Differential expression of genes controlling lymphocyte differentiation and migration in two distinct endotypes of type 1 diabetes

Abstract

AimsMorphological studies of pancreas samples obtained from young people with recent‐onset type 1 diabetes have revealed distinct patterns of immune cell infiltration of the pancreatic islets suggestive of two age‐associated type 1 diabetes endotypes that differ by inflammatory responses and rates of disease progression. The objective of this study was to investigate whether these proposed disease endotypes are associated with pathological differences in immune cell activation and cytokine secretion by applying multiplexed gene expression analysis to pancreatic tissue from recent‐onset type 1 diabetes cases.MethodsRNA was extracted from samples of fixed, paraffin‐embedded pancreas tissue from type 1 diabetes cases characterised by endotype and from controls without diabetes. Expression levels of 750 genes associated with autoimmune inflammation were determined by hybridisation to a panel of capture and reporter probes and these were counted as a measure of gene expression. Normalised counts were analysed for differences in expression between 29 type 1 diabetes cases and 7 controls without diabetes, and between the two type 1 diabetes endotypes.ResultsTen inflammation‐associated genes, including INS, were significantly under‐expressed in both endotypes and 48 genes were more highly expressed. A different set of 13 genes associated with the development, activation and migration of lymphocytes was uniquely overexpressed in the pancreas of people developing diabetes at younger age.ConclusionsThe results provide evidence that histologically defined type 1 diabetes endotypes differ in their immunopathology and identify inflammatory pathways specifically involved in disease developing at a young age, essential for a better understanding of disease heterogeneity.

Insulitis in human type 1 diabetes: lessons from an enigmatic lesion

“…Torabi et al . 47 employed Nanostring nCounter technology to interrogate the expression of immune genes in RNA samples extracted from the pancreases of young people assigned to each T1D endotype and identified several genes that were differentially expressed between them. Foremost among these is IKZF3 , a gene involved in B-cell differentiation which is most abundant in the youngest group of subjects (T1DE1) consistent with the differential involvement of B-cells in the insulitis between the endotypes.…”

“…Interestingly, and fully consistent with these findings, earlier work had implicated this same gene as predisposing to type 1 diabetes selectively in very young children. 48 A dozen additional immune genes were also cited as differentially expressed in the pancreas between T1DE1 and T1DE2 47 suggesting that analysis of such gene expression profiles may provide a fertile means to define the immune cell subtypes present in human islets during insulitis, more fully.…”