# Histamine-Releasing Factor Oligomers in Food Allergy

> **NIH NIH R01** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2021 · $634,331

## Abstract

PROJECT SUMMARY
The prevalence of food allergy has been dramatically increasing for the last few decades. Although studies
using murine models of food allergy have greatly advanced our understanding of its pathogenesis, there are
still significant knowledge gaps. Histamine-releasing factor (HRF) activate mast cells and basophils in an IgE-
dependent manner. As its secretion was found in body fluids during late-phase allergic reactions, HRF has
been implicated in allergic diseases. However, whether HRF is involved in allergic diseases had remained
enigmatic, although its molecular identity was revealed in 1995. Our 2012 study changed this situation by
identifying a subset of IgE and IgG molecules as HRF receptors: mapping of the immunoglobulin (Ig) Fab-
binding sites within the HRF molecule led to the discovery of HRF sequence-based inhibitors, N19 and H3
peptides, as well as a monomeric mutant HRF-2CA, all of which blocked HRF-Ig interactions; prophylactic
administration of these inhibitors, which targeted mast cells, strongly reduced the incidence of allergic diarrhea
and anaphylaxis, as well as the severity of intestinal inflammation in an IgE/FcεRI (high-affinity IgE
receptor)/mast cell-dependent mouse model of food allergy. HRF is present as a monomer and disulfide-linked
oligomers including a dimer. HRF dimer, but not monomer, has an ability to activate IgE-primed mast cells and
basophils and to enhance allergen-triggered activation of these cells. HRF oligomers increased in the small
intestine of food allergic animals. Our results collectively suggest that HRF oligomers crosslink IgE-bound
FcεRI on intestinal mast cells, leading to their activation, which is required for allergen-induced maximal
intestinal type 2 inflammation. Based upon these novel data, we hypothesize that HRF oligomerization and
HRF-IgE interactions are two critical events to initiate and amplify intestinal inflammation in food allergy. To
test this hypothesis, we will conduct food allergy experiments with novel mutant mice lacking normal HRF
dimer (Aim 1), and seek to identify the enzyme system that catalyzes oligomerization of HRF (Aim 2). We will
also investigate the effects of HRF oligomerization and N-glycosylation of HRF and IgEs on HRF-IgE
interactions, and potential regulation of HRF-IgE interactions at the atomic level during food allergy (Aim 3).
Therefore, this study will likely establish a novel paradigm that FcεRI-mediated mast cell activation triggered by
antigen is amplified by HRF oligomers that cause a heightened inflammation in food allergy.

## Key facts

- **NIH application ID:** 10212221
- **Project number:** 5R01AI146042-03
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** TOSHIAKI KAWAKAMI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $634,331
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212221

## Citation

> US National Institutes of Health, RePORTER application 10212221, Histamine-Releasing Factor Oligomers in Food Allergy (5R01AI146042-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10212221. Licensed CC0.

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