Homann Dirk, van der Heide Verena, McArdle Sara, Nelson Michael, Cerosaletti Karen, Gnjatic Sacha, Mikulski Zbigniew, Posgai Amanda, Kusmartseva Irina, Atkinson Mark
University of Miami.
Icahn School of Medicine at Mount Sinai.
Res Sq. 2025 Jun 10:rs.3.rs-6673858. doi: 10.21203/rs.3.rs-6673858/v1.
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 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.
1型糖尿病（T1D）是一种渐进性自身免疫性疾病，最终导致产生胰岛素的β细胞丧失。胰腺组织病理学为疾病的起始和进展提供了重要见解，但目前缺乏对致病过程的综合视角。在此，我们结合多重免疫染色、高倍全切片成像、数字病理学和半自动图像分析，对T1D各阶段（包括高危和发病期病例）的胰腺尾部和头部切片进行研究。对约25,000个胰岛的结构特征、内分泌细胞组成、免疫细胞负荷和空间关系进行反卷积分析，有效地将健康状态和T1D疾病中已确立的和新的胰腺特征置于相应背景中。我们的结果揭示了内分泌胰腺在空间上均匀且与胰岛大小相关的结构组织、全器官致病过程的显著协调，以及多种组织病理学关联，这些关联在临床前期就预示了T1D独特的组织病理学特征。总之，我们提出了T1D的修订自然史，这对进一步的组织病理学研究和致病模式的考量具有重要意义。
