ABSTRACT Autoimmune diseases affect more than 20 million people in the United States, and the worldwide prevalence is rising. Patients usually suffer from a lifetime of deteriorating illness because no cures are available for most autoimmune diseases, including type 1 diabetes. Addressing this formidable challenge requires a better understanding of the pathogenic elements eliciting autoreactive responses. Although extensive studies have examined the role of native antigens, whether neoantigens/neoepitopes function to drive the autoimmune process remains poorly understood. The identity of neoantigens, especially post-translational modifications (PTMs) responsible for generating immunogenic neoepitopes, requires a critical examination. Endocrine tissues are commonly targeted by autoimmunity. Diverse endocrine cells use the crinophagic pathway to dispose of excessive amounts of secretory proteins to maintain cellular homeostasis. In this process, the regular secretory granules are directly fused to lysosomes. The resulting vesicle, crinophagic bodies, or crinosomes, are enriched with catabolized peptide segments. In type 1 diabetes, a deteriorating autoimmune disease targeting the insulin-producing β cells in pancreatic islets, crinosomes function as an antigen source providing native peptides for recognition by pathogenic CD4 T cells. Our recent examination by immunopeptidomics uncovered diverse PTMs in crinosome-derived peptides, indicating that crinosomes are a specialized repository of potential neoantigens and neoepitopes related to type 1 diabetes. A novel neoepitope family, C19S (cysteine-to-serine conversion in the insulin B-chain), became progressively prominent along with the development of the diabetic autoimmune process. Most importantly, we identified highly compatible sequences of C19S in mice and humans with T1D. In mice, C19S can be recognized by previously unidentified CD4 T cells distinct from those reactive to the native epitope. It is therefore necessary to determine the pathogenicity of the autoreactive T cells targeting C19S. Furthermore, as a representative neoepitope family, C19S provides a setpoint for delineating how β-cell crinophagy functions as a novel pathogenic component in T1D. C19S may initiate a "feed-forward" loop in T1D pathogenesis by linking β-cell stress with autoimmunity. We also propose to assess translational applications of C19S in human crinophagy and T cell pathobiology. These analyses may lead to a broad identification of neoepitopes generated by human crinophagy, which may serve as valuable targets for T1D pathogenesis and therapeutics. Analysis of potential C19S-reactive T cells in human PBMCs may extend our knowledge of autoimmune pathogenesis beyond the current paradigm defined by native antigens.