Reactivity to N-terminally truncated GAD₆₅(96-585) identifies GAD autoantibodies that are more closely associated with diabetes progression in relatives of patients with type 1 diabetes.

Autoantibodies to glutamate decarboxylase (GADA) identify individuals at increased risk of type 1 diabetes, but many people currently found GADA positive are unlikely to develop clinical disease. More specific GADA assays are therefore needed. Recent international workshops have shown that reactivity of sera from healthy donors varies according to assay type, and indicated that use of N-terminally truncated GAD65 radiolabels in GADA radiobinding assays is associated with higher specificity. To determine whether a radiobinding assay using radiolabeled GAD65(96-585) identified individuals at higher diabetes risk, samples from recent-onset patients and GADA positive first-degree relatives participating in the Bart's-Oxford type 1 diabetes family study were re-assayed with full-length or N-terminally truncated GAD using the NIDDK harmonized protocol. The sensitivity in patients was the same with both labels, but fewer relatives re-tested positive with truncated GAD. Among relatives who progressed to diabetes, similar proportions were GADA positive when tested with either label, but because of their higher specificity the cumulative risk of diabetes was higher in those with autoantibodies to GAD65(96-585). Autoantibodies to GAD65(96-585) in relatives are more closely associated with diabetes risk than those to full-length GAD, suggesting assays using N-terminally truncated GAD should be used to select participants for intervention trials

Risk of pediatric celiac disease according to HLA haplotype and country.

BACKGROUND: The presence of HLA haplotype DR3-DQ2 or DR4-DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG). METHODS: We studied 6403 children with HLA haplotype DR3-DQ2 or DR4-DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies. RESULTS: The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3-DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3-DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4-DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25). CONCLUSIONS: Children with the HLA haplotype DR3-DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries highlights the importance of studying environmental factors associated with celiac disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)

Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes

Transplantation and autoimmunit

The story of NAIMIT - A framework 7 project on type 1 diabetes

NAIMIT (acronym for Natural Immune Modulation for Intervention in Type 1 Diabetes) is a large-scale collaborative programme of the 7th framework from the European Commission. The aim of the consortium is to bring together a group of leading European researchers spanning the field from genetics, through pancreatic beta-cell, dendritic cells and T-cell biology, towards clinical interventions. The ultimate goal is to develop novel and personalised interventional therapies in recent-onset type 1 diabetic patients, with minimal immune system interference, leading to beta-cell protection and restoration, based on a solid understanding of the disease pathogenesis, enabling experimental findings to be adopted for clinical applications.SCOPUS: ar.jinfo:eu-repo/semantics/publishe