Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes

J Diana, Y Simoni, L Furio, L Beaudoin, B Agerberth… - Nature medicine, 2013 - nature.com
J Diana, Y Simoni, L Furio, L Beaudoin, B Agerberth, F Barrat, A Lehuen
Nature medicine, 2013nature.com
Type 1 diabetes develops over many years and is characterized ultimately by the destruction
of insulin-producing pancreatic beta cells by autoreactive T cells. Nonetheless, the role of
innate cells in the initiation of this disease remains poorly understood. Here, we show that in
young female nonobese diabetic mice, physiological beta cell death induces the recruitment
and activation of B-1a cells, neutrophils and plasmacytoid dendritic cells (pDCs) to the
pancreas. Activated B-1a cells secrete IgGs specific for double-stranded DNA. IgGs activate …
Abstract
Type 1 diabetes develops over many years and is characterized ultimately by the destruction of insulin-producing pancreatic beta cells by autoreactive T cells. Nonetheless, the role of innate cells in the initiation of this disease remains poorly understood. Here, we show that in young female nonobese diabetic mice, physiological beta cell death induces the recruitment and activation of B-1a cells, neutrophils and plasmacytoid dendritic cells (pDCs) to the pancreas. Activated B-1a cells secrete IgGs specific for double-stranded DNA. IgGs activate neutrophils to release DNA-binding cathelicidin-related antimicrobial peptide (CRAMP), which binds self DNA. Then, self DNA, DNA-specific IgG and CRAMP peptide activate pDCs through the Toll-like receptor 9–myeloid differentiation factor 88 pathway, leading to interferon-α production in pancreatic islets. We further demonstrate through the use of depleting treatments that B-1a cells, neutrophils and IFN-α–producing pDCs are required for the initiation of the diabetogenic T cell response and type 1 diabetes development. These findings reveal that an innate immune cell crosstalk takes place in the pancreas of young NOD mice and leads to the initiation of T1D.
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