Tuesday, April 29, 2025
4/29/2025
Clonal expansion: a marker of disease activity in stage 1 T1D - SUMMARY Type 1 Diabetes (T1D) is an immune mediated disease in which immune cells destroy insulin producing beta cells of the pancreas. Yet, T1D pathogenesis starts even before damage to beta cells can be detected as overt dysglycemia with the appearance of two or more islet-specific autoantibodies (AAb), defined as stage 1 T1D. Yet, AAb number and type can be unstable overtime in stage 1. In the proposed studies, we determine whether islet antigen reactive T and B cell clonal expansion is a stable early biomarker of disease activity in stage 1 T1D. The central hypothesis is that islet antigen reactive clonal expansion of pathogenic cell subsets is indicative of disease activity in Stage 1 T1D and disease progression to Stage 2 or 3 occurs when clonal expansion within pathogenic cells exceeds clonal expansion within protective cells. We will address this question by investigating well annotated cross sectional and longitudinal samples from the TrialNet Pathway to Prevention Study. The cross sectional cohort will include age and HLA matched stage 1 individuals with stable versus variable AAb in the prior year, Variable AAb will be defined as increased AAb number or change in AAb as a longitudinal measure of disease activity. The longitudinal cohort will compare paired samples from stage 1 individuals who do or do not progress to stage 2 or 3 T1D. The approach leverages our expertise in islet antigen specific T and B cell identification, cellular immunology of T1D, and systems biology single cell multi- model analyses. Together, these expertise will allow us to define clonal expansion in protective and pathogenic cell subsets of stage 1 individuals and explore the functional nature of the expanding cells. Specifically, in Aim 1 we will determine the degree of pathogenic islet antigen reactive clonal expansion that marks disease activity and progression using single cell T cell receptor (TCR)- or B cell receptor (BCR)-, CITE-, and RNA-seq in cross sectional cohorts defined by stage of disease and stability of AAb composition. In Aim 2 we will determine the functional quality of clonally expanded cells in early T1D by assessing changes in the transcriptome and epigenome over time of pathogenic and protective populations selected based on the degree of clonal expansion, association with outcome, and enrichment in IAR cells. Ultimately, the knowledge gained from this work will identify stable disease activity markers early in disease that may guide timing of treatment, expand our understanding of immunity at Stage 1 T1D, and identify pathogenic and protective features that may be targeted therapeutically.
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