W121 - Immune Repertoire Profiling in Type 1 Diabetes (T1D): Insights from BCR Analysis Across Multiple Tissues

Abstract Text: T1D is an autoimmune disease driven by T cell–mediated β-cell destruction, with B cells contributing as antigen-presenting cells. Despite current diagnostic tools, there remains a critical need for biomarkers to track early disease progression and caputre individual variation in immune activity. B and T cell receptor (BCR and TCR) analysis provides an approach to monitor autoreactive immune acitivity, with potential to capture early disease dynamics and progression risk. This study analyzed BCR heavy-chain sequences from 57 donors from the Network for Pancreatic Organ Donors with Diabetes (nPOD), including spleen and pancreatic lymph node (pLN) tissues, to identify immune signatures distinguishing No Diabetes (ND, N=17), Autoantibody-positive (AAb+, N=19), and T1D (N=21) states. Donors were 18–22 years old, with 49% female. CDR3 length analysis revealed significant demographic influences but no disease-specific differences. Mean CDR3 length was shorter in females(p=0.004), decreased with age (p < 0.001), and shorter in African American individuals than European White donors (p < 0.001). V gene usage showed disease-associated biases. In the spleen, IGHV4-39 and IGHV4-59 were elevated in T1D, while IGHV3-1, IGHV3-49, and IGHV7-81 were reduced (p < 0.05). IGHV3-23 was higher in T1D than Aab+. In the pLN, IGHV3-30, IGHV3-43 and IGHV3-49 were reduced in T1D vs. ND (p < 0.05). The selective enrichment and depletion of V genes may reflect disease-associated immune processes, highlighting B-cell repertoire remodeling in T1D. Future work will focus on clonotype expansion and somatic hypermutation analysis, with emphasis on linking these patterns to antigen specificity, shared motifs, and public clones to better understand their relevance in disease.