Histamine-releasing factor enhances food allergy
Tomoaki Ando, … , Yuko Kawakami, Toshiaki Kawakami
Tomoaki Ando, … , Yuko Kawakami, Toshiaki Kawakami
Published November 13, 2017
Citation Information: J Clin Invest. 2017;127(12):4541-4553. https://doi.org/10.1172/JCI96525.
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Research Article Inflammation

Histamine-releasing factor enhances food allergy

Abstract

Food allergy occurs due to IgE- and mast cell–dependent intestinal inflammation. Previously, we showed that histamine-releasing factor (HRF), a multifunctional protein secreted during allergy, interacts with a subset of IgE molecules and that the HRF dimer activates mast cells in an HRF-reactive IgE-dependent manner. In this study, we investigated whether HRF plays any role in food allergy. Specifically, we determined that prophylactic and therapeutic administration of HRF inhibitors that block HRF-IgE interactions reduces the incidence of diarrhea and mastocytosis in a murine model of food allergy. Food allergy–associated intestinal inflammation was accompanied by increased secretion of the HRF dimer into the intestine in response to proinflammatory, Th2, and epithelial-derived cytokines and HRF-reactive IgE levels at the elicitation phase. Consistent with these data, patients with egg allergy had higher blood levels of HRF-reactive IgE compared with individuals that were not hypersensitive. Successful oral immunotherapy in egg-allergy patients and food-allergic mice reduced HRF-reactive IgE levels, thereby suggesting a pathological role for HRF in food allergy. Together, these results suggest that antigen and HRF dimer amplify intestinal inflammation by synergistically activating mast cells and indicate that HRF has potential as a therapeutic target in food allergy.

Authors

Tomoaki Ando, Jun-ichi Kashiwakura, Naoka Itoh-Nagato, Hirotaka Yamashita, Minato Baba, Yu Kawakami, Shih Han Tsai, Naoki Inagaki, Kiyoshi Takeda, Tsutomu Iwata, Naoki Shimojo, Takao Fujisawa, Mizuho Nagao, Kenji Matsumoto, Yuko Kawakami, Toshiaki Kawakami

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Figure 7

HRF-reactive IgE levels are low in desensitized mice.

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HRF-reactive IgE levels are low in desensitized mice. (A) Mice were unse...
(A) Mice were unsensitized (Cont) or i.p. sensitized as described in the Figure 1 legend and i.g. challenged with OVA with nonpretreated (OVA) or i.g. pretreated HRF-2CA (2CA). HRF-reactive IgE and IgG and OVA-specific IgE and IgG after sensitization (before OVA gavages) and after OVA gavages were measured. n = 4 for nonsensitized group; n = 14 for OVA group; n = 14 for 2CA group, pooled data of 2 independent experiments. **P < 0.01; ***P < 0.001; ****P < 0.0001, paired t test. (B and C) Five daily oral administrations of 1 mg OVA from day –11 to day –7 were followed by sensitization with OVA and then by OVA challenges in mice. Without oral pretreatment, which prevented diarrhea, all OVA-sensitized mice developed allergic diarrhea. At the end of the experiment, HRF-reactive IgE and total IgE were quantified. n = 5 for nonsensitized group; n = 10 for OVA group; n = 9 for OIT/OVA group, pooled data of 2 independent experiments. *P < 0.05, Student’s t test (C). (D and E) Mice were intradermally sensitized with OVA followed by oral OVA challenges. All mice showed diarrhea. Then some mice received hourly increasing amounts of OVA for 3 consecutive days (OIT). Levels of HRF-reactive IgE and IgG as well as OVA-specific IgE and IgG were quantified by ELISA before and after OIT (n = 4 for no OIT group and n = 5 for OIT group). Statistics by paired t test.