title: Mechanisms of diabetic autoimmunity: I--the inductive interface between islets and the immune system at onset of inflammation.
abstract: The mechanisms of autoimmune reactivity onset in type 1 diabetes (T1D) remain elusive despite extensive experimentation and discussion. We reconsider several key aspects of the early stages of autoimmunity at four levels: islets, pancreatic lymph nodes, thymic function and peripheral immune homeostasis. Antigen presentation is the islets and has the capacity to provoke immune sensitization, either in the process of physiological neonatal β cell apoptosis or as a consequence of cytolytic activity of self-reactive thymocytes that escaped negative regulation. Diabetogenic effectors are efficiently expanded in both the islets and the lymph nodes under conditions of empty lymphoid niches during a period of time coinciding with a synchronized wave of β cell apoptosis surrounding weaning. A major drive of effector cell activation and expansion is inherent peripheral lymphopenia characteristic of neonates, though it remains unclear when is autoimmunity triggered in subjects displaying hyperglycemia in late adolescence. Our analysis suggests that T1D evolves through coordinated activity of multiple physiological mechanisms of stimulation within specific characteristics of the neonate immune system.
authors.affiliation: The Leah and Edward M. Frankel Laboratory of Experimental Bone Marrow Transplantation, 14 Kaplan Street, 49202, Petach Tikva, Israel. anadir@012.net.il.
authors.forename: Nadir
authors.initials: N
authors.lastname: Askenasy
mesh_terms: D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004198:Disease Susceptibility; D006706:Homeostasis; D006801:Humans; D007107:Immune System / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007157:Immunologic Surveillance; D007249:Inflammation / Q000276:immunology; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D001324:Autoantigens
keywords: Diabetogenic cells; Islets; Neonatal lymphopenia; Pancreatic lymph nodes; T cell effectors; Thymus; Type 1 diabetes onset