Novel minor HLA DR associated antigens in type 1 diabetes.

Type 1 diabetes is an autoimmune disease leading to insulin deficiency. Autoantibodies to beta cell proteins are already present in the asymptomatic phase of type 1 diabetes. Recent findings have suggested a number of additional minor autoantigens in patients with type 1 diabetes. We have established luciferase immunoprecipitation systems (LIPS) for anti-MTIF3, anti-PPIL2, anti-NUP50 and anti-MLH1 and analyzed samples from 500 patients with type 1 diabetes at onset of clinical disease and 200 healthy individuals who had a family history of type 1 diabetes but no evidence of beta cell autoantibodies. We show significantly higher frequencies of anti-MTIF3, anti-PPIL2 and anti-MLH1 in recent onset type 1 diabetes patients in comparison to controls. In addition, antibodies to NUP50 were associated with HLA-DRB1*03 and antibodies to MLH1 were associated with HLA-DRB1*04 genotypes.

Tetraspanin 7 autoantibodies in type 1 diabetes.

AIMS/HYPOTHESIS: Autoantibodies to pancreatic beta cell proteins are markers of asymptomatic type 1 diabetes. The aim was to determine whether autoantibodies to the beta cell protein tetraspanin 7 would improve the ability to identify autoimmunity against pancreatic beta cells. METHODS: Full length and external domain fragments of tetraspanin 7 were expressed as luciferase-tagged fusion proteins and used in immunoprecipitation assays to measure autoantibodies in samples from 363 patients with type 1 diabetes at onset of disease, 503 beta cell autoantibody negative first-degree relatives of patients, and 212 relatives with autoantibodies to insulin, glutamic acid decarboxylase, insulinoma antigen 2 or zinc transporter 8. RESULTS: Antibody binding was observed against the full length and external domains of tetraspanin 7, and was strongest against the full length protein. Autoantibodies that could be inhibited by untagged tetraspanin 7 were detected in 5 (1%) of 503 autoantibody negative relatives, 3 (3.2%) of 94 autoantibody negative patients, 95 (35.3%) of 269 autoantibody positive patients, 1 (1%) of 98 single autoantibody positive relatives and 25 (21.9%) of 114 multiple autoantibody positive relatives. Progression to diabetes did not differ between multiple autoantibody positive relatives with and without tetraspanin 7 autoantibodies. CONCLUSIONS/INTERPRETATION: Tetraspanin 7 is an autoantigen in type 1 diabetes. Tetraspanin 7 autoantibodies are a marker of type 1 diabetes, but provide minor additional value to existing autoantibodies in identifying beta cell autoimmunity.