
abstract: The IA-2 is a major autoantigen of type 1 diabetes belonging to the protein tyrosine phosphatase family. We report on the humoral autoimmunity to an alternatively-spliced variant of IA-2 (IA-2 variant) and autoimmune-mediated diabetes age of onset association with IA-2 autoantibody epitope specificities, in 144 recent-onset patients with type 1 diabetes and 54 GAD autoantibody-positive patients with type 2 diabetes. The cytoplasmic domain of IA-2 (IA-2ic) detected a somewhat greater proportion of patients expressing autoantibodies than IA-2 variant (56%vs. 52% of patients with type 1 diabetes and 17%vs. 9% of GAD autoantibody-positive patients with type 2 diabetes). Conversely, only 1% of IA-2 variant autoantibody-positive patients failed to react to IA-2ic construct. Among 80 patients with type 1 diabetes who were positive for autoantibodies to IA-2ic, 8% recognized the juxtamembrane region (JM, representing amino acids 601-629) only, 64% bound the protein tyrosine phosphatase (PTP)-like domain of IA-2 only, and 29% bound both JM and PTP epitopes. Autoantibodies to the PTP-like domain were prevalent in children and adolescents with type 1 diabetes. The age of disease onset in patients with IA-2JM autoantibodies only, was significantly higher than those in patients reacted with the PTP-like domain of IA-2 (P< 0.02). Among GAD autoantibody-positive patients with type 2 diabetes reacted with IA-2ic, 44% bound the JM region only, and 33% bound epitopes in the PTP-like domain only; 22% had autoantibodies to both regions. The frequency of GAD autoantibody-positive patients with type 2 diabetes positive for autoantibodies to the JM region only, was significantly higher than that in patients with type 1 diabetes (P< 0.01). IA-2PTP autoantibodies were significantly associated with HLA-DR4, while the additional reactivity to IA-2JM was associated with HLA-DR9 allele. These results suggest that autoantibody recognition of IA-2 epitopes in autoimmune diabetes is associated with age of disease onset, which may reflect the intensity of the beta-cell destruction process.
authors.affiliation: The First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, 852-8501, Japan. f1196@cc.nagasaki-u.ac.jp
authors.forename: E
authors.initials: E
authors.lastname: Kawasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Sera
authors.forename: N
authors.initials: N
authors.lastname: Fujita
authors.forename: M
authors.initials: M
authors.lastname: Yamauchi
authors.forename: M
authors.initials: M
authors.lastname: Ozaki
authors.forename: T
authors.initials: T
authors.lastname: Abe
authors.forename: K
authors.initials: K
authors.lastname: Yamakawa
authors.forename: S
authors.initials: S
authors.lastname: Uotani
authors.forename: H
authors.initials: H
authors.lastname: Takino
authors.forename: H
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Uchigata
authors.forename: N
authors.initials: N
authors.lastname: Matsuura
authors.forename: K
authors.initials: K
authors.lastname: Eguchi
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000918:Antibody Specificity / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000276:immunology* / Q000503:physiopathology; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged
chemical_list: D001323:Autoantibodies; D000939:Epitopes; C096322:ICA512 autoantibody