The goal of this proposal is to elucidate the interplay between the innate immune system and marginal zone (MZ) B cells in humans. MZ B cells interface with the circulation and rapidly produce protective antibodies to blood-born 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 neutrophils (NC cells) present in our circulation. 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 sinusoidal endothelial cells release NC cell- attracting chemokines and IL-10 upon sensing blood-born bacteria through Toll-like receptors. We also argue that IL-10 from sinusoidal endothelial cells stimulates NC cells to differentiate into NBH cells 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 dissect the interplay between neutrophils and MZ B cells by taking advantage of unique cells and tissues from healthy individuals and patients with rare primary immunodeficiencies. Results from these studies may lead to the identification of novel neutrophil-targeting strategies that may enhance vaccine-induced antibody responses by harnessing the B cell helper activity of NBH cells.

Public Health Relevance

MZ B cells provide immune protection by rapidly producing antibodies against blood- born microbes. The proposed studies will explore a novel immune pathway involving an unexpected interplay between MZ B cells and a unique population of neutrophils present in the human spleen. Our work may lead to the development of novel vaccine strategies harnessing the antibody-inducing function of neutrophils. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI057653-06
Application #
8237267
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Ferguson, Stacy E
Project Start
2003-12-01
Project End
2016-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
6
Fiscal Year
2012
Total Cost
$423,750
Indirect Cost
$173,750
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Oropallo, Michael A; Cerutti, Andrea (2014) Germinal center reaction: antigen affinity and presentation explain it all. Trends Immunol 35:287-9
Magri, Giuliana; Miyajima, Michio; Bascones, Sabrina et al. (2014) Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat Immunol 15:354-64
Romberg, Neil; Chamberlain, Nicolas; Saadoun, David et al. (2013) CVID-associated TACI mutations affect autoreactive B cell selection and activation. J Clin Invest 123:4283-93
Cerutti, Andrea; Cols, Montserrat; Puga, Irene (2013) Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol 13:118-32
Shan, Meimei; Gentile, Maurizio; Yeiser, John R et al. (2013) Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 342:447-53
Almejun, Maria B; Cols, Montserrat; Zelazko, Marta et al. (2013) Naturally occurring mutation affecting the MyD88-binding site of TNFRSF13B impairs triggering of class switch recombination. Eur J Immunol 43:805-14
Cerutti, Andrea; Puga, Irene; Magri, Giuliana (2013) The B cell helper side of neutrophils. J Leukoc Biol 94:677-82
Chorny, Alejo; Puga, Irene; Cerutti, Andrea (2012) Regulation of frontline antibody responses by innate immune signals. Immunol Res 54:4-13
Klasse, Per Johan; Sanders, Rogier W; Cerutti, Andrea et al. (2012) How can HIV-type-1-Env immunogenicity be improved to facilitate antibody-based vaccine development? AIDS Res Hum Retroviruses 28:1-15

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