Benkahla, M. A. | bioRxiv Science

bioRxiv2025

Whole tissue spatial cellular analysis reveals increased macrophage infiltration in pancreata of autoantibody positive donors and patients with type 1 diabetes

While extensive efforts have characterized lymphoid populations that contribute to pancreatic insulitis in type 1 diabetes, significant gaps remain regarding key properties of macrophages in this inflammatory lesion. Hence, we quantified the spatial distribution of macrophages infiltrating human pancreatic tissue sections across disease states. Whole slide images of immunofluoresent stainings were analyzed with a semiautomated machine learning approach to study the distribution of macrophages throughout pancreatic sections from non-diabetic, auto-antibody positive (Aab+), and type 1 diabetes organ donors. Across the entire tissue section, macrophage infiltration was highest in donors with type 1 diabetes, and appeared contingent on the prescence of insulin-containing islets. Aab+ donors had higher macrophage densities in islet and peri-islet regions than non-diabetic individuals, but there was large case-by-case variation. Additionally, a greater proportion of macrophages highly expressed HLA class II (HLA-II) near and within islet regions of the type 1 diabetes group, which correlated with the proportion of stressed beta cells expressing HLA-II. The higher density of macrophages in the Aab+ and type 1 diabetes donors, taken together with higher expression of HLA-II in the type 1 diabetes pancreas, suggests that macrophages play a pivotal role in human type 1 diabetes initiation and progression. Article HighlightsO_LIMacrophage infiltration is increased in all pancreatic regions of patients with type 1 diabetes, and this infiltration appears contingent on the presence of insulin-containing islets. C_LIO_LIAab+ donors have higher macrophage densities in islet and peri-islet regions than non-diabetic individuals, but there is large case-by-case variation within the Aab+ group. C_LIO_LIThe proportion of macrophages highly expressing HLA-II is increased near and within islets only in patients with type 1 diabetes, and this correlates with the proportion of stressed beta cells expressing HLA-II within the islet. C_LIO_LIMacrophages are linked to human type 1 diabetes initiation and progression, hence forming a rationale to examine therapeutic strategies involving this cellular population. C_LI

pathology↗

bioRxiv2020

Overexpression of HLA class I predominantly on alpha cell in at risk individuals for type 1 diabetes

Human leukocyte antigens of class-I (HLA-I) molecules are hyper-expressed in insulin-containing islets (ICI) of type 1 diabetic (T1D) donors. This study investigated the HLA-I expression in autoantibody positive (AAB+) donors and more closely defined its intra-islet and intracellular localization as well as proximity to infiltrating CD8 T cells with high-resolution confocal microscopy. We found HLA-I hyper-expression had already occurred prior to clinical diagnosis of T1D in islets of AAB+ donors. Interestingly, throughout all stages of disease, HLA-I was mostly expressed by alpha cells. Hyper-expression in AAB+ and T1D donors was associated with intra-cellular accumulation in the Golgi. Proximity analysis showed a moderate but significant correlation between HLA-I and infiltrating CD8 T cells only in ICI of T1D donors, but not in AAB+ donors. These observations not only demonstrate a very early, islet-intrinsic immune-independent increase of HLA-I during diabetes pathogenesis, but also point towards a role for alpha cells in T1D. SummaryHuman leukocyte antigens of class-I (HLA-I) are hyper-expressed in insulin-containing islets of type 1 diabetic (T1D) donors. This study finds HLA-I hyper-expression occurs prior to clinical diagnosis of T1D in islets of autoantibody-positive donors and mostly expressed by alpha cells.

immunology↗