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

ABSTRACT

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.