Several physiological and pathological events taking place postnatally in or around the pancreatic islets of Langerhans have been implicated in the initiation of type 1 diabetes. A new study highlights the contribution of neutrophils and how they, together with B1a cells and plasmacytoid dendritic cells (pDCs), may start the autoimmune process
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Early pathophysiological events in the pancreatic islets lead to the release of self DNA and self antigens from dying beta cells, which prompts the arrival of macrophages to clear up cell debris. Diana et al. now show that in the NOD mouse, these macrophages are recruited along with neutrophils, pDCs, cDCs and B cells (including a substantial number of B1a cells, which start to secrete DNA-specific antibodies). DNA–antibody immune complexes activate neutrophils to release CRAMP. DNA–antibody immune complexes and CRAMP act synergistically to potently stimulate pDCs to secrete IFN-α, which, in turn, activates cDCs as well as neutrophils and B cells. cDCs pick up self antigens and, upon activation, migrate to the pancreatic lymph nodes to present beta cell antigen–derived peptides. Due to various defects in central and peripheral tolerance in NOD mice, an abnormal number of self-reactive T cells are present in the periphery. Upon encounter with cDCs loaded with beta cell antigens, diabetogenic T cells become fully activated and home to the islets to progressively mediate the destruction of beta cells. Verdict: all suspects are guilty.