World Allergy Forum: The Epithelium as a Modulator of the Allergic Response
Allergic diseases manifest in a variety of organs, most frequently, in the skin and the mucous membranes, i.e. the border between the individuum and its environment. Since the discovery of immunoglobin E, lymphocyte subpopulation (TH1, TH2, TH 3?) the elucidation of the major histocompatibility complex (MHC) and its role in antigen presentation together with the T-cell receptor the pathophysiology of immediate-type allergic reactions has become clearer over the last years.
At the same time, the autochthonous cells in the skin and in the airway mucosa, especially the epithelial cells, have long been regarded only as by-standers or inert structural components. However, it has been shown that epithelial cells, such as kerationcytes in the skin – are able to produce biologically active cytokines with possible relevance for the allergic inflammation.
Until today, it is unknown why certain allergic reactions only take place in the skin and not in the airway mucosa as well as why skin and respiratory atopic diseases sometimes influence each other in a so called "alternate" clinical course (changes from asthma to eczema and vice versa).
In this symposium the role of the epithelium – both in the respiratory mucosa and in the skin – shall be discussed with regard to its effect in modulating the deviated immune response in allergy. We hope to gain new understanding for the pathophysiological mechanisms, particularly with regard to environmental influences, as well as ideas for future strategies in therapy and prevention
Stephen T. Holgate
Epithelial surfaces represent the interface between the external and internal environments and therefore play a special role in defending us against hostile factors. As a physical barrier, epithelia are designed to repair rapidly once injured (healing by "primary" intention) involving the elaboration of a range of growth factors such as the epidermal-like growth factors, keratinocyte growth factor (FGF-7) and acidic fibroblast growth factor (FGF-4). Upon epithelial injury the autocrine actions of these factors drive epithelial migration and proliferative responses.
The epithelium is also host to importance immune cells that sample the environment and, when appropriate, respond by driving defensive immune and inflammatory responses. Notable amongst these are dendritic and related Langerhans’ cells which are specialised to take up, process and present allergens to T-cells involving MHC Class II and TCR respectively. For effective immune responses co-stimulation is also required that engages adhesion molecules such as CD80 (B-7.1) and CD86 (B-7.2) on APCs and CD28 on T-cells. The direction which a T cell response is directed depends also on the cytokine microenvironment IL-12/-18 selecting a Th-1 response and IL-10/PGE2 on Th-2 response. In allergic disease antigen processing is further enhanced by Fce R1 and Fce R2 which, through specific IgE, captures allergens and enhances their uptake 100-1000-fold.
In asthma and eczematous there is increased loss of epithelial cells following their premature apoptosis. In eczema this is probably mediated by IFN-g secreted by activated T-cells whereas, in asthma, it seems there is an intrinsic abnormality of epithelial cells to enter programmed cell death especially when activated by enzymic allergens or oxidant pollutants. The net result is epithelial loss and delayed repair probably due to the enhanced secretion of members of the TGF-b family of growth factors. These not only drive subepithelial fibroblasts to generate excess repair collagens and matrix but also further inhibit epithelial repair by competing with MAPK signalling. The consequence of these events is impaired epithelial restitution and healing by "secondary intention" (scarring).
The recognition that the epithelium is able to direct organogenesis in the fetus involving the same pathways (apoptosis, EGF, TGF-b ) and activation of morphogenetic genes suggests that chronic inflammation and tissue remodelling in chronic allergic disorders represents an extension of morphogenesis. Understanding the intercellular and intracellular signalling pathways involved in these processes will lead to new preventative and therapeutic options which will increase tissue resistance to injury rather than rely on suppressing inflammation. Understanding how the environment interfaces with susceptibility genes in the epithelial-mesenchymal trophic unit will be the challenge for the post-genome era.