Imaging mass cytometry reveals early β-cell dysfunction and changes in immune signatures during type 1 diabetes progression in human pancreata.
Nathan Steenbuck (Bodenmiller Lab)
Zurich Seminars in Bioinformatics
- 12:15 UZH Irchel Y55-l-06/08 and ZOOM Call
Abstract The natural history and pathogenesis of type 1 diabetes, particularly during the autoantibody-positive stages preceding clinical onset, are not well understood, in part, due to limited availability of human pancreatic samples. Here, we studied 88 organ donors, including 28 single autoantibody-positive and 10 multiple autoantibody-positive donors, by imaging mass cytometry.
We spatially analyzed over 10,000 islets and 16 million single-cells using 79 antibodies revealing both β-cell states and the islet-immune interface. We identified IAPP loss, prior to Insulin loss, from β-cells as a major indicator of pre-clinical disease. Alterations in Interferon signatures and downregulation across lineage and functional markers, including markers of endoplasmic reticulum stress, were characteristic of recent-onset disease. We studied adaptive and innate immune states and identified a pro-inflammatory macrophage – exhausted-like T-cell axis as characteristic for early disease stages, and as a central component of (peri-)insulitic lesions. Multiple immune cell subtypes were associated with young age and insulitis, thus potentially modulating the higher disease severity observed in younger type 1 diabetics.
Altogether, we generated a first-of-its-kind dataset that deepens our understanding of early type 1 diabetes progression that reveals multiple novel and potentially clinically actionable disease features.