Allergy as an epithelial barrier disease

Mattila, Pirkko; Joenväära, Sakari; Renkonen, Jutta; Toppila‐Salmi, Sanna; Renkonen, Risto

doi:10.1186/2045-7022-1-5

Cited by 52 publications

(60 citation statements)

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“…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].…”

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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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confidence: 99%

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

2015

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“…The dysregulation and dysfunction of the airway epithelium seen in asthmatic patients have been hypothesized to be responsible for skewed signalling from AEC, promoting inflammatory responses instead of upholding homeostasis [9,45,46]. Exposing the AEC line, 16HBE14o -, to birch pollen, grass pollen or HDM extracts showed a general trend of down-regulation of the production of the chemokines IP-10, MDC, MIP-1b and MCP-1, which are all associated with the recruitment of monocytes, DCs and T cells [47][48][49][50], implicating that these allergens do not induce any inflammatory signalling from AEC at steady state conditions.…”

Section: Discussionmentioning

confidence: 99%

“…An imbalanced and overactive immune response against allergens has long been thought to be the primary mechanism behind allergy. A more recent hypothesis points to the dysregulation of the epithelial barrier and its interactions with resident immune cells as the primary defect in the pathogenesis of allergic reactions [8,9].…”

Section: Cd11cmentioning

confidence: 99%

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Direct contact between dendritic cells and bronchial epithelial cells inhibits T cell recall responses towards mite and pollen allergen extracts in vitro

Wagtmann

Hansen

Würtzen

2015

Clinical and Experimental Immunology

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SummaryAirway epithelial cells (AECs) form a polarized barrier along the respiratory tract. They are the first point of contact with airborne antigens and are able to instruct resident immune cells to mount appropriate immune responses by either soluble or contact-dependent mechanisms. We hypothesize that a healthy, polarized epithelial cell layer inhibits inflammatory responses towards allergens to uphold homeostasis. Using an in-vitro co-culture model of the airway epithelium, where a polarized cell layer of bronchial epithelial cells can interact with dendritic cells (DCs), we have investigated recall T cell responses in allergic patients sensitized to house dust mite, grass and birch pollen. Using allergen extract-loaded DCs to stimulate autologous allergen-specific T cell lines, we show that AEC-imprinted DCs inhibit T cell proliferation significantly of Bet v 1-specific T cell lines as well as decrease interleukin (IL)-5 and IL-13 production, whereas inhibition of Phl p 5-specific T cells varied between different donors. Stimulating autologous CD4 1 T cells from allergic patients with AEC-imprinted DCs also inhibited proliferation significantly and decreased production of both T helper type 1 (Th1) and Th2 cytokines upon rechallenge. The inhibitory effects of AECs' contact with DCs were absent when allergen extract-loaded DCs had been exposed only to AECs supernatants, but present after direct contact with AECs. We conclude that direct contact between DCs and AECs inhibits T cell recall responses towards birch, grass and house dust mite allergens in vitro, suggesting that AECs-DC contact in vivo constitute a key element in mucosal homeostasis in relation to allergic sensitisation.

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“…Airway epithelial cell barrier dysfunction is hypothesized to be another contributor to pathogenesis of AR and CRSwNP [67][68][69][70] (Fig. 1 B).…”

Section: Potential Causes Of Treg Dysfunctionmentioning

confidence: 99%