title: Early development and spreading of autoantibodies to epitopes of IA-2 and their association with progression to type 1 diabetes.
abstract: Autoimmunity precedes clinical type 1 diabetes, and indicators of maturing autoimmune responses may be useful markers for disease prediction. To study this, epitope maturation of autoantibodies to the related protein tyrosine phosphatase (PTP)-like autoantigens IA-2 and IA-2beta was examined in sequential samples from birth in a cohort of 21 offspring developing multiple islet autoantibodies and a similar cohort of 48 relatives of patients with type 1 diabetes recruited at an older age. Initial reactivity in offspring was heterogeneous against the IA-2 juxtamembrane region (10/21) and PTP domains (13/21), and both specificity and extent of initial IA-2/IA-2beta autoantibodies were associated with HLA class II genotype. Intra-IA-2 epitope spreading and/or intermolecular spreading to IA-2beta epitopes were observed in seven offspring. In contrast, in older relatives, IA-2/IA-2beta Ab reactivity was stable and spreading rare. Development of diabetes in children was associated with the presence of Abs to the IA-2 juxtamembrane region (risk by age 5 yr, 52% vs 0% in those with PTP domain Abs only; p < 0.02), and 5 of 26 relatives who developed diabetes had IA-2 Abs only against the juxtamembrane region. The findings show that autoantibody reactivity to IA-2/IA-2beta is dynamic in the young, show that the juxtamembrane region of IA-2 is an early IA-2 autoantibody target, and suggest that these Abs are a risk factor for development of type 1 diabetes in infancy.
authors.affiliation: Diabetes Research Institute and 3rd Medical Department, Hospital München-Schwabing, Munich, Germany.
authors.forename: H E
authors.initials: HE
authors.lastname: Naserke
authors.forename: A G
authors.initials: AG
authors.lastname: Ziegler
authors.forename: V
authors.initials: V
authors.lastname: Lampasona
authors.forename: E
authors.initials: E
authors.lastname: Bonifacio
mesh_terms: D000328:Adult; D017668:Age of Onset; D001323:Autoantibodies / Q000032:analysis / Q000096:biosynthesis*; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D001327:Autoimmune Diseases / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D018450:Disease Progression; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005192:Family Health; D020022:Genetic Predisposition to Disease; D005858:Germany / Q000453:epidemiology; D006681:HLA-D Antigens / Q000276:immunology; D006801:Humans; D007223:Infant; D007515:Islets of Langerhans / Q000201:enzymology / Q000276:immunology*; D008565:Membrane Proteins / Q000737:chemistry / Q000276:immunology*; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology*; D011446:Prospective Studies; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000276:immunology*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D006681:HLA-D Antigens; C096322:ICA512 autoantibody; D008565:Membrane Proteins; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8