Background: Although several immunological abnormalities have been demonstrated in Behçet’s disease (BD), the exact mechanism of the inflammatory changes occurring is still unknown. Antigen-presenting cells, such as mononuclear phagocytes, play a major role in the regulation of immune-mediated as well as of non-specific inflammation. Objective: To investigate the serum activity of patients with BD on antigen and chemokine expression of human macrophages in vitro. Methods: Serum of 15 patients (8 women, 7 men; mean age 33 ± 10 years) with BD was incubated with cultured macrophages isolated from peripheral blood of healthy volunteers. Macrophages maintained in patients’ serum, fetal calf serum with/without dexamethasone and interleukin (IL)-4 or γ-interferon were investigated for alternative macrophage-activation-associated CC-chemokine 1 (AMAC-1) and IL-8 mRNA expression by Northern blotting. In addition, cytocentrifuge macrophage preparations were stained with monoclonal antibodies against proteins indicating alternative (anti-inflammatory) macrophage activation, such as MS-1 high-molecular-weight protein (MS-1-HMWP), RM3/1 antigen (CD163) and 25F9, as well as classical (pro-inflammatory) macrophage activation, such as CD11c, class I receptor binding the Fc part of IgG (FcγRI: CD64) and class III receptor binding the Fc part of IgG (FcγRIII: CD16). Results: Macrophages treated with patients’ serum showed neither AMAC-1 expression nor staining with monoclonal antibodies for MS-1-HMWP, CD163 or 25F9. Concomitant treatment with IL-4/dexamethasone up-regulated significantly the expression of CD163. In contrast, IL-8 mRNA expression and staining for CD11c and CD64 were strongly positive after treatment with serum of patients with BD. CD64 positivity and IL-8 mRNA expression were more prominent in patients with active BD than in patients with inactive disease. Conclusion: Taken together, our results indicate that serum of patients with BD induces classical (pro-inflammatory) activation of human peripheral blood macrophages in vitro. Our findings suggest that serum factor(s) may be responsible for inflammatory changes in BD.

Keywords:
Behçet’s disease, Serum, Macrophages, AMAC-1, Interleukin 8, CD64
1.
Sakane T, Takeno M, Suzuki N, Inaba G: Behçet’s disease. N Engl J Med 1999;341:1284–1291.
2.
Sakane T, Suzuki N, Nagafuchi H: Etiopathology of Behçet disease: Immunological aspects. Yonsei Med J 1997;38:350–358.
3.
Zouboulis CC, Kötter I, Djawari D, Kirch W, Kohl PK, Ochsendorf FR, Keitel W, Stadler R, Wollina U, Proksch E, Söhnchen R, Weber H, Gollnick HPM, Hölzle E, Fritz K, Licht T, Orfanos CE: Epidemiological features of Adamantiades-Behçet’s disease in Germany and in Europe. Yonsei Med J 1997;38:411–422.
4.
Adler YD, Mansmann U, Zouboulis CC: Mycophenolate mofetil is ineffective in the treatment of mucocutaneous Adamantiades-Behcet’s disease. Dermatology 2001;203:322–324.
5.
Alpsoy E, Yilmaz E, Coskun M, Savas A, Yegin O: HLA antigens and linkage disequilibrium patterns in Turkish Behçet’s patients. J Dermatol 1998;25:158–162.
6.
Goerdt S, Orfanos CE: Other functions, other genes: Alternative activation of antigen-presenting cells. Immunity 1999;10:137–142.
7.
Stein M, Keshav S, Harris N, Gordon S: Interleukin-4 potently enhances murine macrophage mannose receptor activity: A marker of alternative immunologic macrophage activation. J Exp Med 1992;176:287–292.
8.
Goerdt S, Bhardwaj R, Sorg C: Inducible expression of MS-1 high molecular weight protein by endothelial cells of continuous origin and by dendritic cells/macrophages in vivo and in vitro. Am J Pathol 1993;142:1409–1422.
9.
Zwadlo G, Voegeli R, Schulze-Osthoff K, Sorg C: A monoclonal antibody to a novel differentiation antigen on human macrophages associated with the down-regulatory phase of the inflammatory process. Exp Cell Biol 1987;55:295–304.
10.
Zwadlo G, Bröcker EB, von Bassewitz DB, Feige U, Sorg C: A monoclonal antibody to a differentiation antigen present on mature human macrophages and absent from monocytes. J Immunol 1985;134:1487–1492.
11.
Kodelja V, Müller C, Politz O, Hakij N, Orfanos CE, Goerdt S: Alternative macrophage activation-associated CC-chemokine-1, a novel structural homologue of macrophage inflammatory protein-1 alpha with a Th2-associated expression pattern. J Immunol 1998;160:1411–1418.
12.
International Study Group for Behçet’s disease: Criteria for diagnosis of Behçet’s disease. Lancet 1990;335:1078–1080.
13.
Kodelja V, Goerdt S: Dissection of macrophage differentiation pathways in cutaneous macrophage disorders and in vitro. Exp Dermatol 1994;3:257–268.
14.
Goerdt S, Walsh LJ, Murphy GF, Pober JS: Identification of a novel high molecular weight protein antigen preferentially expressed by sinusoidal endothelial cells in normal human tissues. J Cell Biol 1991;113:1425–1437.
15.
Walsh LJ, Goerdt S, Pober JS, Sueki H, Murphy GF: MS-1 sinusoidal endothelial antigen is expressed by factor XIIIa+, HLA-DR+ dermal perivascular dendritic cells. Lab Invest 1991;65:732–741.
16.
Zwadlo-Klarwasser G, Bent S, Haubeck HD, Sorg C, Schmutzler W: Glucocorticoid-induced appearance of the macrophage subtype RM3/1 in peripheral blood in man. Int Arch Allergy Appl Immunol 1980;91:175–180.
17.
Åström A, Tavakkol A, Pettersson U, Cromie M, Elder JT, Voorhees JJ: Molecular cloning of two human cellular retinoic acid-binding proteins (CRABP). Retinoic acid-induced expression of CRABP-II but not CRABP-I in adult human skin in vivo and in skin fibroblasts in vitro. J Biol Chem 1991;266:17662–17666.
18.
Becker S, Daniel EG: Antagonistic and additive effects of IL-4 and interferon-gamma on human monocytes and macrophages: Effects on Fc receptors, HLA-D antigens, and superoxide production. Cell Immunol 1990;129:351–362.
19.
de Velde AA, Huijbens RJ, de Vries JE, Figdor CG: IL-4 decreases Fc gamma R membrane expression and Fc gamma R-mediated cytotoxic activity of human monocytes. J Immunol 1990;144:3046–3051.
20.
Goerdt S, Kolde G, Bonsmann G, Hamann K, Czarnetzki B, Andreesen R, Luger T, Sorg C: Immunohistochemical comparison of cutaneous histiocytoses and related skin disorders: Diagnostic and histogenetic relevance of MS-1 high molecular weight protein expression. J Pathol 1993:170:421–427.
21.
Wenzel I, Roth J, Sorg C: Identification of a novel surface molecule, RM3/1, that contributes to the adhesion of glucocorticoid-induced human monocytes to endothelial cells. Eur J Immunol 1996;26:2758–2763.
22.
Goerdt S, Kodelja V, Schmuth M, Orfanos CE, Sorg C: The mononuclear phagocyte-dendritic cell dichotomy: Myths, facts, and a revised concept. Clin Exp Immunol 1996;105:1–9.
23.
Topoll H, Zwadlo G, Lange DE, Sorg C: Phenotypic dynamics of macrophage subpopulations during human experimental gingivitis. J Periodontal Res 1989;24:106–112.
24.
Szekanecz Z, Haines GK, Lin TR, Harlow LA, Goerdt S, Rayan G, Koch AE: Differential distribution of intercellular adhesion molecules (ICAM-1, ICAM-2, and ICAM-3) and the MS-1 antigen in normal and diseased human synovia: Their possible pathogenetic and clinical significance in rheumatoid arthritis. Arthritis Rheum 1994;37:221–231.
25.
Djemadji-Oudjiel N, Goerdt S, Kodelja V, Schmuth M, Orfanos CE: Immunohistochemical identification of type II alternatively activated dendritic macrophages (RM3/1+++, MS-1+/–, 25F9–) in psoriatic dermis. Arch Dermatol Res 1996;288:757–764.
26.
Ravetch JV: Fc receptors. Curr Opin Immunol 1997;9:121–125.
27.
Baggiolini M, Dewald B, Moser B: Human chemokines: An update. Annu Rev Immunol 1997;15:675–705.
28.
Zouboulis CC, Katsantonis J, Ketteler R, Treudler R, Kaklamani E, Hornemann S, Kaklamanis P, Orfanos CE: Adamantiades-Behçet’s disease: Interleukin-8 is increased in serum of patients with active oral and neurological manifestations and is secreted by small vessel endothelial cells. Arch Dermatol Res 2000;292:279–284.
29.
Katsantonis J, Adler Y, Orfanos CE, Zouboulis CC: Adamantiades-Behçet’s disease: Serum IL-8 is a more reliable marker for disease activity than C-reactive protein and erythrocyte sedimentation rate. Dermatology 2000;201:37–39.
30.
Kienbaum S, Zouboulis CC, Waibel M, Orfanos CE: Chemotactic neutrophilic vasculitis: A new histopathological pattern of vasculitis found in mucocutaneous lesions of patients with Adamantiades-Behçet’s disease; in Wechsler B, Godeau P (eds): Behçet’s Disease. International Congress Series 1037. Amsterdam, Excerpta Medica, 1993, pp 337–341.
31.
Rizzi B, Bruno S, Dammacco R: Behçet’s disease: An immune-mediated vasculitis involving vessels of all sizes. Int J Clin Lab Res 1997;27:225–232.
32.
Hamzaoui K, Ayed K, Slim A, Hamza M, Touraine J: Natural killer cell activity, interferon-gamma and antibodies to herpes viruses in patient’s with Behçet’s disease. Clin Exp Immunol 1990;79:28–34.
33.
Lew W, Lee SH, Bang D, Lee S, Kim JC, Chung TH: Serum tumor necrosis factor, interleukin-1-beta and interleukin-6 levels in Behçet’s disease. Ann Dermatol 1993;5:69–73.
34.
Mege JL, Dilsen N, Sanguedolce V, Gul A, Bongrand P, Roux H, Ocal L, Inanc M, Capo C: Overproduction of monocyte derived tumor necrosis factor α, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behçet’s disease: A comparative study with familial Mediterranean fever and healthy subjects. J Rheumatol 1993;20:1544–1549.
35.
Itoh R, Takenaka T, Okitsu-Negishi S, Matsushima K, Mizogouchi M: Interleukin 8 in Behçet’s disease. J Dermatol 1994;21:397–404.
36.
Sayinalp N, Özcebe OI, Özdemir O, Haznedaroglu IC, Dündar S, Kirazli S: Cytokines in Behçet’s disease. J Rheumatol 1996;23:321–322.
37.
Alpsoy E, Cayirli C, Er H, Yilmaz E: The levels of plasma interleukin-2 and soluble interleukin-2r in Behçet’s disease, as a marker of disease activity. J Dermatol 1998;25:513–516.
38.
Zouboulis CC: Morbus Adamantiades-Behçet: Klinische und experimentelle Untersuchungen – Erhebungen an 53 Patienten aus dem Berliner Raum; Habilitationsschrift, Fachbereich Humanmedizin der Freien Universität Berlin, 1995.
39.
Lee KH, Bang D, Choi ES, Chun WH, Lee ES, Lee S: Presence of circulating antibodies to a disease-specific antigen on cultured human dermal microvascular endothelial cells in patients with Behçet’s disease. Arch Dermatol Res 1999;291:374–381.
40.
Boyvat A, Sisman-Solak C, Gurler A: Long-term effects of interferon alpha 2a treatment in Behçet’s disease. Dermatology 2000;201:40–43.
41.
Zouboulis CC, Orfanos CE: Treatment of Adamantiades-Behçet disease with systemic interferon alfa. Arch Dermatol 1998;134:1010–1016.
42.
Alpsoy E, Durusoy Ç, Yilmaz E, Özgürel Y, Ermis O, Yazar S, Basaran E: Interferon alpha-2a in the treatment of Behçet’s disease: A randomized, placebo-controlled and double blind study. Arch Dermatol 2002;138:467–471.
43.
Katsantonis J, Seltmann H, Wróbel A, Adler YD, Hornemann S, Orfanos CE, Zouboulis CC: Xenobiotic regulation of endothelial intracellular and secreted interleukin-8 induced by serum of patients with Adamantiades-Behçet’s disease; in Bang D, Lee E-S, Lee S (eds): Behçet’s Disease. Proceedings of the 9th International Conference on Behçet’s Disease and the 8th International Conference on Behçet’s Disease. Seoul, Library of Congress Cataloging, 2001, pp 236–239.
© 2003 S. Karger AG, Basel
2003
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.