Autoimmunity

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 harmonize data from longitudinal studies to identify the characteristics of slow progression to type-1 diabetes. Samples from 125 individuals with multiple islet autoantibodies (IAA, GADA, IA-2A and ZnT8A) for more than 10 years without progression were available from four studies (Bart-Oxford (BOX), UK; BABYDIAB, Germany; DAISY and Pittsburgh Diabetes, USA). Individuals enrolled in BOX provided “Rapid Progressor” (diagnosed <age 5 years) and at diagnosis samples. Intermediate HLA-Class II risk was more frequent in slow (61%) than Rapid Progressors (49%) with a reciprocal reduction in high risk genotypes (24% vs. 48%; pCorr=0.005) but none 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 GADA, IA-2A and ZnT8A even when autoantibody positive status was maintained (p<0.05 for all). In addition, Slow Progressors had lower levels of IA-2AIgG subclasses than individuals sampled close to diagnosis (p<0.05). 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.