IL-33–Mediated Innate Response and Adaptive Immune Cells Contribute to Maximum Responses of Protease Allergen–Induced Allergic Airway Inflammation

Kamijo, Seiji; Takeda, Hisashi; Tokura, Tomoko; Suzuki, Mayu; Inui, Kyoko; Hara, Mutsuko; Matsuda, Hironori; Matsuda, Akira; Oboki, Keisuke; Ohno, Tomohiro; Saito, Hirohisa; Nakae, Susumu; Sudo, Katsuko; Suto, Hajime; Ichikawa, Saori; Ogawa, Hideoki; Okumura, Ko; Takai, Toshiro

doi:10.4049/jimmunol.1201212

Cited by 151 publications

(176 citation statements)

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“…Thus, in experimental arterial hypertrophy mediated by Th2 immune responses, there are at least two pathways: T cell dependent and T cell independent. These pathways may cooperate with or compensate for each other to induce pulmonary arterial hypertrophy, as reported previously in allergic inflammation (41).…”

Section: Discussionmentioning

confidence: 80%

Prolonged activation of IL-5–producing ILC2 causes pulmonary arterial hypertrophy

Ikutani¹,

Tsuneyama²,

Kikuchi³

et al. 2017

JCI Insight

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Section: Discussionmentioning

confidence: 80%

Prolonged activation of IL-5–producing ILC2 causes pulmonary arterial hypertrophy

Ikutani¹,

Tsuneyama²,

Kikuchi³

et al. 2017

JCI Insight

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“…Proteolytic activity of several allergens favours Th2 polarization and IgE responses [16,17,21]. Repeated exposure of airway mucosa with protease allergens leads to lung eosinophilia and higher IgE in a protease-dependent manner [22]. However, physiological targets of proteolytic allergens and the factors promoting allergic sensitization remain to be revealed.…”

Section: Discussionmentioning

confidence: 99%

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

2015

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Proteases are implicated in exacerbation of allergic diseases. In this study, the role of proteolytic activity of Per a 10 was evaluated on Th2 polarization. Intranasal administration of Per a 10 in mice led to allergic airway inflammation as seen by higher IgE levels, cellular infiltration, IL-17A, and Th2 cytokines, whereas, inactive ( )Per a 10 showed attenuated response. There was an increased OX40L expression on lung and lymph node dendritic cells in Per a 10 immunized group and on Per a 10 stimulated BMDCs. Reduction in CD40 expression without any change at transcript level in lungs of Per a 10 immunized mice suggested CD40 cleavage. BMDCs pulsed with Per a 10 showed reduced CD40 expression with lower IL-12p70 secretion as compared to heat inactivated Per a 10. IL-23, TNF-α, and IL-6 levels were significantly higher in Per a 10 stimulated BMDCs supernatant. In DC-T cell coculture studies, Per a 10 pulsed BMDCs showed higher levels of IL-4 and IL-13 that were reduced on blocking of either IL-23 or OX40L. In conclusion, the data suggests a critical role of protease activity of Per a 10 in promoting Th2 polarization by increasing IL-23 secretion and OX40L expression on dendritic cells.Keywords: CD40 r Cytokines r Dendritic cell r OX40L r Protease allergen Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionProteases are known to play an important role in manifestation of diseases like cancer, coagulopathies, respiratory inflammatory diseases, rheumatoid arthritis, and degenerative diseases [1][2][3]. Proteases from sources like house dust mite (Der p 1, Der p 3, Der p 6, Der p 9, Der f 1) and fungi (Asp f 13, Pen c 1, Pen c 13, Epi p 1) have been characterized as potent allergens [4]. Protease allergens act by proteolytic cleavage of an array of cell surface molecules and are known to modulate the functions of a variety of cell types including both immune and structural cells [5]. Proteolytic allergens from house dust mite are known to exacerbate allergic immune responses by selective cleavage of CD23, CD25, DC-SIGN, and DC-SIGNR on surface of immune cells Correspondence: Dr. Naveen Arora e-mail: naveen@igib.res.in; navdelhi@hotmail.com [6,7]. Further, cleavage and subsequent activation of PAR receptors by proteases lead to increased secretion of chemokines, proinflammatory, and pro Th2 cytokines from airway epithelial cells [8,9]. Studies have reported impaired epithelial barrier function as the feature of allergic diseases like asthma and atopic dermatitis [10]. The enzymatic activity of proteases has been reported to compromise epithelial barrier directly by cleaving tight junction proteins ZO-1 and occludin thereby increasing epithelial permeability [11,12]. Proteases can also act as adjuvants to bystander allergens present in the same microenvironment [13,14].Cockroaches have emerged as an important source of indoor allergens worldwide and cockroach extract is shown to be rich in proteases [15]. Previously, Per a 10, a serine protea...

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“…Very recent data demonstrated that cutaneous sensitization of mice to the model allergen papain depended on mast cells and was independent from IL‐33 25. In contrast, inhalant sensitization to papain involved IL‐33 26. Along these lines, we speculate that distinct routes of sensitization involving different pathways, cell types and cytokines may also result in a different distribution of allergen‐specific Th subsets.…”

Section: Discussionmentioning

confidence: 66%

Characterization of the T-cell response to Dau c 1, the Bet v 1-homolog in carrot

Zulehner

Nagl

Briza

et al. 2016

Allergy

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BackgroundIn contrast to other Bet v 1‐related food allergens, the major carrot allergen, Dau c 1, has been suggested to induce food allergy independently from Bet v 1. As T cells are crucial in the sensitization process, we sought to characterize the T‐cell response to Dau c 1 and its cross‐reactivity with Bet v 1.MethodsDau c 1‐specific T‐cell lines (TCL) and clones (TCC) established from PBMC of birch pollen‐allergic patients with carrot allergy were analyzed for reactivity to Bet v 1, epitope specificity, allergen‐induced cytokine secretion, and expression of integrins α4β7 and α4β1, critical for gut and lung homing, respectively. mRNA expression of GATA3 and Tbet was analyzed in sorted CD3+ CD4+ CFSE low cells proliferating upon stimulation of PBMC with Dau c 1 or Bet v 1. Dau c 1 was incubated with endolysosomal proteases, and the resulting fragments were identified by mass spectrometry.ResultsAmong 14 distinct T‐cell‐activating regions, Dau c 1139–153 was recognized by 55% of the patients. Only 6 of 15 (40%) Dau c 1‐specific TCL and 9 of 21 (43%) TCC reacted with Bet v 1. Bet v 1‐nonreactive TCC were mainly Th1‐like and showed a higher expression of the integrin β7 and a significantly lower expression of the integrin β1 than Bet v 1‐positive TCC. A Th1‐like response was also detected in Dau c 1‐reactive CD3+ CD4+ CFSE low cells. Full‐length Dau c 1 was still detectable after 48 h of endolysosomal degradation. Proteolytic fragments of Dau c 1 matched its T‐cell‐activating regions.ConclusionDau c 1 displays several characteristics of sensitizing allergens, namely a major T‐cell‐activating region, low susceptibility to endolysosomal degradation, and induction of a Bet v 1‐independent T‐cell response. These cellular insights confirm that the major carrot allergen has a special status among Bet v 1‐related food allergens.

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IL-33–Mediated Innate Response and Adaptive Immune Cells Contribute to Maximum Responses of Protease Allergen–Induced Allergic Airway Inflammation

Cited by 151 publications

References 56 publications

Prolonged activation of IL-5–producing ILC2 causes pulmonary arterial hypertrophy

Prolonged activation of IL-5–producing ILC2 causes pulmonary arterial hypertrophy

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

Characterization of the T-cell response to Dau c 1, the Bet v 1-homolog in carrot

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