This application is mandated by the RFA for U01, which will allow us to synergize with other outstanding mucosal immunologists and cooperatively uncover and harness the neglected mucosal protective functions of IgD, an evolutionarily conserved yet mysterious class of antibody. Human upper respiratory mucosa contains abundant IgD-producing B cells that release IgD into nasal, lachrymal, salivary, mammary and bronchial secretions. Numerous clinical and immunological observations of IgD in the past 50 years strongly suggest that IgD has important functions in respiratory mucosal immune defense. The broad, long-term objectives of this project are to elucidate the regulation of IgD production as well as the mechanism and function of IgD in respiratory immunity in order to develop vaccines that harness the functions of IgD to combat respiratory infections and therapies to treat immunopathologies associated with IgD hyperproduction. This study hypothesizes that B cells from upper respiratory mucosa undergo IgD production and diversification controlled by vitamin D3 and that IgD produced reacts against respiratory pathogens and contributes to mucosal immunity by activating local and systemic innate immune cells such as basophils and mast cells through interaction with heparin, eosinophil cationic protein and inflammasomes.
Three aims are proposed.
Aim 1 : To elucidate the regulation of IgD class switching and production in the respiratory mucosa.
Aim 2 : To determine the reactivity, clonal diversity, evolution and protective function of mucosal IgD.
Aim 3 : To dissect the mechanisms by which IgD activates mucosal and systemic immune responses. This study will take advantage of cells and tissues from healthy donors and patients with hyper-lgD syndrome, an autoinflammatory periodic fever syndrome, as a disease model. The regulation of IgD production by vitamin D3 and the mechanism by which IgD triggers immune activation will be investigated by biochemical, molecular and cellular biology techniques. The reactivity and protective functions of mucosal and systemic IgD responses upon respiratory pathogen exposure and after vaccination will by studied by single B cell sorting, cloning and expression, high-throughput next-generation sequencing and in vitro cell culture-based methods.
This project will establish clinically relevant information on IgD responses after vaccination and lead to the isolation of protective IgD clones that may be used clinically to combat respiratory infections. It will also support the use of vitamin D modifying regimens in treating immunopathologies and establish that more effective vaccination strategies against respiratory pathogens should actively boost IgD responses.
|Magri, Giuliana; Comerma, Laura; Pybus, Marc et al. (2017) Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals. Immunity 47:118-134.e8|
|Chorny, Alejo; Casas-Recasens, Sandra; Sintes, Jordi et al. (2016) The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells. J Exp Med 213:2167-85|
|Magri, Giuliana; Cerutti, Andrea (2015) Role of group 3 innate lymphoid cells in antibody production. Curr Opin Immunol 33:36-42|
|de Inocencio, Jaime; Mensa-Vilaro, Anna; Tejada-Palacios, Pilar et al. (2015) Somatic NOD2 mosaicism in Blau syndrome. J Allergy Clin Immunol 136:484-7.e2|
|Gutzeit, Cindy; Nagy, Noemi; Gentile, Maurizio et al. (2014) Exosomes derived from Burkitt's lymphoma cell lines induce proliferation, differentiation, and class-switch recombination in B cells. J Immunol 192:5852-62|
|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 15:354-364|
|Gutzeit, Cindy; Magri, Giuliana; Cerutti, Andrea (2014) Intestinal IgA production and its role in host-microbe interaction. Immunol Rev 260:76-85|
|Oropallo, Michael A; Cerutti, Andrea (2014) Germinal center reaction: antigen affinity and presentation explain it all. Trends Immunol 35:287-9|
|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|
|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|
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