Antiislet autoantibodies usually develop sequentially rather than simultaneously.

Abstract

The goal of this study was to address whether antiislet autoantibodies appear sequentially or simultaneously before the onset of type I diabetes. We analyzed sequential serum samples from 155 siblings and offspring (aged < 7 yr) of patients with type I diabetes from the Denver Diabetes Autoimmunity Study in the Young study and from a separate group of first degree relatives (aged 2-40 yr) for autoantibodies reacting with three defined autoantigens: glutamic acid decarboxylase (GAD65), insulin, and ICA512/IA-2. The youngest age at which 1 of the 3 autoantibodies appeared was 1.1 yr, and the oldest was 60.9 yr. Of the total 26 autoantibody conversion events observed, in only 3 instances did more than 1 autoantibody appear simultaneously. Among individuals (n = 12) with sequential conversion to expression of multiple autoantibodies, anti-GAD65 autoantibodies or antiinsulin autoantibodies appeared first (4 expressed antiinsulin autoantibodies first, and 8 anti-GAD65 autoantibodies first). We conclude that antiislet autoantibodies usually appear sequentially and not simultaneously. This corroborates early suggestions that humoral autoimmunity to islets develops chronically in a process usually measured in months to years. As expression of multiple autoantibodies is associated with a high risk of progression to diabetes, and sequential appearance of autoantibodies can occur late in life, long term follow-up is necessary to fully delineate the relationship of diabetes risk to autoantibody expression.

Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes

“…A recent study in siblings of type 1 diabetic patients [13] confirmed the generally held view that the risk of diabetes increases with the number of islet autoantibody specificities [4][5][6][7][8][9], but in addition indicated that the presence of autoantibodies against the intracellular domain of insulinomaassociated protein-2 (IA-2 autoantibodies, IA-2A), which is often associated with multiple antibody positivity [13][14][15][16], confers a higher risk of rapid progression towards clinical onset than multiple antibody positivity per se [13]. In persistently IA-2A-negative siblings the risk of diabetes increased significantly with the number of other autoantibodies present (GADA, IAA and/or ICA), but the progression rate remained less than 10% within 5 years [13].…”

Cytokine overproduction in healthy first degree relatives of patients with IDDM

“…ICA represent a risk factor for progression to IDDM when found in relatives of affected patients [34]. A number of other autoantibodies have also been associated with increased risk of diabetes in first degree relatives including those directed to glutamic acid decarboxylase (GAD), IA-2 and insulin [35]. Consequently, it will be interesting to determine in future studies whether cytokine levels correlate with the presence of any of these markers of islet cell autoimmunity.…”

Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects

“…Peripheral blood was obtained for T-cell assays, islet autoantibodies, and HLA genotyping. Islet autoantibodies to insulin, GAD65, IA-2, and ZnT8 were measured from the serum by radioimmunoassay as previously described (34). HLA-DRB, DQA, and DQB genotyping was performed using linear arrays of immobilized sequencespecific oligonucleotides similar to previously described methodology (35).…”