Insulitis in human type 1 diabetes: The quest for an elusive lesion

Abstract

The histopathology of type 1 diabetes is defined by a decreased β-cell mass in association with insulitis, a characteristic lymphocytic infiltration limited to the islets of Langerhans and prominent in early stage disease in children. A cytotoxic T-cell mediated destruction of insulin-producing β-cells is thought to be initiated by an unknown (auto)antigen, leading to the destruction > 75% of β-cell mass at clinical diagnosis. Although considered to be pathognomonic for recent onset disease, insulitis has only been described in approximately 150 cases over the past century. This review describes the quest for this elusive lesion and gives its incidence in various patient subpopulations stratified for age of onset and duration of the disease. It discusses recent new insights into the regenerative capacity of the β-cell mass in the pre-clinical stages of the disease and relates these findings to the inflammatory processes within the islet tissue.

Figure 1

Histopathology of islets of Langerhans from a two year old female patient with recent onset (9 days) type 1 diabetes (case SP57/130 from W Gepts collection; ref. 12): insulitis in an islet immunohistochemically stained for insulin (A), pseudoatrophic islet stained for glucagon (B), islet with normal architecture stained for insulin (C). Section of pancreas from a three year old male patient with recent onset (60 days) type 1 diabetes (case ChHB 60/184 from W Gepts collection; ref. 12), showing marked islet hyperplasia in a single lobe (D). Insulitis in a 59 year old potentially pre-diabetic male organ donor with serum positivity for multiple autoantibodies against islet cell antigens and a susceptible HLA-DQ genotype (case two from ref. 40) (E). Immunofluorescent staining showing infiltrating CD8⁺ T-cells (red) and residual b-cells stained for insulin (blue) in islets from case two (F).