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.

Increased Neutrophil Elastase and Proteinase 3 and Augmented NETosis Are Closely Associated With β-Cell Autoimmunity in Patients With Type 1 Diabetes

“…After the disease onset, mild neutropenia persists for a few years and then resolves at 5 years after diagnosis (as determined by a longitudinal analysis). In NOD mice with spontaneous development of autoimmune diabetes, neutrophil infiltration and NET formation in the islets are detected as early as 2 weeks after birth, well before the onset of overt diabetes (9). Furthermore, neutrophil depletion at the early stage reduces subsequent development of diabetes in NOD mice (9).…”

“…These autoantibodies have been proven to be instrumental for the prediction and diagnosis of T1D but are deemed not to be pathogenic (6,7). A number of other immune cells, including dendritic cells, macrophages, B cells, and neutrophils, are also implicated in the development of insulitis in T1D (8,9). Neutrophils, which are the most abundant (40-75%) type of white blood cells, have recently been implicated in the onset and progression of T1D (10,11).…”

“…Notably, circulating neutrophil counts are reduced in patients with T1D and in their nondiabetic first-degree relatives but not in patients with type 2 diabetes (11). In nonobese diabetic (NOD) mice (a spontaneous model of T1D), neutrophil infiltration and NET formation in the islets were observed as early as 2 weeks after birth, and blockage of neutrophil activities with an anti-Ly6G antibody reduced the subsequent development of insulitis and diabetes (9).…”

Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients

“…The activation of DCs by NETs appears to play an important role in the pathogenesis of some autoimmune diseases such as psoriasis (Lande et al, 2007), systemic lupus erythematosus (SLE) (Barrat et al, 2005;Garcia-Romo et al, 2011;Lande et al, 2011;Means et al, 2005) small vessel vasculitis (Sangaletti et al, 2012) and type I diabetes (Diana et al, 2013). NETsactivated pDCs produce large amounts of interferon that can lead to the maturation of myeloid DCs (mDCs) and exert an effect on T cell function.…”

La pêche miraculeuse des filets du neutrophile

“…Certaines études récentes suggèrent une participation des NET à la physiopathologie d'autres maladies auto-immunes, comme la polyarthrite rhumatoïde (PR), le syndrome de Felty [10,18], le psoriasis [19] ou le diabète de type 1 [20]. En effet, les NET sont présents dans les foyers inflammatoires caractérisant ces pathologies (liquides synoviaux de PR, lésions cutanées de psoriasis, îlots de Langerhans dans le diabète) et les protéines identifiées à leur surface exerceraient, soit un rôle antigénique (PR), soit un rôle d'activation des pDC (psoriasis et diabète de type 1), soit un rôle directement pro-inflammatoire (psoriasis).…”