Bodansky, A.; Ahyong, V.; Dayao, M.; Asaki, J.; Vanasupa, S.; Dandekar, R.; Chen, S.; Sabatino, J.; Klauer, S.; Knudsen, G.; Lizama Valenzuela, C.; McCutcheon, K.; Zorn, K.; Sidhu, S.; Yu, D.; Garcia, S.; Quandt, Z.; Wang, C.-Y.; Castillo Rojas, B.; Tilton, I.; Citron, Y. R.; Sharathchandra, A.; Gerungan, C.; Tomko, S.; Robbins, N. M.; McKeon, A.; Cooper, T.; Harms, M.; Gomez, R.; Fancy, S. P. J.; Green, A. J.; Caliskan, I.; Cadwell, C. R.; Ostrem, B. E.; Karalius, M.; Braun, L.; Gupta, S.; Francisco, C.; Peng, G.; Reddy, A. T.; Nash, K.; Pleasure, S. J.; Mandel-Brehm, C.; Arnold, T. D.; Conso

Autoimmune diseases arise when B and T lymphocytes lose tolerance to self. Yet in most disorders, the underlying molecular determinants, including autoantibodies, epitopes and lymphocyte clones that drive tissue injury remain undefined. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is a rare and often fatal pediatric neuroendocrine syndrome with strong evidence of antigen-driven paraneoplastic autoimmunity, including association with the intracellular autoantigen ZSCAN1. However, the effector immune circuit and the epitope-level determinants operating within the hypothalamus and brainstem have remained unknown. To address this challenge in ROHHAD and more broadly in autoimmune disease, we developed the Autoimmune Epitope and immunoGlobulin/Immune-receptor identification System (AEGIS), an integrated framework that links immune repertoires to their cognate self-epitopes. AEGIS combines B cell and T cell receptor profiling from sites of tissue injury with high-resolution epitope mapping, direct sequencing of antigen-specific autoantibodies, in silico antibody-antigen folding, selection, and T cell antigen discovery. Applied to a deeply phenotyped child with ROHHAD, AEGIS revealed a compartmentalized, clonally restricted immune response in which brain-deposited IgG and expanded cerebrospinal fluid B cell and CD4 T cell clonotypes converged on shared ZSCAN1 epitopes, resolved to minimal determinants and peptide-MHC ligands. These findings provide a clone- and epitope-linked mechanistic map of ROHHAD autoimmunity and establish a generalizable framework for identifying candidate pathogenic clones and antigens across diverse autoimmune diseases.