From Disposal to Display: Crinophagy as a β-Cell Source of Neoantigens in Type 1 Diabetes.

Type 1 diabetes (T1D) arises when autoreactive lymphocytes target pancreatic β-cells, yet the mechanisms that convert β-cell self-proteins into disease-relevant antigens remain incompletely defined. β-cells are uniquely positioned to generate neoantigens because they devote extraordinary protein synthesis capacity to insulin production and maintain thousands of dense-core insulin granules. While a small fraction of granules undergoes glucose-stimulated exocytosis, excess, aged, or immature granules can be degraded through crinophagy, a lysosomal pathway in which secretory granules fuse with lysosomes to form crinosomes. Recent immunopeptidomic studies suggest that crinosomes are not merely disposal compartments but antigen-editing organelles that remodel insulin granule cargo into pathogenic epitopes. These include free insulin B-chain peptides, hybrid insulin peptides, post-translationally modified insulin and C-peptide epitopes, and stress-induced insulin sequence variants such as insulin B-peptide C19S. Because several crinosome-associated epitopes are poorly represented in the thymus, crinophagy may create a peripheral antigen repertoire that permits escape from central tolerance and activation of autoreactive T cells in islets and draining lymphoid tissues. This review discusses the physiology of β-cell granule turnover, the mechanisms of crinosome-associated neoantigen generation, and their implications for T1D pathogenesis, biomarkers, and therapeutic targeting.