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

Abstract

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