In insulin-autoantibody-positive children from the general population, antibody affinity identifies those at high and low risk

Abstract

Aims/hypothesis: Insulin autoantibodies (IAA) precede and predict the onset of type 1 diabetes, but not all children with IAA develop the disease. In affected families, IAA affinity can identify IAA-positive children who are more likely to progress to diabetes. The purpose of this study was to determine whether affinity is a useful marker to stratify type 1 diabetes risk in IAA-positive children from the general population. Methods: IAA affinity was determined by competitive binding to 125 Iinsulin with increasing concentrations of cold insulin and with cold proinsulin in sera from 46 IAA-positive children identified in the Karlsburg Type 1 Diabetes Risk Study of a Normal Schoolchild Population in north-eastern Germany. Results: IAA affinity ranged between 5×10 6 and 1.2×10 11 l/mol. IAA affinity was higher in 24 children who developed multiple islet autoantibodies or diabetes (median 3.5×10 9 l/mol; interquartile range [IQR] 2.1×10 9 to 2.1×10 10 l/mol) than in 22 children who did not develop multiple islet autoantibodies or diabetes (median 1.3×10 8 l/mol; IQR 3.8×10 7 to 7.2×10 8 l/mol; p<0.0001). Using a threshold of ≥10 9 l/mol, 22 of the 24 children who developed multiple islet autoantibodies or diabetes were correctly identified by high-affinity IAA and 18 of 22 who did not develop multiple islet autoantibodies or diabetes were correctly identified by low-affinity IAA. IAA affinity was significantly higher in samples with proinsulin reactive IAA (p<0.0001). Conclusions/interpretation: IAA affinity measurement provides robust identification of IAA associated with high diabetes risk.

GAD autoantibody affinity in schoolchildren from the general population

“…Only one child displaying profile P2, and no child with profile P3, developed type 1 diabetes during the observation time. These findings in the GADA-positive children from the general population are consistent with what we and others have previously observed for GADA, IAA or IA-2A in first-degree relatives and in IAA-positive children without a familial predisposition [14,25,26,28,29].…”

“…It has recently become evident that besides the autoantibody level, both affinity and epitope specificity may be used to further stratify risk [12,14,25,26]. We were previously able to demonstrate in children who had at least one parent affected by type 1 diabetes that an assessment of GADA affinity and epitope specificity allowed us to define discrete GADA profiles associated with risk of type 1 diabetes [14].…”

A Costimulatory Function for T Cell CD40

“…NOR mice, like their NOD counterparts, have CD40-expressing T cells, yet do not develop disease (17). Similarly, the presence of autoantibodies does not necessarily indicate pathogenesis (77)(78)(79). Cooperation between cell types and signals from the environment to the immune response determine development of disease (80,81).…”

Affinity maturation of immunoglobulin A anti-tissue transglutaminase autoantibodies during development of coeliac disease

“…systematic lupus erythematosus (SLE) [25] and type 1 diabetes [26,27]. In type 1 diabetes, affinity maturation seems to be dependent on the antigen specificity of the autoantibodies [28].…”