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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Antigen-Antibody Reactions / genetics
-
Autoantibodies / analysis*
-
Autoantibodies / biosynthesis
-
Autoantibodies / genetics
-
Autoantigens / analysis*
-
Autoantigens / genetics
-
Autoantigens / immunology
-
Binding Sites, Antibody / genetics
-
Binding, Competitive / genetics
-
Binding, Competitive / immunology
-
Diabetes Mellitus, Type 1 / genetics
-
Diabetes Mellitus, Type 1 / immunology*
-
HLA-DR Antigens / genetics
-
HLA-DR Antigens / metabolism*
-
Humans
-
Hydrolysis
-
Immunodominant Epitopes / analysis*
-
Immunodominant Epitopes / biosynthesis
-
Immunodominant Epitopes / genetics
-
Islets of Langerhans / enzymology
-
Islets of Langerhans / immunology*
-
Membrane Proteins / analysis*
-
Membrane Proteins / biosynthesis
-
Membrane Proteins / genetics
-
Peptide Fragments / immunology
-
Peptide Fragments / metabolism
-
Protein Footprinting
-
Protein Tyrosine Phosphatase, Non-Receptor Type 1
-
Protein Tyrosine Phosphatases / analysis*
-
Protein Tyrosine Phosphatases / biosynthesis
-
Protein Tyrosine Phosphatases / genetics
-
Receptor-Like Protein Tyrosine Phosphatases, Class 8
-
Recombinant Fusion Proteins / chemical synthesis
-
Recombinant Fusion Proteins / immunology
-
Recombinant Fusion Proteins / metabolism
-
Risk Factors
-
Trypsin / metabolism
Substances
-
Autoantibodies
-
Autoantigens
-
HLA-DR Antigens
-
Immunodominant Epitopes
-
Membrane Proteins
-
Peptide Fragments
-
Recombinant Fusion Proteins
-
PTPRN protein, human
-
PTPRN2 protein, human
-
Protein Tyrosine Phosphatase, Non-Receptor Type 1
-
Protein Tyrosine Phosphatases
-
Receptor-Like Protein Tyrosine Phosphatases, Class 8
-
Trypsin