Differences in immune cell profiles around the time of islet autoimmunity seroconversion in children with and without type 1 diabetes

Seroconversion (SV) marks the initiation of islet autoimmunity (IA) and pre-clinical phase of type 1 diabetes, yet the contributions of immune cells beyond cytotoxic T cells remain unclear. We applied high-resolution immune cell-type deconvolution using peripheral blood DNA methylation data from nested case-control samples of the Diabetes Autoimmunity Study in the Young (DAISY; n=151) and The Environmental Determinants of Diabetes in the Young (TEDDY; n=166) to estimate immune cell proportions across pre-SV and SV timepoints and construct functional ratios, such as the neutrophil-to-lymphocyte ratio (NLR). Using linear models, we evaluated differences between type 1 diabetes cases and controls at pre-SV, SV, and the change across timepoints. Pre-SV, cases had higher NLR and lower CD4T/CD8T cell ratios. At SV, the combined B-CD4T-CD8T memory/naive ratio was reduced in cases. From pre-SV to SV, cases showed attenuations in NLR, B-memory/naive, and B-CD4T-CD8T memory/naive ratios. These patterns may reflect delayed or disrupted immune maturation with the persistence or expansion of naive cells or impaired transition to memory subsets following antigen exposure. Our findings highlight early shifts in innate and adaptive immune cell dynamics during type 1 diabetes pathogenesis and support immune cell ratios as potential biomarkers for risk stratification and mechanistic insight. Article HighlightsO_LIWe sought to examine immune cells around the time of IA seroconversion in children at higher risk for type 1 diabetes. C_LIO_LIWe wanted to answer whether immune cell ratio differences exist between type 1 diabetes cases and controls around IA at pre-SV, SV, and the change pre-SV to SV. C_LIO_LIWe found immune cell ratio differences between type 1 diabetes cases and controls before, during, and across SV timepoints, suggesting potential etiological and pathophysiological roles. C_LIO_LIOur findings highlight the complexity of immunodynamics around IA seroconversion and potential role for immune cell ratios in type 1 diabetes risk stratification and intervention. C_LI