Patients with allergic diseases invariably have elevated IgE levels. The acquisition of specific immune sensitivity to allergens in these same individuals is linked to their cumulative environmental allergen exposure. These associations suggest that IgE may promote allergic sensitization. Recent data from this laboratory have established such a function for IgE antibodies in contact sensitivity responses, where they enhance immune sensitization to epicutaneously-applied chemical haptens using a mechanism that requires their interaction with mast cells via FcEepsilonRI. Preliminary studies have shown that responses to contact sensitizers are markedly impaired in IgE-/- and mast cell-deficient (W/W') mice as well as animals lacking FcepsilonRI. IgE antibodies support the production of cytokines by mast cells in irritant-exposed skin in an antigen-independent manner consistent with monomeric IgE signaling. The skin of both mast cell- and IgE-deficient animals has abnormally low levels of TNF, a mast cell cytokine previously shown to be critical in contact sensitivity. Intradermal injection of TNF completely restores the contact sensitivity responses of IgE-/- and W/W' mice. Pulmonary responses to contact sensitizers are also IgE-dependent. These findings give rise to the hypothesis that IgE primes dermal mast cells for irritant-induced production of TNF and IL-6 and that these mast cell-derived cytokines activate tissue dendritic cells to drive effective immune sensitization. This hypothesis will be examined with the following aims: I. The contact sensitivity system will be used to establish the effects of mast cells and of mast cell-derived cytokines TNF and IL-6 on dermal dendritic cells and Langerhans cells. ll. The """"""""priming"""""""" function of IgE antibodies for mast cell responses to chemical irritants and secretagogues and the mechanism of monomeric IgE signaling will be characterized in cultured mast cells and in vivo. III. A murine model of occupational asthma will be used to examine the roles of IgE antibodies, mast cells, IL-6 and TNF in the induction of airway inflammation following inhalation of contact sensitizers.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunological Sciences Study Section (IMS)
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Dong, Gang
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Children's Hospital Boston
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Poddighe, D; Mathias, C B; Freyschmidt, E J et al. (2014) Basophils are rapidly mobilized following initial aeroallergen encounter in naïve mice and provide a priming source of IL-4 in adaptive immune responses. J Biol Regul Homeost Agents 28:91-103
Mathias, Clinton B; Hobson, Suejy A; Garcia-Lloret, Maria et al. (2011) IgE-mediated systemic anaphylaxis and impaired tolerance to food antigens in mice with enhanced IL-4 receptor signaling. J Allergy Clin Immunol 127:795-805.e1-6
Burton, Oliver T; Oettgen, Hans C (2011) Beyond immediate hypersensitivity: evolving roles for IgE antibodies in immune homeostasis and allergic diseases. Immunol Rev 242:128-43
Fried, Ari J; Oettgen, Hans C (2010) Anti-IgE in the treatment of allergic disorders in pediatrics. Curr Opin Pediatr 22:758-64
Tachdjian, Raffi; Al Khatib, Shadi; Schwinglshackl, Andreas et al. (2010) In vivo regulation of the allergic response by the IL-4 receptor alpha chain immunoreceptor tyrosine-based inhibitory motif. J Allergy Clin Immunol 125:1128-1136.e8
Kashiwakura, Jun-ichi; Kawakami, Yuko; Yuki, Keisuke et al. (2009) Polyclonal IgE induces mast cell survival and cytokine production. Allergol Int 58:411-9
Mathias, Clinton B; Freyschmidt, Eva-Jasmin; Caplan, Benjamin et al. (2009) IgE influences the number and function of mature mast cells, but not progenitor recruitment in allergic pulmonary inflammation. J Immunol 182:2416-24
Tachdjian, Raffi; Mathias, Clinton; Al Khatib, Shadi et al. (2009) Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma. J Exp Med 206:2191-204
Charles, Nicolas; Watford, Wendy T; Ramos, Haydeé L et al. (2009) Lyn kinase controls basophil GATA-3 transcription factor expression and induction of Th2 cell differentiation. Immunity 30:533-43
Mathias, C B; Freyschmidt, E-J; Oettgen, H C (2009) Immunoglobulin E antibodies enhance pulmonary inflammation induced by inhalation of a chemical hapten. Clin Exp Allergy 39:417-25

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