Losing a grip on the notion of β-cell specificity for immune responses in type 1 diabetes: can we handle the truth?

Abstract

You can’t handle the truth!— Jack Nicholson, A Few Good Men Research utilizing human pancreata to define a role for the immune response in the pathogenesis of what we now term type 1 diabetes (T1D) has come a long way since 1902 when Schmidt, a German pathologist, noted a small cellular peri-islet infiltrate upon microscopic evaluation of the pancreas obtained from a 10-year-old child with diabetes (1). Efforts by Shields Warren in the 1920s drew attention to the relationship between this infiltrate and the age of diabetes onset (2), while the term “insulitis” was not coined until 1940 by the famous liver pathologist Hanns von Meyenburg (3). Subsequent work led by Gepts (4), LeCompte (5), Foulis (6), and others in ensuing decades (7,8) taught us much regarding this inflammatory lesion. We gained insight into its relative infrequency in older individuals diagnosed with the disease, the association with reduction in β-cell mass, identification of “pseudo-atrophic” islets (i.e., islets devoid of insulin-containing cells), the preferential targeting of insulitis for β-cells containing insulin, upregulation of class I MHC, and many other seminal findings. Taken collectively, these efforts not only formed an “intellectual cornerstone” upon which much of the research enterprise in T1D over the last 40 years has been built but also led to the oft-cited notion that T1D results from an autoimmune destruction of the insulin-secreting pancreatic β-cells. As a community of researchers, we built our models regarding the natural history of T1D around this …