Abstract
Type 1 diabetes (T1D) is a progressive autoimmune condition that culminates in loss of insulin-producing beta cells. Pancreatic histopathology provides essential insights into disease initiation and progression yet an integrated perspective onto in situ pathogenic processes is lacking. Here, we combined multiplexed immunostaining, high-magnification whole-slide imaging, digital pathology, and semi-automated image analyses to interrogate pancreatic tail and head sections across T1D stages, including at-risk and at-onset cases. Deconvolution of architectural features, endocrine cell composition, immune cell burden, and spatial relations of ~ 25,000 islets effectively contextualizes established and novel pancreatic hallmarks in health and T1D disease. Our results reveal a spatially homogenous and islet size-contingent architectural organization of the endocrine pancreas, a notable coordination of organ-wide pathogenic processes, and multiple histopathological correlates that foreshadow distinctive T1D histopathology already at the preclinical stage. Altogether, we propose a revised natural history of T1D with implications for further histopathological investigations and considerations of pathogenetic modalities.