Type 1 diabetes (T1D) is a chronic autoimmune disease long thought to primarily affect children and adolescents. However, recent data suggest that nearly 70 percent of new T1D cases occur in adults. Striking differences in genetic, metabolic, and immune features as well as in diabetes management have been described between childhood- and adult-onset T1D, but many of these variances are poorly understood. An improved understanding of childhood- and adult-onset T1D heterogeneity is essential to provide optimal diabetes care but in addition, for designing novel disease-modifying therapies to prevent or arrest ongoing beta cell autoimmunity. I propose to implement the most advanced high-plex in situ assay platforms to study, at gene and protein level, the spatial context and interaction of cellular subtypes in pancreatic tissues obtained from childhood- and adult-onset T1D cases. Integrated data analyses will not only provide novel insights into precise cellular localizations but also identify cellular differentiation / activation states and neighborhoods. This will provide the best map yet of what is occurring in the pancreas at disease onset and how this differs between children and adults. Such knowledge is key to developing new treatments to cure T1D and to better define optimal treatment regimens.
Update: Type 1 diabetes (T1D) is a chronic autoimmune disease long considered to predominantly affect children and adolescents. However, recent epidemiological data indicate that nearly 70% of new T1D cases now occur in adults. Childhood–and adult–onset T1D differ markedly in genetic risk, metabolic trajectory, immune responses, and clinical management, yet the biological basis of this heterogeneity remains poorly understood. A deeper mechanistic understanding of age–dependent disease onset is essential not only to optimize diabetes care, but also to guide the development of disease–modifying therapies aimed at preventing or halting ongoing β–cell autoimmunity.
In recent years, our knowledge of pancreatic architecture in T1D has expanded rapidly through single–cell and spatial transcriptomic studies. These pioneering efforts have revealed immune infiltration patterns, β–cell stress states, and alterations in the exocrine compartment, fundamentally reshaping our view of the diseased pancreas. Nevertheless, most available studies remain limited by a strong focus on adult donors, incomplete age stratification, and restricted integration of transcriptomic and proteomic information. Moreover, while immune infiltration is a central feature of T1D pathology, the spatial organization and functional heterogeneity of immune cell subtypes within the pancreatic microenvironment, particularly at disease onset, remain incompletely resolved.
The proposed work builds on and extends these advances by implementing state–of–the–art, high–plex in situ platforms to interrogate pancreatic tissues from both childhood–and adult–onset T1D at gene and protein level, with a specific focus on spatial context and cell–cell interactions. A particular strength of our laboratory is its recent interest in neutrophil biology and neutrophil heterogeneity in autoimmune and inflammatory settings, including T1D. This project will therefore place special emphasis on identifying neutrophil subtypes, activation states, and spatial niches within the pancreas. Importantly, this focus will be embedded within a comprehensive analysis of the broader immune landscape, including adaptive and innate immune cell populations, to ensure an integrated view of pancreatic immune architecture.
By integrating high–dimensional spatial transcriptomic and proteomic data, we will move beyond static cell–type catalogs toward a contextual understanding of how immune and non–immune cell states, differentiation trajectories, and functional activation areorganized within distinct spatial neighborhoods. This approach will enable identification of age–specific immune niches, including neutrophil–enriched microenvironments, as well as β–cell stress responses and stromal interactions that may explain differences in disease aggressiveness and progression between children and adults.
Together, these integrated spatial analyses will provide the most detailed comparative map to date of pancreatic pathology at T1D onset across the lifespan. Such knowledge is essential for refining patient stratification, informing age–adapted therapeuticstrategies, and identifying novel targets for interventions aimed at preventing or curing T1D.
