Objective The long-term goal of this proposal is to explore a novel immune pathway that involves an unexpected interplay between marginal zone (MZ) B cells and neutrophils. MZ B cells are strategically positioned at the interface between the immune system and the circulation and rapidly produce protective antibodies to blood-borne pathogens through a T cell-independent pathway that remains poorly understood. We recently found that the human spleen contains a novel subset of B cell helper neutrophils (NBH cells) with a phenotype and gene expression profile distinct from those of conventional circulating neutrophils (NC cells). In this proposal, we hypothesize that NC cells undergo splenic reprogramming into NBH cells through an IL-10-dependent pathway involving perifollicular sinusoidal endothelial cells. We contend that these unique endothelial cells release NC cell-attracting chemokines and IL-10 upon sensing blood-borne bacteria through Toll-like receptors. We also argue that IL-10 from sinusoidal endothelial cells stimulates NC cells to differentiate into NBH cells equipped with powerful MZ B cell-stimulating activity. The following three aims will be pursued. Aim 1 is to determine the mechanisms by which splenic sinusoidal endothelial cells induce reprogramming of NC cells into NBH cells upon sensing bacteria through Toll-like receptors. Aim 2 is to elucidate the mechanisms by which NBH cells induce IgM production, IgG and IgA class switching, and plasma cell differentiation in MZ B cells. Aim 3 is to evaluate the mechanisms by which NBH cells induce V(D)J gene somatic hypermutation and high-affinity antibody production in MZ B cells. These studies will uncover previously unknown facets of the immunological function of neutrophils by taking advantage of unique cells and tissues from patients with rare primary immunodeficiencies and by making use of selected mouse models. Results from these studies may also lead to the identification of novel vaccine strategies. Fields of science natural sciencesbiological sciencesmicrobiologybacteriologymedical and health sciencesbasic medicineimmunologymedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS6 - ERC Advanced Grant - Immunity and infection Call for proposal ERC-2011-ADG_20110310 See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Coordinator FUNDACIO INSTITUT HOSPITAL DEL MAR D INVESTIGACIONS MEDIQUES Address Doctor aiguader 88 08003 Barcelona Spain See on map Region Este Cataluña Barcelona Activity type Research Organisations Administrative Contact Andreu Fort (Mr.) Principal investigator Andrea Cerutti (Dr.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all FUNDACIO INSTITUT HOSPITAL DEL MAR D INVESTIGACIONS MEDIQUES Spain EU contribution € 2 214 035,31 Address Doctor aiguader 88 08003 Barcelona See on map Region Este Cataluña Barcelona Activity type Research Organisations Administrative Contact Andreu Fort (Mr.) Principal investigator Andrea Cerutti (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Other funding No data
