Histamine-releasing factor enhances food allergy
Tomoaki Ando, … , Yuko Kawakami, Toshiaki Kawakami
Tomoaki Ando, … , Yuko Kawakami, Toshiaki Kawakami
Published December 1, 2017; First 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 1

GST-N19 inhibits the development of diarrhea and intestinal mastocytosis in murine food allergy.

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GST-N19 inhibits the development of diarrhea and intestinal mastocytosis...
Mice were i.p. sensitized with OVA (50 μg/mouse) plus alum on days 0 and 14. From day 28, mice were i.g. challenged with OVA (50 mg) 3 times a week. Sensitized mice were either nonpretreated (–) or i.g. pretreated with 100 μg of GST or GST-N19 (N19). (A) Procedure schematic. (B) The development of diarrhea was monitored for 90 minutes after each OVA challenge. n = 5 for nonsensitized group; n = 3 for inhibitor nonpretreated group; n = 4 for GST group; n = 6 for N19 group. Data are representative of at least 3 independent experiments. log-rank test: P = 0.028 (GST vs. GST-N19), P = 0.036 (control vs. GST-N19). Nonsensitized mice did not exhibit diarrhea after OVA gavages (not shown). (C–E) Total IgE, IgG1, HRF, and HRF-reactive IgE and IgG in sera were measured by ELISA. (F) Serum mMCP-1 was also measured by ELISA. (G) Sections of jejunum were stained with chloroacetate esterase to identify mast cells. Sections indicated by rectangles are enlarged in lower rows. Scale bars: 100 μm; 50 μm (insets). (H) Flow cytometry was performed to enumerate MMC9s (Lin–c-Kit+ST2+IL-17RB–Integrin β7lo) in jejunum. n = 14 for nonsensitized group; n = 15 for inhibitor nonpretreated group; n = 9 for GST group; n = 9 for GST-N19 group, pooled data of 3 independent experiments. (I) Cytokine mRNAs in jejunum were quantified by qRT-PCR. *P < 0.05; **P < 0.01; ***P < 0.001, ANOVA with Tukey’s multiple comparison. Cont, control.