Allergen endotoxins induce T-cell–dependent and non–IgE-mediated nasal hypersensitivity in mice

• Published in: Journal of allergy and clinical immunology 2017-01, Vol.139 (1), p.258-268.e10
• Main Authors: Iwasaki, Naruhito, MD, Matsushita, Kazufumi, PhD, Fukuoka, Ayumi, PhD, Nakahira, Masakiyo, MD, PhD, Matsumoto, Makoto, MD, PhD, Akasaki, Shoko, BPharm, Yasuda, Koubun, PhD, Shimizu, Takeshi, MD, PhD, Yoshimoto, Tomohiro, MD, PhD
• Format: Article
• Language: English
• Subjects: Allergens - immunology; Allergic rhinitis; Allergies; Allergy and Immunology; Animals; Antigens; CD4+ T cell; Drug dosages; endotoxin; Endotoxins - immunology; Experiments; Gene expression; histamine; Histamine - immunology; hypersensitivity; IgE; Immunoglobulin E - immunology; Laboratories; LPS; Lymphatic system; Lymphocytes; Mice, Inbred BALB C; Mice, Knockout; monocyte/macrophage; Myeloid Differentiation Factor 88 - immunology; Nasal Mucosa; nonallergic rhinitis; Ovalbumin - immunology; Respiratory Hypersensitivity; Rhinitis, Allergic - immunology; T-Lymphocytes - immunology; Toll-Like Receptor 4 - immunology
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2016.03.023

Background Allergen-mediated cross-linking of IgE on mast cells/basophils is a well-recognized trigger for type 1 allergic diseases such as allergic rhinitis (AR). However, allergens may not be the sole trigger for AR, and several allergic-like reactions are induced by non–IgE-mediated mechanisms. Objective We sought to describe a novel non–IgE-mediated, endotoxin-triggered nasal type-1-hypersensitivity-like reaction in mice. Methods To investigate whether endotoxin affects sneezing responses, mice were intraperitoneally immunized with ovalbumin (OVA), then nasally challenged with endotoxin-free or endotoxin-containing OVA. To investigate the role of T cells and mechanisms of the endotoxin-induced response, mice were adoptively transferred with in vitro –differentiated OVA-specific TH 2 cells, then nasally challenged with endotoxin-free or endotoxin-containing OVA. Results Endotoxin-containing, but not endotoxin-free, OVA elicited sneezing responses in mice independent from IgE-mediated signaling. OVA-specific TH 2 cell adoptive transfer to mice demonstrated that local activation of antigen-specific TH 2 cells was required for the response. The Toll-like receptor 4-myeloid differentiation factor 88 signaling pathway was indispensable for endotoxin-containing OVA-elicited rhinitis. In addition, LPS directly triggered sneezing responses in OVA-specific TH 2-transferred and nasally endotoxin-free OVA–primed mice. Although antihistamines suppressed sneezing responses, mast-cell/basophil-depleted mice had normal sneezing responses to endotoxin-containing OVA. Clodronate treatment abrogated endotoxin-containing OVA-elicited rhinitis, suggesting the involvement of monocytes/macrophages in this response. Conclusions Antigen-specific nasal activation of CD4+ T cells followed by endotoxin exposure induces mast cell/basophil-independent histamine release in the nose that elicits sneezing responses. Thus, environmental or nasal residential bacteria may exacerbate AR symptoms. In addition, this novel phenomenon might explain currently unknown mechanisms in allergic(-like) disorders.