title: Two distinctly HLA-associated contiguous linear epitopes uniquely expressed within the islet antigen 2 molecule are major autoantibody epitopes of the diabetes-specific tyrosine phosphatase-like protein autoantigens.
abstract: The related tyrosine phosphatase-like proteins islet Ag (IA)-2 and IA-2beta are autoantigens of type 1 diabetes in humans. Autoantibodies are predominantly against IA-2, and IA-2-specific epitopes are major autoantibody targets. We used the close homology of IA-2 and IA-2beta to design chimeras and mutants to identify humoral IA-2-specific epitopes. Two major IA-2 epitopes that are absent from the related autoantigens IA-2beta and IA-2Delta 13 splice variant ICA512.bdc were found contiguous to each other within IA-2 juxtamembrane amino acids 611-620 (epitope JM1) and 621-630 (epitope JM2). JM1 and JM2 are recognized by sera from 67% of patients with IA-2 Abs, and relatives of patients with type 1 diabetes having Abs to either JM epitope had a >50% risk for developing type 1 diabetes within 6 years, even in the absence of diabetes-associated HLA genotypes. Remarkably, the presence of Abs to one of these two epitopes was mutually exclusive of the other; JM2 Abs and not JM1 Abs were found in relatives with HLA DR3/4, DR4/13, or DR1/4 genotypes; and the binding of autoantibodies to the JM2 epitope, but not the JM1 epitope, markedly affected proteolysis of IA-2. This is a unique demonstration of HLA-associated B cell responses to epitopes within a single autoantigen in humans and is consistent with modification of Ag processing by specific Ab-influencing peptide presentation by HLA molecules.
authors.affiliation: Department of Medicine 1 and Medicine Laboratory, Istituto Scientifico San Raffaele, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bearzatto
authors.forename: Heike
authors.initials: H
authors.lastname: Naserke
authors.forename: Sandra
authors.initials: S
authors.lastname: Piquer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Koczwara
authors.forename: Vito
authors.initials: V
authors.lastname: Lampasona
authors.forename: Alistair
authors.initials: A
authors.lastname: Williams
authors.forename: Michael R
authors.initials: MR
authors.lastname: Christie
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.forename: Anette-G
authors.initials: AG
authors.lastname: Ziegler
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
mesh_terms: D000937:Antigen-Antibody Reactions / Q000235:genetics; D001323:Autoantibodies / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D001324:Autoantigens / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D001666:Binding Sites, Antibody / Q000235:genetics; D001667:Binding, Competitive / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D016056:Immunodominant Epitopes / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D007515:Islets of Langerhans / Q000201:enzymology / Q000276:immunology*; D008565:Membrane Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D023302:Protein Footprinting; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000276:immunology / Q000378:metabolism; D012307:Risk Factors; D014357:Trypsin / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D006684:HLA-DR Antigens; D016056:Immunodominant Epitopes; D008565:Membrane Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C516862:PTPRN protein, human; C102889:PTPRN2 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D014357:Trypsin