Background: Atopic dermatitis (AD) is frequently associated with skin infections that may be a consequence of an impaired function of the innate immune response. Conversely, the frequent bacterial colonization may also influence the systemic immune reactions, including the Toll-like receptor (TLR) system, through the translocation of bacterial components into the circulation. Therefore, we characterized phenotypic and functional properties of the TLR system in patients with extrinsic and intrinsic AD. Methods: The absolute number of surface CD14, TLR2, TLR4 and CD180 and the CD14-mediated uptake of bodipy-labeled endotoxin and bacteria by whole blood leukocytes was studied by flow cytometry. We measured the serum soluble CD14 concentration by an inhibitory flow cytometric method. Results: We observed a significant overexpression of TLR2 and TLR4 on monocytes, TLR2 and CD14 on granulocytes and CD180 on lymphocytes of intrinsic AD patients compared to healthy controls. The serum soluble CD14 was not different in the intrinsic AD patients, while it was diminished in the extrinsic AD group compared to the controls. The endotoxin and bacterium uptake showed no differences. Conclusions: The observed upregulation of CD14, TLR2, TLR4 and CD180 on peripheral leukocytes seems to be rather a consequence than the cause of the repeated bacterial infections in AD.

Keywords:
Atopic dermatitis, CD14, Toll-like receptor 2, Toll-like receptor 4, CD180
1.
Leung DY: Atopic dermatitis: new insights and opportunities for therapeutic intervention. J Allergy Clin Immunol 2000;105:860–876.
2.
Wüthrich B: Atopic dermatitis flare provoked by inhalant allergens. Dermatologica 1989;178:51–53.
3.
Öhman S, Johansson SG: Immunoglobulins in atopic dermatitis with special reference to IgE. Acta Derm Venereol 1974;54:193–202.
4.
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, Motala C, Ortega Martell JA, Platts-Mills TA, Ring J, Thien F, Van Cauwenberge P, Williams HC: Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization. J Allergy Clin Immunol 2004;113:832–836.
5.
Novak N, Bieber T: Allergic and nonallergic forms of atopic diseases. J Aller Clin Immunol 2003;112:252–262.
6.
Leung DY: Atopic dermatitis and the immune system: the role of superantigens and bacteria. J Am Acad Dermatol 2001;45:S13–16.
7.
Leung DY, Harbeck R, Bina P, Reiser RF, Yang E, Norris DA, et al: Presence of IgE antibodies to staphylococcal exotoxins on the skin of patients with atopic dermatitis: evidence for a new group of allergens. J Clin Invest 1993;92:1374–1380.
8.
Horner AA, Raz E: Do microbes influence the pathogenesis of allergic diseases? Building the case for Toll-like receptor ligands. Curr Opin Immunol 2003;15:614–619.
9.
Lien E, Sellati TJ, Yoshimura A, Flo TH, Rawadi G, Finberg RW, et al: Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products. J Biol Chem 1999;274:33419–33425.
10.
Lien E, Means TK, Heine H, Yoshimura A, Kusumoto S, Fukase K, et al: Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. J Clin Invest 2000;105:497–504.
11.
Frey EA, Miller DS, Jahr TG, et al: Soluble CD14 participates in the response of cells to lipopolysaccharide. J Exp Med 1992;176:1665–1671.
12.
Pulendran B: Modulating vaccine responses with dendritic cells and Toll-like receptors. Immunol Rev 2004;199:227–50.
13.
Antal-Szalmás P, Poppelier MJJG, Sümegi A, Van der Bruggen T, Verhoef J, Van Kessel KPM, et al: Spare CD14 molecules on human monocytes enhance the sensitivity for low LPS concentrations. Immunol Letters 2004;93:11–15.
14.
Antal-Szalmás P, Szöllősi I, Lakos G, Kiss E, Csípő I, Sümegi A, et al: A novel flow cytometric assay to quantify soluble CD14 concentration in human serum. Cytometry 2001;45:115–123.
15.
Zarember KA, Godowski PJ: Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 2002;168:554–561.
16.
Grunwald U, Fan X, Jack RS, Workalemahu G, Kallies A, Stelter F, et al: Monocytes can phagocytose Gram-negative bacteria by a CD14-dependent mechanism. J Immunol 1996;157:4119–4125.
17.
Leung DY, Jain N, Leo HL: New concepts in the pathogenesis of atopic dermatitis. Curr Opin Immunol 2003;15:634–638.
18.
Leung DY: Infection in atopic dermatitis. Curr Opin Pediatr 2003;15:399–404.
19.
Galli E, Cicconi R, Rossi P, Casati A, Brunetti E, Mancino G: Atopic dermatitis: molecular mechanisms, clinical aspects and new therapeutical approaches. Curr Mol Med 2003;3:127–138.
20.
Cho SH, Strickland I, Boguniewicz M, Leung DY: Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin. J Allergy Clin Immunol 2001;108:269–274.
21.
Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, et al: Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002;347:1151–1160.
22.
Antal-Szalmás P: Evaluation of CD14 in host defence. Eur J Clin Invest 2000;30:167–179.
23.
Hadley JS, Wang JE, Foster SJ, Thiemermann C, Hinds CJ: Peptidoglycan of Staphylococcus aureus upregulates monocyte expression of CD14, Toll-like receptor 2 (TLR2), and TLR4 in human blood: possible implications for priming of lipopolysaccharide signaling. Infect Immun 2005;73:7613–7619.
24.
Wittebole X, Coyle SM, Kumar A, Goshima M, Lowry SF, Calvano SE: Expression of tumour necrosis factor receptor and Toll-like receptor 2 and 4 on peripheral blood leukocytes of human volunteers after endotoxin challenge: a comparison of flow cytometric light scatter and immunofluorescence gating. Clin Exp Immunol 2005;141:99–106.
25.
Tsujimoto H, Ono S, Majima T, Kawarabayashi N, Takayama E, Kinoshita M, et al: Neutrophil elastase, MIP-2, and TLR-4 expression during human and experimental sepsis. Shock 2005;23:39–44.
26.
Harter L, Mica L, Stocker R, Trentz O, Keel M: Increased expression of Toll-like receptor-2 and -4 on leukocytes from patients with sepsis. Shock 2004;22:403–409.
27.
Nagai Y, Shimazu R, Ogata H, Akashi S, Sudo K, Yamasaki H, et al: Requirement for MD-1 in cell surface expression of RP105/CD180 and B-cell responsiveness to lipopolysaccharide. Blood 2002;99;1699–1705.
28.
Kimoto M, Nagasawa K, Miyake K: Role of TLR4/MD-2 and RP105/MD-1 in innate recognition of lipopolysaccharide. Scand J Infect Dis 2003;35;568–572.
29.
Ricci G, Patrizi A, Neri I, Bendandi B, Masi M: Frequency and clinical role of Staphylococcus aureus overinfection in atopic dermatitis in children. Pediatr Dermatol 2003;20:389–392.
30.
Novak N, Allam JP, Bierber T: Allergic hyperreactivity to microbial components: a trigger factor of ‘intrinsic’ atopic dermatitis? J Allergy Clin Immunol 2003;112:215–216.
31.
Labeta MO, Durieux JJ, Fernandez N, Herrmann R, Ferrara P: Release from a human monocyte-like cell line of two different soluble forms of the lipopolysaccharide receptor, CD14. Eur J Immunol 1993;23:2144–2151.
32.
Zdolsek HA, Jenmalm MC: Reduced levels of soluble CD14 in atopic children. Clin Exp Allergy 2004;34:532–539.
33.
Wüthrich B, Kagi MK, Joller-Jemelka H: Soluble CD14 but not interleukin-6 is a new marker for clinical activity in atopic dermatitis. Arch Dermatol Res 1992;284:339–342.
34.
Furue M, Koga T, Yamashita N: Soluble E-selectin and eosinophil cationic protein are distinct serum markers that differentially represent clinical features of atopic dermatitis. Br J Dermatol 1999;140:67–72.
35.
Blumenthal MN: New thoughts regarding the genetics of atopy. Am J Respir Crit Care Med 2004;169:555–556.
36.
O’Donnell AR, Toelle BG, Marks GB, Hayden CM, Laing IA, Peat JK, et al: Age-specific relationship between CD14 and atopy in a cohort assessed from age 8 to 25 years. Am J Respir Crit Care Med 2004;169:615–622.
37.
Smith KB, Ellis SA: Standardisation of a procedure for quantifying surface antigens by indirect immunofluorescence. J Immunol Methods 1999;228:29–36.
38.
Antal-Szalmas P, Van Strijp JA, Weersink AJ, Verhoef J, Van Kessel KP: Quantitation of surface CD14 on human monocytes and neutrophils. J Leukoc Biol 1997;61:721–728.
© 2007 S. Karger AG, Basel
2007
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.