title: Autoimmune responses to the beta cell autoantigen, insulin, and the INS VNTR-IDDM2 locus.
abstract: Type 1 diabetes is associated with autoimmunity to insulin. Genetic susceptibility to type 1 diabetes is polygenic and includes the INS VNTR-IDDM2 locus which may regulate the expression of insulin in pancreas and thymus. In order to determine whether insulin autoimmunity could be attributed to a genetic susceptibility conferred by the INS VNTR-IDDM2 locus, peripheral blood T cell proliferation to human insulin and insulin autoantibodies (IAA) was measured in patients with new onset type 1 diabetes and control subjects. IAA were detected in 21 of 53 patients and in none of 25 control subjects, while T cell responses were low (stimulation index range 0.4-7.2) and similar in both groups. Both antibody and T cell responses were higher in younger subjects and IAA were more prevalent in patients with the HLA-DR4 allele. No relationship was observed between humoral and cellular responses to insulin. No association was found between the INS VNTR-IDDM2-susceptible allele and insulin autoimmunity. Increased T cell responses and IAA were found in patients with either the diabetes-susceptible or the diabetes-protective INS VNTR-IDDM2 locus genotypes, and increased T cell responses were also found in control subjects with either susceptible or protective INS VNTR-IDDM2 locus genotypes. This study confirms that primary T cell proliferative responses to insulin are low and detectable also in control subjects. The detection of T cell proliferation and autoantibodies to insulin in subjects with and without the protective INS VNTR-IDDM2 locus genotypes does not support the hypothesis of an allele-specific capacity for tolerance induction which could determine a susceptibility to develop autoimmunity against the insulin protein and subsequently diabetes.
authors.affiliation: Departments of Internal Medicine, Instituto Scientifico San Raffaele, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Sarugeri
authors.forename: N
authors.initials: N
authors.lastname: Dozio
authors.forename: C
authors.initials: C
authors.lastname: Belloni
authors.forename: F
authors.initials: F
authors.lastname: Meschi
authors.forename: M R
authors.initials: MR
authors.lastname: Pastore
authors.forename: E
authors.initials: E
authors.lastname: Bonifacio
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000917:Antibody Formation / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007223:Infant; D007328:Insulin / Q000235:genetics / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats
chemical_list: D001324:Autoantigens; D015803:HLA-DR3 Antigen; D015804:HLA-DR4 Antigen; D007328:Insulin