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April 13, 2015

How Allergens Cross Respiratory Membranes

Question

You would agree that one of the major functions of the respiratory membranes is to keep foreign material, i.e., allergens, from crossing the respiratory membranes and priming the immune system for subsequent activation of the allergic cascade. Activation of the allergic cascade then leads to inflammation of the respiratory membranes which leads to further compromise of the respiratory membranes and increased leakage of allergens into the body and ever increasing magnification of the immune response. It seems intuitively logical that the etiologic cause of allergy and asthma on a microscopic basis has to be an inherent instability of the respiratory membranes in individuals at risk for allergy and asthma. Why are there no studies on how allergens are able to cross the respiratory membranes? An agent which would stabilize the respiratory membranes would offer a much more effective way of treating allergy and asthma than currently exists. Such an agent would have the power to actually prevent the activation of the allergy cascade by shutting off the leakage of allergens across the respiratory membranes. Such an agent used for a long enough time would also lead to a pseudo cure of allergy and asthma through decay of IgE antibodies.

Answers

From the Editors: Epithelial barriers, be it skin, respiratory or gastrointestinal, play an integral role in the immune response, be it protective or dysfunctional.  It appears that we are just starting to "scratch the surface" in understanding how epithelial barriers behave in normal and abnormal immune responses.

 

By Professor Stephen Holgate

There is now strong evidence that in many allergic diseases (asthma, food allergy, rhinosinusitis and atopic dermatitis) there is a breakdown in epithelial integrity both as a physical and functional barrier. In addition, many allergens exert biological properties such as proteolytic enymatic activity or mimicking danger signals that add to this epithelial "lesion". Breakdown in physical barrier occurs when cell adhesion mechanisms are disrupted especially apical tight junctions. At a functional level, reduced secretion of protective molecules such as anti-microbial proteins and anti-oxidant defences is a further manifestation of disordered epithelial activity in allergic disease. However, penetration of the epithelium by allergens into the deeper tissues is not the only way sensitisation occurs. Dendritic cells, which recognise and present allergens to naive T cells in local lymphoid collections extend processes through the epithelium, so that they can interact with allergens on the airway surface. Nevertheless, attempting to restore barrier function seems a logical and new way of preventing or treating allergy. One example is the use of surfactant lipids and vitamin D to help achieve this. However more active agents are needed.

References
Environmental and genetic contribution in airway epithelial barrier in asthma pathogenesis. Tsicopoulos A, de Nadai P, Glineur C. Curr Opin Allergy Clin Immunol. 2013 Oct;13(5):495-9.
Defective epithelial barrier function in asthma. Xiao C, Puddicombe SM, Field S, Haywood J, Broughton-Head V, Puxeddu I, Haitchi HM, Vernon-Wilson E, Sammut D, Bedke N, Cremin C, Sones J, Djukanović R, Howarth PH, Collins JE, Holgate ST, Monk P, Davies DE. J Allergy Clin Immunol. 2011 Sep;128(3):549-56
Barrier responses of human bronchial epithelial cells to grass pollen exposure. Blume C, Swindle EJ, Dennison P, Jayasekera NP, Dudley S, Monk P, Behrendt H, Schmidt-Weber CB, Holgate ST, Howarth PH, Traidl-Hoffmann C, Davies DE. Eur Respir J. 2013 Jul;42(1):87-97.
Innate and adaptive immune responses in asthma. Holgate ST. Nat Med. 2012 May 4;18(5):673-83

Stephen Holgate, BSc MD DSc FRCP
Medical Research Council
Clinical Professor of Immunopharmacology and Honorary Consultant Physician
University of Southampton
Southampton, United Kingdom

 

By Prof Edward Knol

Our epithelial linings in skin, gut, lung and nose have important functions to keep foreign material out. In allergic diseases this epithelial barrier is affected and challenged in two different ways. The first one is intrinsically in which the barrier is weakened by genetic predisposition or due to the cytokine milieu of allergic inflammation. The strongest genetic predisposition for allergy is found in atopic dermatitis where loss-of-function mutations in the barrier protein filaggrin are linked to disease (Ref 1). The second challenge comes from the outside, namely environmental factors such as proteolytic house dust mite and pollen allergens as well as virus infections. This type of challenge is affecting barrier integrity, most pronounced via affecting tight junctions (Ref 2). For the transepithelial penetration of the allergens the proteolytic properties are of great importance, but a burden for the patient because this can be the initiation of an allergic immune response

There are many studies that examine in great detail how allergens affect the epithelial lining at different levels. Information gained from these studies will help us to understand exactly how allergens are able to penetrate our epithelial barriers. New drugs aiming at preventing the barrier passage on one side of allergens by directly inhibiting proteolytic activities of the allergens, but on the other side by correcting barrier dysfunction are in development and trials on different potential drugs can be found on ClinicalTrials.gov.

References
1) Palmer, CNA. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat. Genet. 38, 441–446 (2006).
2) Wan H, Winton HL, Soeller C, et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest 1999;104:123e33

Edward F. Knol, PhD
Associate Professor at Departments of Immunology and Dermatology/Allergology
University Medical Center Utrecht
Utrecht, Netherlands


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