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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Davidson, Wendy F
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Wechsler, J B; Szabo, A; Hsu, C L et al. (2018) Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis. Mucosal Immunol 11:861-870
Gonsalves, N; Berdnikovs, S; Schroeder, H et al. (2017) Gender-specific differences in the molecular signatures of adult Eosinophilic Oesophagitis. Clin Exp Allergy 47:969-971
Pelz, B J; Wechsler, J B; Amsden, K et al. (2016) IgE-associated food allergy alters the presentation of paediatric eosinophilic esophagitis. Clin Exp Allergy 46:1431-1440
Johnston, Laura K; Hsu, Chia-Lin; Krier-Burris, Rebecca A et al. (2016) IL-33 Precedes IL-5 in Regulating Eosinophil Commitment and Is Required for Eosinophil Homeostasis. J Immunol 197:3445-3453
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Wechsler, Joshua B; Bryce, Paul J (2014) Allergic mechanisms in eosinophilic esophagitis. Gastroenterol Clin North Am 43:281-96
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
Johnston, Laura K; Chien, Karen B; Bryce, Paul J (2014) The immunology of food allergy. J Immunol 192:2529-34

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