8. Seaton A, Godden DJ, Brown K. Increase in asthma: a more toxic environment or a more susceptible population? Thorax 1994; 49: 171–174. 9. Holgate ST. The epidemic of allergy and asthma. Nature 1999; 402 (6760 Suppl): B2 –B4. 10. Holt PG, Macaubas C, Stumbles PA, Sly PD. The role of allergy in the development of asthma [review]. Nature 1999; 402: B12 –B17. 11. Strachan DP, Harkins LS, Johnson ID, Anderson HR. Childhood ante- cedents of allergic sensitization in young British adults. J Allergy Clin Immunol 1997; 99: 6 –12. 12. Ishizaka K, Ishizaka T, Hornbrook MM. Physico-chemical properties of human reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic activity. J Immunol 1966; 97: 75 –85. 13. Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Loh R, Holt PG. Reciprocal age-related patterns of allergen-specific T-cell immunity in normal vs. atopic infants. Clin Exp Allergy 1998; 28: 39 –44. 14. Miles EA, Warner JA, Jones AC, Colwell BM, Bryant TN, Warner JO. Peripheral blood mononuclear cell proliferative responses in the first year of life in babies born to allergic parents. Clin Exp Allergy 1996; 26: 780 –788. 15. Platts-Mills TAE, Woodfolk JA. Cord blood proliferative responses to inhaled allergens: is there a phenomenon? [editorial]. J Allergy Clin Immunol 2000; 106: 441–443. 16. Rowntree S, Cogswell JJ, Platts-Mills TAE, Mitchell EB. Development of IgE and IgG antibodies to food and inhalant allergens in children at risk of allergic disease. Arch Dis Child 1985; 60: 727–735. 17. Sporik R, Squillace SP, Ingram JM, Rakes G, Honsinger RW, Platts-Mills TAE. Mite, cat and cockroach exposure, allergen sensitization, and asthma in children: a case-control study of three schools. Thorax 1999; 54: 675 –680. 18. Hasselmar B, Aberg N, Aberg B, Eriksson B, Bjorksten B. Does early exposure to cat or dog protect against later allergy development? Clin Exp Allergy 1999; 29: 611–617. 19. Svane C, Jarvis D, Chinn S, Burney P. Childhood environment and adult atopy: results from the European Community Respiratory Health Survey. J Allergy Clin Immunol 1999; 103: 415 –420. 20. Platts-Mills T, Vaughan J, Squillace S, Woodfolk J, Sporik R. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. The Lancet 2001; 357: 752 –756. 21. Fredburg JJ, Inouye DS, Mijailovich SM, Butler JP. Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in bronchospasm. Am J Resp Crit Care Med 1999; 159: 959 –967. 22. Skloot G, Permutt S, Togias A. Airway hyperresponsiveness in asthma. J Clin Invest 1995; 96: 2393–2403. 23. Luder E, Melnik TA, DiMaio M. Association of being overweight with greater asthma symptoms in inner city black and Hispanic children. J Peds 1998; 132: 699 –703. 24. Camargo CA, Weiss ST, Zhang S, Willett WC, Spetzer FE. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med 1999; 159: 2582. 25. Platts-Mills TAE, Woodfolk JA, Chapman MD, Heymann PW. Changing concepts of allergic disease: the attempt to keep up with real changes in lifestyles [review]. J Allergy Clin Immunol 1996; 98: S297–S306. Atopic dermatitis: a paradigmatic allergic skin disease Thomas Bieber Department of Dermatology, Friedrich-Wilhelms-University, Sigmund-Freud-Stra be 25, D-53105 Bonn, Germany Tel: +49 228 287 4388 Fax: +49 228 287 4881 E-mail: thomas.bieber@meb.uni-bonn.de Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease clinically and histologically highly similar to allergic contact dermatitis. Recently, it has been proposed to subdivide AD into two distinct forms: the extrinsic form (occurring in the context of sensitiza- tion toward environmental allergens), and the intrin- sic form (occurring in the absence of any typical atopical background).1 While the pathophysiology of the intrinsic form remains almost elusive, tremendous progress has been made in the understanding of the extrinsic form. Thus, since IgE plays a major role in other atopic diseases such as asthma and rhinitis, it is assumed that, in this extrinsic form, immunoglobulin E (IgE) also mediated the specificity of the inflamma- tory conditions in the skin. Presence of IgE-bearing dendritic cells in the skin of patients with AD The emergence of extrinsic AD (i.e. a cell-mediated inflammation) in atopic patients (i.e. individuals prone to have increased IgE production and to develop IgE-mediated hypersensitivity reactions) remained puzzling until the mid-1980s, when the presence of IgE molecules on the surface of Langer- hans cells (LC) from patients presenting AD was first reported.2 ,3 A new pathophysiological concept was proposed in which LC and inflammatory dendritic epidermal cells (IDEC)4 armed with allergen-specific IgE would trigger an eczematous inflammation. Molecular structure, regulation and function of Fc«RI on human dendritic cells The identity of the relevant IgE-binding structure of cutaneous dendritic cells (DC) was unclear for some years, until other workers and myself demonstrated the presence of the high-affinity receptor for IgE (Fc«RI) on these cells as well as on other antigen presenting cells (APC), including monocytes, and circulating DC.5 – 7 It also became clear that Fc«RI on APC lacks the classical b-chain and thus, in contrast to effector cells of anaphylaxis (i.e. mast cells and basophils that express an a,b,g2 conformation), APC display an a,g2 conformation that implies profound functional consequences. Moreover, its expression and the function may be highly variable, depending on the microenvironment.8 However, the highest expression is specifically observed in AD skin.9 One may speculate that Fc«RI ligation on APC putatively triggers the synthesis and release of mediators that may initiate a local inflammatory reaction, as has been demonstrated for mast cells. Fc«RI/IgE-mediated allergen uptake and subsequent antigen presentation has been attributed a key event in the pathogenesis of atopic dermatitis.1 0 Using this kind of antigen uptake, APC may, in the presence of antigen- specific IgE, increase their presenting capacity up to 100-fold.1 1 This mechanism, also known as ‘antigen focusing’ or ‘facilitated antigen presentation’, has been shown effective by different research groups in different cell systems. The observation that the Mini Reviews Mediators of Inflammation · Vol 10 · 2001 291 presence of Fc«RI-expressing LC/IDEC, bearing IgE molecules, is a prerequisite to provoking eczematous lesions, observed after application of aeroallergens to the skin of atopic patients, strongly supports this concept. Thereby, IgE receptors are the connecting link between the specificity gaining IgE molecules and the APC. However, Fc«RI seems to play the major role in these phenomena. It should be noted that Fc«RI expressed on circulating monocytes may have other functions, mainly in regulating their survival and differentiation outcome.1 2 Following the presentation of allergens to T cells, allergen-specific B cells may be activated to produce high amounts of allergen-specific IgE. This IgE may then in turn bind to the Fc«RI on the APC, closing a vicious circle of facilitated antigen presentation. The intermittent or continuous supply of aeroallergens or autoantigens to the process of facilitated antigen presentation may define the pathophysiological basis of the recurrent or self-perpetuating course of AD frequently seen in untreated patients. The successful application of aeroallergens such as cat dander in the recently standardized atopy patch test1 3 shows that it is possible to elicit eczematous skin lesions by solely external application of aeroallergens to the skin. Based on the facilitated antigen presentation model of AD, the need for an identification of the individual provocation factors in each patient calls for diagnostic procedures based on the allergen-specific IgE. Cat dander, house dust mite allergens and a variety of food allergens may be successfully avoided following a thoroughly undertaken prick test and in vitro IgE diagnostic evaluation. Conclusion Consequently, AD may represent a paradigm of IgE/ Fc«RI-mediated, delayed-type hypersensitivity reac- tion. A similar role could be attributed to other Fc«RI- expressing DC in the lung, where such cells may also be considered as putative targets for new therapeutic strategies. References 1. Wüthrich B. Neurodermitis atopica. Wien Med Wochenschr 1989; 139: 156 –165. 2. Bruijnzeel-Koomen C, van Wichen DF, Toonstra J, et al. The presence of IgE molecules on epidermal Langerhans cells in patients with atopic dermatitis. Arch Dermatol Res 1986; 278: 199 –205. 3. Bieber T, Dannenberg B, Prinz JC, Rieber EP, Stolz W, Ring J, Braun-Falco O. Occurence of IgE bearing Langerhans cells in atopic eczema: a study of the time course and with regard to the IgE serum level. J Invest Dermatol 1989; 92: 215 –219. 4. Wollenberg A, Kraft S, Hanau D, Bieber T. Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inf lam- matory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J Invest Dermatol 1996; 106: 446 –453. 5. Bieber T, de la Salle H, Wollenberg A, et al. Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (Fc epsilon RI). J Exp Med 1992; 175: 1285–1290. 6. Wang B, Rieger A, Kilgus O, et al. Epidermal Langerhans cells from normal human skin bind monomeric IgE via FceRI. J Exp Med 1992; 175: 1353 –1365. 7. Maurer D, Fiebiger E, Reininger B, et al. Expression of functional high affinity immunoglobulin E receptors (Fc epsilon ri) on monocytes of atopic individuals. J Exp Med 1994; 179: 745–750. 8. Jürgens M, Wollenberg A, de la Salle H, Hanau D, Bieber T. Activation of human dendritic Langerhans cells by engagement of the high affinity receptor for IgE Fc«RI. J Immunol 1995; 155: 5184–5189. 9. Wollenberg A, Wen S, Bieber T. Langerhans cell phenotyping: a new tool for differential diagnosis of inflammatory skin diseases. Lancet 1995; 346: 1626–1627. 10. Bieber T. Fc«RI-expressing antigen-presenting cells: new players in the atopic game. Immunol Today 1997; 18: 311–313. 11. Maurer D, Ebner C, Reininger R, Fiebiger E, Kraft D, Kinet JP, Stingl G. The high affinity IgE receptor (Fc«RI) mediates IgE-dependent allerge n presentation. J Immunol 1995; 154: 6285–6290. 12. Katoh N, Kraft S, Wessendorf JH, Bieber T. The high-affinity IgE receptor (FcepsilonRI) blocks apoptosis in normal human monocytes. J Clin Invest 2000; 105: 183 –190. 13. Darsow U, Vieluf D, Ring J. Atopy patch test with different vehicles and allergen concentrations: an approach to standardization. J Allergy Clin Immunol 1995; 95: 677–684. Mini Reviews 292 Mediators of Inflammation · Vol 10 · 2001 Why is the prevalence of allergic diseases increasing? A critical assessment of some classical risk factors Denis CharpinCA and Marion Gouitaa Department of Chest Diseases & Allergy, Hospital North, Marseille, France C A Corresponding author Tel: +33 4 91 96 86 31 Fax: +33 4 91 09 09 94 E-mail: dcharpin@ap-hm.fr Introduction Many epidemiological surveys, among which repeated cross-sectional surveys have most validity, have demonstrated a twofold increase in the preva- lence of allergic and asthma during the past two decades.1 ,2 The next presentations will deal with newly- identified or suspected risk factors such as repeated childhood infections, the role of the gut flora and the potential protective effect of contact with farm animals. In this paper, we review some risk factors whose responsibility is often given for granted but which do not actually appear to play a major role in the increase of allergic diseases, namely allergen exposure, air pollution and passive smoking. Allergen exposure Among allergens, house-dust mites have been advo- cated to be responsible for the increasing trend in the prevalence of allergic diseases.3 We will present the pros and cons of this hypothesis. d Because of the worldwide energy crisis in the 1970s, there has been a large decrease in the ventilation rate of private houses in Western countries, which could have led to multiplication of house-dust mites. Actually, there is a single study supporting this latter statement.4 Another hypoth- Submit your manuscripts at http://www.hindawi.com Stem Cells International Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 MEDIATORS INFLAMMATION of Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Behavioural Neurology Endocrinology International Journal of Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Disease Markers Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 BioMed Research International Oncology Journal of Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Oxidative Medicine and Cellular Longevity Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 PPAR Research The Scientific World Journal Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Immunology Research Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Journal of Obesity Journal of Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Computational and Mathematical Methods in Medicine Ophthalmology Journal of Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Diabetes Research Journal of Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Research and Treatment AIDS Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Gastroenterology Research and Practice Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 Parkinson’s Disease Evidence-Based Complementary and Alternative Medicine Volume 2014 Hindawi Publishing Corporation http://www.hindawi.com