Reduction of Circulating Neutrophils Precedes and Accompanies Type 1 Diabetes

Human type 1 diabetes (T1D) is an autoimmune disease associated with MHC polymorphisms, β-cell autoantibodies and autoreactive T-cells. However, there is increasing evidence that innate cells may also play critical roles in T1D. We aimed at monitoring peripheral immune cells in early stages of T1D (i.e., in healthy autoantibody positive subjects) and in more advanced phases of the disease (i.e., at disease onset and years after diagnosis). We found a mild, but significant and reproducible, peripheral neutropenia that both precedes and accompanies T1D onset. This reduction was not due to peripheral neutrophil cell-death, impaired differentiation or the presence of anti-neutrophil antibodies. Neutrophils were observed by electron microscopy and immunohistochemical analysis in the exocrine pancreas of multi-organ donors with T1D (both at onset and at later stages of the disease) and not in that of donors with T2D or non-diabetic donors. These pancreas-infiltrating neutrophils mainly localized at the level of very small blood vessels. Our findings suggest the existence of a hitherto unrecognized clinical phenotype that might reflect yet unexplored pathogenic pathways underlying T1D.