Abstract
Human type 1 diabetes (T1D) is considered to be an autoimmune disease, with CD8+ T-cell-mediated cytotoxicity being directed against the insulin-producing beta cells, leading to a gradual decrease in beta cell mass and the development of chronic hyperglycemia. The histopathologically defining lesion in recent-onset T1D patients is insulitis, a relatively subtle leucocytic infiltration present in approximately 10 % of the islets of Langerhans from children with recent-onset (<1 year) disease. Due to the transient nature of the infiltrate, its heterogeneous distribution in the pancreas and the nature of the patient population, material for research is extremely rare and limited to a cumulative total of approximately 150 cases collected over the past century. Most studies on the etiopathogenesis of T1D have therefore focused on the non-obese diabetic (NOD) mouse model, which shares many genetic and immunological disease characteristics with human T1D, although its islet histopathology is remarkably different. In view of these differences and in view of the limited success of clinical immune interventions based on observations in the NOD mouse, there is a renewed focus on studying the pathogenetic process in patient material.
Highlights
Human type 1 diabetes (T1D) is considered to be an autoimmune disease, with CD8+ T-cell-mediated cytotoxicity being directed against the insulin-producing beta cells, leading to a gradual decrease in beta cell mass and the development of chronic hyperglycemia
The presence of autoantibodies is usually taken as a sign of ongoing beta cell destruction, with beta cell mass decreasing as autoimmunity expands as witnessed by the increasing number of autoantibodies
From a histopathological point of view, the insulitic lesions in the islet of Langerhans of recent-onset T1D patients are very different from those observed in the nonobese diabetic (NOD) mouse
Summary
Insulitis is defined as a predominantly lymphocytic infiltration, limited to the islets of Langerhans. In a 1978 follow-up study [23], using the newly developed immunohistochemical staining techniques for islet hormones, he observed that insulitis preferentially targeted islets with remaining beta cells and that it was virtually absent in islets from which the beta cells had disappeared This led him to propose that ‘insulitis represents an immune reaction of the delayed type, directed against beta cells’. His studies were confirmed by Foulis [24], who used a computerized survey of deaths in the UK and was able to retrieve tissue blocks of 119 patients who died in diabetic ketoacidosis before the age of 20. Major follow-up studies have been lacking due to the reasons outlined above, and only recently a renewed effort to study insulitis in human T1D was initiated using large biobanks of human donor pancreas in Brussels and Gainesville-FL (JDRF-nPOD)
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