Distinct genetic and immunological features in patients with onset of IDDM before and after age 40

Young age at onset is a relevant parameter associated with a rapid progression of IDDM. Our major aim was to define differences between IDDM patients with age at diagnosis > 40 years and adult IDDM with onset at a younger age.

The correlation between islet-related antibodies (islet cell antibodies [ICAs] and antibodies [Abs] to GAD and the tyrosine phosphatase IA2), T-cell responses to GAD peptides and HLA class II isotypes was investigated in 23 IDDM patients 12-38 years of age at onset (group 1), 24 patients with IDDM > 40 years of age at onset (group 2), and 12 healthy control subjects. ICAs were measured by indirect immunofluorescence, and GAD-Ab and IA2-Ab were measured by immunoprecipitation tests. T-cell responses against GAD peptides, which had been identified as typical for IDDM, were tested by 5-day proliferation assays. HLA class II alleles were typed by polymerase chain reaction.

ICAs and GAD-Abs were more prevalent in IDDM patients than in control subjects (P < 0.001), but only IDDM group 1 had IA2-Abs (P < 0.001 compared with IDDM group 2 and control subjects). Moreover, antibody combinations differed between IDDM patients of groups 1 and 2. T-cell responses to GAD peptides were seen in 67% of IDDM group 1 and in 71% of IDDM group 2 (P < 0.02 compared with control subjects). IDDM patients of group 1 were more frequently DR4+/DQ8+ and less frequently DR2+/DQ0602+ compared with IDDM patients of group 2 (P < 0.05).

Our data provide strong evidence for humoral and cellular autoimmunity in adult IDDM patients with onset both before and after 40 years of age. However, late-onset differs from young-onset IDDM with respect to Ab profiles, especially a lack of IA2-Ab, and HLA class II types. These findings have consequences for the diagnostic strategy for identifying slow-onset IDDM in individuals after 40 years of age.