The Immune Pathogenesis of Type 1 Diabetes: Not Only Thinking Outside the Cell but Also Outside the Islet and Out of the Box.

Abstract

Around 1960, observations of lymphocytic insulitis and the presence of islet cell autoantibodies in patients with type 1 diabetes led to the concept of type 1 diabetes being an organ-specific autoimmune disease. Much work has since been done to unravel the mechanisms behind the aberrant self-directed immune response and to predict disease progression, as it appeared that the autoimmune reaction preceded clinical diabetes, often for many years. Research focused on the identification of the primary autoantigen(s) to which the antibodies were directed. Important targets, such as insulin, GAD65, and IA-2, were discovered. However, research into the pathogenic mechanisms was hampered because the pancreas tissue of patients in the initial phases was rarely available. For that reason, animal models, such as the NOD mouse and the diabetes-prone BioBreeding (BBDP) rat, that developed autoimmune diabetes spontaneously were used to study prestages of the disease and to test therapeutic interventions. Studies in these animal models have mainly focused on autoreactive T-cell–mediated inflammatory destructive reactions to the islets of Langerhans, and balances between a multitude of regulatory and effector mechanisms became gradually apparent (1). However, translation of these animal data to the human disease was a controversial issue. Nevertheless, from all this work the view developed that the central pathogenic mechanism is an antigen-driven T lymphocyte–mediated inflammatory reaction of the islets, which specifically affects the β-cells disappearing in the reaction. This excessive reaction is allowed by defective tolerance mechanisms, and particular emphasis has been on the population of thymus-derived CD4+CD25+FOXP3+ T regulatory cells (excellently reviewed in ref. 1). However, many questions remained (1), among which were, “What are the initiating factors?” and “How are innate immune responses involved?” A consortium of research groups (Network for Pancreatic Organ Donors with Diabetes [nPOD]) embarked on collecting relevant tissues from organ donors …