This proposal seeks to understand the role of chitin in activating allergic-type immunity in living animals. Chitin is a natural constituent of many organisms, including Crustacea, insects, fungi and worms, that have been associated with allergic-like immune responses in humans. Such immune responses contribute a large and increasing health care burden to the country, and are particularly prevalent in children. Recently, we have established that chitin can activate innate infiltration of tissues with allergy-associated cells, including eosinophils, basophils and alternatively activated macrophages. This grant will seek to characterize the kinetics of this response and the role of chitin in modulating signals from prevalent microbial constituents, such as LPS, and will use a physiologic infection with the model helminth, Nippostrongylus brasiliensis. The key experimental strategy builds on the use of reporter mice with markers inserted into critical genes implicated in these types of immune responses. In turn, collaboration with each of the investigators on this PPG will be used to create mice in which classic inflammatory signals are modulated negatively or positively, thus testing the hypothesis that immune responses to chitin may serve to dampen inflammatory responses at mucosal barriers. This will be tested in 3 specific aims that will address the induction of the allergic immune response, the capacity to induce adaptive Th2-associated responses through activation of dendritic cells, and the modulation afforded by induction of mucosal chitinase, which degrades the chitin signal, and cytokines such as TSLP that may positively regulate the response. The major investigative modalities will be multiparameter flow cytometry that allows precise correlation of cell types with functions, together with immunohistochemistry approaches that facilitate insights towards cell positioning. This two modalities will be supported as core facilities in this Program Project. Achievement of these aims will greatly facilitate our understanding of the genesis of allergic immunity, and potentially suggest novel therapeutic strategies in allergic immunity, helminth immunity and in creating new adjuvants targeting mucosal immune responses. (LAY) Allergic immunity is an increasing problem in developed countries, including the United States. Almost nothing is known about how these types of immune responses are inititated by various environmental insults. This grant will examine how chitin, a constituent of worms, shellfish, molds and insects, all of which have been associated with human allergy, induces allergic immune responses in model animal worm infections. Such insights may contribute to new methods for control of these immune reactions.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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University of California San Francisco
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Costa, Sara; Marini, Olivia; Bevilacqua, Dalila et al. (2017) Role of MyD88 signaling in the imiquimod-induced mouse model of psoriasis: focus on innate myeloid cells. J Leukoc Biol 102:791-803
Molofsky, Ari B; Van Gool, Frédéric; Liang, Hong-Erh et al. (2015) Interleukin-33 and Interferon-? Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation. Immunity 43:161-74
Hua, Zhaolin; Gross, Andrew J; Lamagna, Chrystelle et al. (2014) Requirement for MyD88 signaling in B cells and dendritic cells for germinal center anti-nuclear antibody production in Lyn-deficient mice. J Immunol 192:875-85
Mayadas, Tanya N; Cullere, Xavier; Lowell, Clifford A (2014) The multifaceted functions of neutrophils. Annu Rev Pathol 9:181-218
Lamagna, Chrystelle; Hu, Yongmei; DeFranco, Anthony L et al. (2014) B cell-specific loss of Lyn kinase leads to autoimmunity. J Immunol 192:919-28
Abram, Clare L; Roberge, Gray L; Hu, Yongmei et al. (2014) Comparative analysis of the efficiency and specificity of myeloid-Cre deleting strains using ROSA-EYFP reporter mice. J Immunol Methods 408:89-100
Van Gool, Frédéric; Molofsky, Ari B; Morar, Malika M et al. (2014) Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy. Blood 124:3572-6
Molofsky, Ari B; Nussbaum, Jesse C; Liang, Hong-Erh et al. (2013) Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 210:535-49
Hammer, Gianna Elena; Ma, Averil (2013) Molecular control of steady-state dendritic cell maturation and immune homeostasis. Annu Rev Immunol 31:743-91
Lamagna, Chrystelle; Scapini, Patrizia; van Ziffle, Jessica A et al. (2013) Hyperactivated MyD88 signaling in dendritic cells, through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation. Proc Natl Acad Sci U S A 110:E3311-20

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