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



We sought to describe a novel non-IgE-mediated, endotoxin-triggered nasal type-1-hypersensitivity-like reaction in mice.



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 TH2 cells, then nasally challenged with endotoxin-free or endotoxin-containing OVA.



Endotoxin-containing, but not endotoxin-free, OVA elicited sneezing responses in mice independent from IgE-mediated signaling. OVA-specific TH2 cell adoptive transfer to mice demonstrated that local activation of antigen-specific TH2 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 TH2-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.



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.
Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan; Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan.
Naruhito
N
Iwasaki
Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Kazufumi
K
Matsushita
Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Ayumi
A
Fukuoka
Department of Immunology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Masakiyo
M
Nakahira
Department of Immunology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Makoto
M
Matsumoto
Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Shoko
S
Akasaki
Department of Immunology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Koubun
K
Yasuda
Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Shiga, Japan.
Takeshi
T
Shimizu
Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan; Department of Immunology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan. Electronic address: tomo@hyo-med.ac.jp.
Tomohiro
T
Yoshimoto
D000485:Allergens / Q000276:immunology*; D000818:Animals; D004731:Endotoxins / Q000276:immunology*; D006632:Histamine / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D009297:Nasal Mucosa; D010047:Ovalbumin / Q000276:immunology*; D012130:Respiratory Hypersensitivity; D065631:Rhinitis, Allergic / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology
D000485:Allergens; D004731:Endotoxins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D007073:Immunoglobulin E; D006632:Histamine; D010047:Ovalbumin
Allergic rhinitis; CD4(+) T cell; IgE; LPS; endotoxin; histamine; hypersensitivity; monocyte/macrophage; nonallergic rhinitis