title: Predominantly recognized proinsulin T helper cell epitopes in individuals with and without islet cell autoimmunity.
abstract: Antibody response to insulin and to its precursor ProInsulin is associated with increased risk for type 1 diabetes (T1D), though little is known about T cell reactivity to this molecule. In the present study from peripheral blood mononuclear cells (PBMC), in vivo primed CD45RO+ memory T helper (Th) cells were enriched and their reactivity to eight overlapping ProInsulin peptides and to protein was analyzed. Individuals with high risk HLA-DRB1*04, DQB1*0302 alleles were investigated: relatives of patients with T1D having humoral markers of islet cell autoimmunity (autoantibody positive, Ab+; n=11), patients with T1D (n=8), and healthy control individuals (n=16). The ProInsulin epitope which was most frequently recognized in all the tested individuals was C-peptide (C) 18-A-chain (A)1. In Ab+ relatives the responses to this epitope and to two additional parts of the ProInsulin, B-chain (B) 11-C24 and C28-A21, was observed. In T1D patients who have already been treated with insulin, response to peptide B20-C4 and to the entire insulin molecule predominates. Our findings suggest that the spontaneous memory Th cell response to ProInsulin in individuals with high risk HLA alleles is predominantly directed to one epitope which maps to the central, C-peptide region. In individuals with humoral markers of islet cell autoimmunity and in patients with T1D, spread response to distinct ProInsulin regions was observed.
authors.affiliation: Diabetes Research Institute of the Academic Hospital München-Schwabing, Koelner Platz 1, 80804 Munich, Germany. ivana.durinovic-bello@medizin.uni-ulm.de
authors.forename: Ivana
authors.initials: I
authors.lastname: Durinovic-Belló
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: Anette-G
authors.initials: AG
authors.lastname: Ziegler
mesh_terms: D000293:Adolescent; D000328:Adult; D000918:Antibody Specificity; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D006684:HLA-DR Antigens / Q000276:immunology; D059811:HLA-DRB1 Chains; D006239:Haplotypes / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007223:Infant; D007515:Islets of Langerhans / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000276:immunology; D008137:Longitudinal Studies; D008213:Lymphocyte Activation / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011384:Proinsulin / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D012307:Risk Factors; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010446:Peptide Fragments; C024211:islet cell antibody; D011384:Proinsulin; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1