OBJECTIVE—Autoantibodies to insulin and GAD are features of preclinical type 1 diabetes in children. For insulin autoantibodies, the antibody affinity and epitope specificity predict which children progress to diabetes. We asked whether autoantibodies to GAD (GADAs) are heterogeneous in affinity and epitope recognition and whether diabetes-related GADA are restricted to high-affinity responses. RESEARCH DESIGN AND METHODS—GADA affinity was measured by competitive binding experiments with [125I]-labeled and -unlabeled recombinant human GAD65 in the first GADA-positive sample from 95 children with a type 1 diabetes family history who were prospectively followed from birth and in follow-up samples from 65 of these children. RESULTS—At first GADA appearance, affinity ranged from 107 to 1010 l/mol. Affinity was higher in multiple islet autoantibody-positive children (P < 0.0001) and in HLA DR3–positive children (P = 0.006). GADA affinities were >109 l/mol in 52 of 53 multiple autoantibody-positive children. In contrast, children who were single GADA positive often had lower affinity GADA and/or GADA with specificities that were restricted to minor NH2-terminal GAD65 epitopes. At follow-up, affinity increased from low to high in 3 of 65 children. All 24 children who developed diabetes had high-affinity GADAs before diabetes onset. CONCLUSIONS—Children develop discrete, heterogeneous antibody responses to GAD that could arise from distinct immunization events, only some of which are diabetes relevant. Subtyping the GADA responses using affinity measurement will improve type 1 diabetes risk assessment.

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.

The diabetes risk in schoolchildren with multiple autoantibodies was similar to the risk reported in other studies for genetically preselected probands; thus, a combined autoantibody-based screening could effectively identify at-risk individuals from the general population for future intervention trials.

The aim of this study was to evaluate the influence of the coating of polymer implants upon the individual humoral immune response to the polymer matrix. Intramuscular implantation and explantation of samples from three different polyester vascular prostheses coated with collagen, gelatin, or human serum albumin was performed in LEW.1A rats and subsequently compared to sham operated control animals. Antibodies in serum samples were detected by means of enzyme immunoassays employing particles of pure polyester and the respective prosthesis, or solid phase bound coating substances as targets. In contrast to the controls, all animals with implants demonstrated a high antipolyester antibody response with a broad individual variability graduated according to the prosthesis coatings: gelatin > albumin > collagen. This was further significantly increased after the second implantation/first explantation and declined following the last explantation. Only animals with albumin-coated implants revealed specific antibodies to the coating as well as the strongest overall immunological reaction against the prosthesis already on day 8. Specificity of polymer antibodies was demonstrated by competitive inhibition of median antibody binding. Our results showed a specific immune reaction as a result of the applied polymer, which varied due to the surface-coating and individual factors.

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