News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2018)

The mechanisms regulating intestinal mast cell activation in patients with food allergy are incompletely understood. Ando et al (J Clin Invest 2017; https://doi.org/10.1172/JCI96525) examined the effect of the protein ‐histamine-releasing factor (HRF). Also known as translationally controlled tumor protein and fortilin, this multifunctional protein is secreted during allergic responses and activates mast cells through direct interaction with IgE. The authors showed that intestinal HRF release occurred during elicitation of a murine food allergy model. In vivo treatment of mice with inhibitors of the interaction between HRF and IgE reduced symptoms of food allergy, including diarrhea and mastocytosis. Higher levels of HRF-reactive IgE were present in the sera of human subjects with known allergy to egg compared with control subjects, and levels of HRF-reactive IgE were decreased after successful oral immunotherapy in both patients with food allergy and mice with experimental food allergy. Collectively, these results show that HRF promotes food allergy by increasing mast cell activation in response to allergen. Inhibition of HRF might be a promising therapeutic strategy for immunomodulation of food-induced allergic responses, and HRF-reactive IgE could serve as a biomarker for successful oral immunotherapy.HRF promotes food allergy by increasing mast cell activation HRF promotes food allergy by increasing mast cell activation Mast cells promote the abnormal vascularization seen in patients with diseases with chronic inflammation and tissue remodeling. Matsuda et al (J Clin Invest 2017;127:3987-4000; https://doi.org/10.1172/JCI89893) defined the role of mast cells in this ‐process using a murine model of oxygen-induced retinopathy involving capillary damage after hyperoxic exposure and subsequent hypoxia and angiogenesis on ‐return to room air. Genetic deficiency of mast cells prevented retinal neovascularization, and this protection was reversed on administration of either mast cells or the mast cell–derived enzyme tryptase. Mechanistically, hypoxia was shown to directly stimulate mast cell degranulation, which led to release of monocyte chemotactic protein 1 and proangiogenic factors by retinal endothelial cells and sprouting angiogenesis. Importantly, development of oxygen-induced retinopathy in mice was prevented through treatment with mast cell stabilizers or inhibitors of tryptase and monocyte chemotactic protein 1. These results are likely generalizable to human subjects because premature infants with retinopathy of prematurity had higher plasma tryptase levels compared with control subjects. In total, these findings demonstrate that hypoxia-induced mast cell activation leads to sprouting angiogenesis and might be applicable to allergic and inflammatory diseases with known abnormal vascularization.Hypoxia-induced mast cell activation leads to sprouting angiogenesis Hypoxia-induced mast cell activation leads to sprouting angiogenesis We asked Hiroshi Matsuda, DVM, PhD, of Tokyo University of Agriculture and Technology, Tokyo, Japan, to comment on the study. He writes, “When we discuss the significance of mast cells in the process of the development of oxygen-induced retinopathy, we believe that our novel scientific findings are extremely important. Therefore targeting mast cells might be an effective and viable strategy for prevention and treatment of retinopathy of prematurity and other common causes of blindness induced by neovascularization.” Maternal transfer of immunoglobulins to offspring classically mediates transient passive immunity. Ohsaki et al (J Exp Med 2017; https://doi.org/10.1084/jem.20171163) have identified a role for this process in establishing tolerance to food allergens in offspring. After epicutaneous sensitization of female mice with the model food allergen ovalbumin (OVA) or peanut, offspring had decreased anaphylactic reactions, production of allergen-specific IgE, and intestinal mastocytosis on epicutaneous sensitization and oral challenge with the same allergen. Mechanistically, immune complexes containing maternal IgG and allergen (IgG-IC) were transferred to offspring through breast milk and presented by CD11c+ dendritic cells to T cells in a neonatal crystallizable fragment receptor (FcRn)–dependent manner, ‐leading to induction of allergen-specific regulatory T cells. Finally, administration of human breast milk with OVA-containing IgG-IC to mice expressing only the human FcRn protein led to increased numbers of OVA-specific regulatory T cells and oral tolerance, supporting the concept that the IgG-IC–FcRn pathway’s contribution to neonatal tolerance might extend to human subjects. In summation, the authors have identified novel experimental evidence supporting a critical role of maternal immune complexes transferred through breast milk in establishing effective tolerance to food allergens in offspring, extending well beyond the previously known roles of maternal antibodies and FcRn in providing passive immunity. This process might be able to be manipulated therapeutically to prevent pediatric food allergy. Image credit to user Dan1gia2 (Own work) [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons.Maternal immune complexes are transferred through breast milk to induce tolerance to food allergens in offspring Maternal immune complexes are transferred through breast milk to induce tolerance to food allergens in offspring Desensitization through continuous epicutaneous immunotherapy is a promising therapeutic strategy approach to prevent peanut allergy. Sampson et al (JAMA 2017;318:1798-1809; https://doi.org/10.1001/jama.2017.16591) performed a phase 2, double-blind, placebo-controlled, randomized trial to determine the effect of a range of doses of peanut epicutaneous immunotherapy on the response to peanut protein exposure. Two hundred twenty-one human subjects with known peanut allergy were randomized to receive daily epidermal patches containing 50, 100, or 250 μg of peanut protein or placebo for 1 year, with a positive treatment response being defined as requiring either a 10-fold higher dose or 1 g total of peanut protein to elicit an allergic reaction. Significant improvement in response rates was observed in the 250-μg peanut protein treatment group (response rate of 50% vs 25% for placebo, P = .01) but not with the 50- or 100-μg doses. Moreover, a significant effect was found in children but not in adolescents or adults. Importantly, no dose-related serious adverse events were recorded. The authors conclude that daily 250-μg peanut patch exposure for 1 year successfully raises the threshold for reactions in allergic patients; that further improvement occurs over time, as seen in patients continuing in the 2-year extension trial; and that epicutaneous immunotherapy warrants further study in a phase 3 trial.Daily 250-μg peanut patch exposure for 1 year successfully raises the threshold for reactions in allergic patients Daily 250-μg peanut patch exposure for 1 year successfully raises the threshold for reactions in allergic patients We asked first author Hugh Sampson, MD, of the Icahn School of Medicine at Mount Sinai Hospital, New York, NY, to comment on the study. He writes “We are just beginning to realize the power of the skin immune system in regulating hypersensitivity reactions. Applying a 25-μg peanut patch for 3 years induced significant protection in more than 80% of children treated while exposing them to less peanut protein than that contained in a single peanut.”News items were written by medical writer Jared Travers, PhD.Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. News items were written by medical writer Jared Travers, PhD. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.