ESPE Yearbook of Paediatric Endocrinology

Brief Summary: Longitudinally collected samples from the Type 1 Diabetes Prediction and Prevention (DIPP) study were used to assess potential differences in immune responses in children at genetic risk of type 1 diabetes (T1D) who later progressed to clinical disease, stratified by autoantibody appearance (IAA-first, GADA-first, ≥2 autoantibodies (AAb)-first groups). Differences in the composition of peripheral blood monoclonal cells (PBMC) were found between the IAA-first, GADA-first, and ≥2AAb groups, highlighting the importance of endotype-specific analyses.

The prospective DIPP cohort study recruited newborns based on HLA-conferred genetic susceptibility to T1D at Turku, Oulu and Tampere University Hospitals. They were followed to age 15 years or clinical onset of T1D, with regular assessment of islet autoantibodies (1).

This DIPP analysis tested the hypothesis that children who later develop clinical T1D have different early immune responses, depending on the type of the first appearing AAb: autoantibody to insulin (IAA) vs glutamic acid decarboxylase (GADA). Previous data suggested that the rate of progression to clinical T1D is faster in IAA-first children (2).

Three groups (or endotypes) were compared, IAA-first and GADA-first children and a third group including children who tested positive for ≥2 AAb in the first available sample, and related controls. The composition of PBMC differed between IAA-first, GADA-first, and ≥2 AAb-first groups, with differences in NK cell, B cells, CD4+, CD8+ and γδ TCR T cell proportions. These differences were endotype-specific and not seen when samples from all the three groups were analysed together. Differences between cases and controls were also detected in the expression of proteins in NK cells, CD4+T cells and CD8+T cells. In addition, increased expression of CD161 was detected in NK cells in children with ≥2 AAb compared to controls.

These findings highlight the importance of endotype-specific analyses and shed light on differences in immune responses related to T1D autoantibody, which may be useful for disease prediction and management. The study included a small number of individuals per group, and validation is needed in a larger cohort.

References: 1. Ilonen, J. et al. Patterns of β-cell autoantibody appearance and genetic associations during the first years of life. Diabetes. 2013;62, 3636–3640.2. Bauer W, Veijola R, Lempainen J, Kiviniemi M, Härkönen T, Toppari J, et al. Age at Seroconversion, HLA Genotype, and Specificity of Autoantibodies in Progression of Islet Autoimmunity in Childhood. J Clin Endocrinol Metab. 2019;104(10):4521-30.