Cytokines and their receptors have an incredible ability to regulate a diverse range of cellular responses, important for homeostasis and control of protective immune responses. Increasingly, context or cell-specific influences of cytokines are being observed but the mechanisms that regulate this remain unclear given the limited repertoire of intracellular signaling molecules within the Jak and Stat family. Recently, the concept of "modifiers" of cytokine receptor functions has emerged, whereby signals from other receptors can alter those through the cytokine receptor. Our exciting findings have established that histamine, acting via its receptor H2R, is necessary for cellular responses to IL-4. This cytokine is critically important in allergic responses and we have demonstrated that H2R KO mice have ablated IgE generation and eosinophil recruitment to the lungs. In studying this interaction further, we have identified that both hematopoietic and non-hematopoietic cells possess histamine-dependent and independent responsiveness to IL-4. We hypothesize that H2R functions as a modifier of signaling from the IL-4 receptor and is necessary for switching from the homeostatic functions of IL-4 to a pro- allergic response. We propose to examine this with three specific aims that investigate this concept in murine models and in allergic patients.
Specific Aim 1 will examine the functional requirements for H2R on responses through the IL-4Ralpha chain (in collaboration with Dr Talal Chatila).
Specific Aim 2 will map the unique profile of histamine-dependent and independent genes in human and murine cells using state-of-the-art mRNA deep sequencing (in collaboration with Dr Nadereh Jafari).
Specific Aim 3 will examine histamine-associated gene patterns in the pathogenesis of eosinophilic esophagitis and build on our existing work demonstrating the mast cells and histamine are important in this disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI076456-07
Application #
8663826
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Davidson, Wendy F
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60611
Wechsler, Joshua B; Hsu, Chia-Lin; Bryce, Paul J (2014) IgE-mediated mast cell responses are inhibited by thymol-mediated, activation-induced cell death in skin inflammation. J Allergy Clin Immunol 133:1735-43
Wechsler, Joshua B; Bryce, Paul J (2014) Allergic mechanisms in eosinophilic esophagitis. Gastroenterol Clin North Am 43:281-96
Johnston, Laura K; Chien, Karen B; Bryce, Paul J (2014) The immunology of food allergy. J Immunol 192:2529-34
Sena, Laura A; Li, Sha; Jairaman, Amit et al. (2013) Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38:225-36
Ganeshan, Kirthana; Johnston, Laura K; Bryce, Paul J (2013) TGF-*1 limits the onset of innate lung inflammation by promoting mast cell-derived IL-6. J Immunol 190:5731-8
Ganeshan, Kirthana; Bryce, Paul J (2012) Regulatory T cells enhance mast cell production of IL-6 via surface-bound TGF-ýý. J Immunol 188:594-603
Swartzendruber, Julie A; Byrne, Adam J; Bryce, Paul J (2012) Cutting edge: histamine is required for IL-4-driven eosinophilic allergic responses. J Immunol 188:536-40
Wills-Karp, Marsha; Rani, Reena; Dienger, Krista et al. (2012) Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J Exp Med 209:607-22
Smuda, Craig; Wechsler, Joshua B; Bryce, Paul J (2011) TLR-induced activation of neutrophils promotes histamine production via a PI3 kinase dependent mechanism. Immunol Lett 141:102-8
Smuda, Craig; Bryce, Paul J (2011) New developments in the use of histamine and histamine receptors. Curr Allergy Asthma Rep 11:94-100

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