Is there regulation of the autoimmune response in slow progressors to type 1 diabetes?

Background and aims: Multiple islet autoimmunity increases risk of diabetes but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. The SNAIL Study seeks to harmonise data from longitudinal studies to identify the characteristics of slow progression to type 1 diabetes. Materials and methods: Samples from 131 individuals with multiple islet autoantibodies (IAA, GADA, IA-2A, and ZnT8A) followed for more than 10 years without progression were available from five studies (Bart's-Oxford (BOX)-UK; BABYDIAB-Germany; DAISY and Pittsburgh Diabetes- USA; ABIS- Sweden). Individuals enrolled in BOX provided "Rapid Progressor" (diagnosed <age 5yrs) and "at diagnosis" samples. HLA Class I and II were analysed by PCR-SSP. Islet autoantibody profile was analysed by radioimmunoassay and/or ECL. Results: Intermediate HLA-Class II risk was more frequent in Slow (60%) than Rapid Progressors (42%) with a reciprocal reduction in high risk genotypes (24% vs. 48%; pCorr=0.005); one one carried protective HLA DQ6. Slow Progressors carried fewer HLA-Class I B risk alleles (48%) than Rapid Progressors (86%; pCorr<0.001). Of 35 Slow Progressors with longitudinal data available, only 13 (37%) retained multiple autoantibodies after 10 years (p<0.001). A reduction in positivity for IAA and GADA was observed (p<0.001 and p=0.016, respectively) and in levels of IA-2A and ZnT8A even though autoantibody positive status had not changed (p<0.05 for all). In addition, Slow Progressors had lower levels of all IA-2A IgG (1-4) subclasses than individuals sampled close to diagnosis (p<0.05). Conclusion: Multiple autoantibody positivity is not maintained in some Slow Progressors suggesting regulation of the autoimmune response. Continued immuno-phenotyping of these individuals is required to elucidate the mechanisms underlying a decreased humoral response and delayed progression.