Abstract
Type 1 diabetes (T1D) is characterized by a chronic, progressive autoimmune attack against pancreas-specific antigens, effecting the destruction of insulin-producing β-cells. Here we show interleukin-2 (IL-2) is a non-pancreatic autoimmune target in T1D. Anti-IL-2 autoantibodies, as well as T cells specific for a single orthologous epitope of IL-2, are present in the peripheral blood of non-obese diabetic (NOD) mice and patients with T1D. In NOD mice, the generation of anti-IL-2 autoantibodies is genetically determined and their titre increases with age and disease onset. In T1D patients, circulating IgG memory B cells specific for IL-2 or insulin are present at similar frequencies. Anti-IL-2 autoantibodies cloned from T1D patients demonstrate clonality, a high degree of somatic hypermutation and nanomolar affinities, indicating a germinal centre origin and underscoring the synergy between cognate autoreactive T and B cells leading to defective immune tolerance.
Highlights
Type 1 diabetes (T1D) is characterized by a chronic, progressive autoimmune attack against pancreas-specific antigens, effecting the destruction of insulin-producing b-cells
We have previously shown that administration of low doses of recombinant human IL-2 at onset reverts disease in about half of the treated non-obese diabetic (NOD) mice[8]
We observed that these higher recombinant human IL-2 (rhIL-2) doses were, in a dosedependent manner: (i) lethally toxic in half of the mice; (ii) precipitated diabetes onset in around 25% of them; or intriguingly, (iii) induced no apparent clinical signs in around 25% of the mice, even after a 30-day administration (Fig. 1a–c)
Summary
Type 1 diabetes (T1D) is characterized by a chronic, progressive autoimmune attack against pancreas-specific antigens, effecting the destruction of insulin-producing b-cells. Anti-IL-2 autoantibodies, as well as T cells specific for a single orthologous epitope of IL-2, are present in the peripheral blood of non-obese diabetic (NOD) mice and patients with T1D. In type 1 diabetes (T1D), circulating, pancreas-specific autoantibodies are correlated with the onset of a chronic, pancreatic autoimmune attack leading to the progressive loss of insulin-producing b-cells[4]. Defects in the induction of central and peripheral tolerance checkpoints[5] are notable contributors to T1D pathology Illustrating this point, non-obese diabetic (NOD) mice, which recapitulate many characteristics of the complex pathogenesis of human T1D6, and T1D patients develop both islet-specific autoantibodies and autoreactive T cells, and feature syntenic genetic linkage to disease[7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
