Abstract
ABSTRACT
Pancreatic beta cells are active participants in the loss of immune tolerance because their high secretory demand creates exceptional vulnerability to inflammatory exposure, endoplasmic reticulum (ER) stress, calcium dysregulation, and redox imbalance. These conditions can promote enzymatic and nonenzymatic changes in self‐proteins, generating post‐translationally modified (PTM) antigens and neoepitopes that were absent or poorly represented during immune tolerance. This review integrates the contributions with the broader type 1 diabetes (T1D) field to examine how beta cell stress, transglutaminase‐2 dependent reactions, peptidyl‐arginine deiminase mediated citrullination, oxidative modifications, and post‐translational peptide fusion reshape the antigenic landscape. We consider how these products alter antigen presentation and recognition by autoreactive T cells and how an evolving neoepitope repertoire may promote antigenic diversification and epitope spreading. Importantly, clonal recruitment of new determinants must be distinguished from apparent broadening caused by T cell receptor (TCR) cross‐reactivity, dual‐TCR expression, bystander activation, or tissue redistribution. Defining when modified epitopes arise, which are naturally presented, and which responses contribute to pathogenesis could improve biomarker development, patient stratification, and therapeutic strategies designed to reduce beta cell stress, thus enhancing survival and identity maintenance, while restoring immune tolerance.