Characteristics of slow progression to diabetes in multiple islet autoantibody-positive individuals from five longitudinal cohorts: the SNAIL study

Abstract

Aims/hypothesis Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. Major islet autoantibodies recognise insulin (IAA), GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A). Here we describe the baseline characteristics of a unique cohort of 'slow progressors' (n = 132) who were positive for multiple islet autoantibodies (IAA, GADA, IA-2A or ZnT8A) but did not progress to diabetes within 10 years. Methods Individuals were identified from five studies (BABYDIAB, Germany; Diabetes Autoimmunity Study in the Young [DAISY], USA; All Babies in Southeast Sweden [ABIS], Sweden; Bart's Oxford Family Study [BOX], UK and the Pittsburgh Family Study, USA). Multiple islet autoantibody characteristics were determined using harmonised assays where possible. HLA class II risk was compared between slow progressors and rapid progressors (n = 348 diagnosed <5 years old from BOX) using the χ 2 test. Results In the first available samples with detectable multiple antibodies, the most frequent autoantibodies were GADA (92%), followed by ZnT8A (62%), IAA (59%) and IA-2A (41%). High risk HLA class II genotypes were less frequent in slow (28%) than rapid progressors (42%, p = 0.011), but only two slow progressors carried the protective HLA DQ6 allele. Conclusion No distinguishing characteristics of slow progressors at first detection of multiple antibodies have yet been identified. Continued investigation of these individuals may provide insights into slow progression that will inform future efforts to slow or prevent progression to clinical diabetes.Keywords HLA class II . Islet autoantibodies . Slow progression . Type 1 diabetes Diabetologia (2018Diabetologia ( ) 61:1484Diabetologia ( -1490 https://doi.org/10.1007/s00125-018-4591-5Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4591-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

The risk of progression to type 1 diabetes is highly variable in individuals with multiple autoantibodies following screening

“…In our study, we identified a subset of participants with low risk of progression based on age, autoantibody type and metabolic status. In comparison, using a combination of birth and screened cohorts across a broad age range but a smaller sample size, Long et al [36] did not demonstrate autoantibody differences in individuals characterised as slow progressors (diabetes-free 10 years after mAb determination). The Diabetes in Autoimmunity Study in the Young (DAISY) birth cohort identified mAb-positive slow progressors that were set apart from rapid progressors by IAA titre and the rate of progression from single to mAb positivity [7].…”

Slow progressors to type 1 diabetes lose islet autoantibodies over time, have few islet antigen-specific CD8+ T cells and exhibit a distinct CD95hi B cell phenotype

“…Of 36 slow progressors identified in the BOX study, confirmed as multiple islet autoantibody positive using current harmonised assays [2], 19 were not included in the current analysis: 11 were excluded because they developed diabetes more than 10 years after the initial serum sample (and no follow-up serum sample was available after the 10 year point before they had developed diabetes); seven were lost to follow-up; and one had chronic lymphocytic leukaemia.…”

“…Longitudinal studies of at-risk individuals have shown, however, that up to 30% of people positive for multiple autoantibodies do not progress to type 1 diabetes within 10 years [1]. Such individuals were recruited to the Slow or Non-progressive Autoimmunity to the Islets of Langerhans (SNAIL) study from five other cohort studies, including the Bart's Oxford Family Study (BOX) [2]. All four major autoantibodies, specific for GAD (GADA), islet antigen-2 (IA-2A), insulin (IAA) and zinc transporter 8 (ZnT8A), were found in these slow progressors to type 1 diabetes (hereafter referred to as 'slow progressors').…”

Characteristics of Slow Progression to Type 1 Diabetes in Children With Increased HLA-Conferred Disease Risk

“…IAA as the first autoantibody peaks during the second year of life, while GADA reactivity tends to appear later, and with a considerably lower and broader peak (35)(36)(37). Individuals testing positive for multiple autoantibodies but remaining unaffected for ≥10 years after the seroconversion are frequently GADA positive in their first sample positive for multiple autoantibodies (38). As the T1D-linked Coxsackievirus B1 infections have been associated with the appearance of IAA as the first autoantibody, but not with initial GADA positivity (39), the current observations support the idea that the triggers of the autoimmune process may be heterogeneous.…”