IMMUNOLOGICAL HETEROGENEITY IN TYPE-I DIABETES - PRESENCE OF DISTINCTAUTOANTIBODY PATTERNS IN PATIENTS WITH ACUTE ONSET AND SLOWLY PROGRESSIVE DISEASE

Type I diabetes mellitus may represent a heterogeneous disorder with a distinct pathogenesis in patients with young and adult onset of the d isease. To investigate whether serological markers directed to differe nt autoantigens have the potential to distinguish acute onset from slo wly progressive Type I diabetes we analysed antibodies to tyrosine pho sphatases IA-2/ICA512 (IA-2A) and IA-2 beta/phogrin (IA2 beta A), anti bodies to GAD65 (GADA) and cytoplasmic islet cell antibodies (ICA) in a non-selected group of diabetic patients clinically classified as hav ing Type I or Type II diabetes at diagnosis. Both IA-2A and IA-2 beta A were found to be positively associated with onset before the age of 20 years and the presentation of classical features of Type I diabetes . In Type I diabetes 56 % (112/200) of patients were positive for IA-2 A and 38 % (76/200) for IA-2 beta A. In contrast, only 1 of 785 (0.1 % ) patients with Type II diabetes had IA-2A and all of them were negati ve for IA-2 beta A (p < 0.001). Among the patients with Type II diabet es 7.6 % (n = 60) were ICA positive and 2.8 % (n = 22) had GADA sugges ting the presence of slowly progressive Type I diabetes. GADA were fou nd in 8 of 60 (13.3 %) ICA positive subjects which was lower than the percentage detected in patients with acute onset of diabetes (115/157 73.2 %) (p < 0.001). Blocking of double antibody positive sera showed that only 3 of 8 (37.5 %) patients with slowly progressive diabetes ha d ICA restricted to GAD or IA-2 whereas ICA were completely inhibited in 12 of 20 (60.0 %) patients with Type I diabetes. Among 193 patients with Type II diabetes available for follow-up, 35 % of ICA positives, 58 % of GADA positives and 60 % of those positive for both markers re quired insulin by 3 years. However. using strict criteria for the swit ch to insulin treatment the corresponding sensitivity of each marker w as only low (9 %, 10 % and 5 %). We show that clinical subtypes of Typ e I diabetes are associated with distinct humoral autoimmunity. IA-2A and GADA were associated with classical features of Type I diabetes wh ereas GADA and an uncharacterized ICA subspecificity indicate slowly p rogressive disease.