title: Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes.
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.
authors.affiliation: Institut National de Santé et de Recherche Médicale (INSERM), U986, Paris, France. julien.diana@inserm.fr
authors.forename: Julien
authors.initials: J
authors.lastname: Diana
authors.forename: Yannick
authors.initials: Y
authors.lastname: Simoni
authors.forename: Laetitia
authors.initials: L
authors.lastname: Furio
authors.forename: Lucie
authors.initials: L
authors.lastname: Beaudoin
authors.forename: Birgitta
authors.initials: B
authors.lastname: Agerberth
authors.forename: Franck
authors.initials: F
authors.lastname: Barrat
authors.forename: Agnès
authors.initials: A
authors.lastname: Lehuen
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D054804:Cathelicidins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010179:Pancreas / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D016898:Interferon-alpha; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9