Background:Staphylococcus aureus-producing superantigens (SAgs), such as staphylococcal enterotoxin B (SEB) or toxic shock syndrome toxin-1 (TSST-1), are frequently observed in atopic dermatitis (AD). However, little has been done to establish the association of immune responses to SAgs and the therapeutic response to immunosuppressive drugs in AD. Therefore, we investigated the prevalence and role of SAgs in the pathophysiology and immunosuppressive drug sensitivity in AD patients. Methods: We classified 29 patients into two groups on the basis of their clinical AD scores: a low-score group (n = 14) corresponding to mild to moderate patients and a high-score group (n = 15) corresponding to severe patients. We estimated the plasma anti-SEB or TSST-1 IgE of these patients and healthy subjects by ELISA. We also estimated individual drug sensitivity by determining drug concentrations that would give 50% inhibition (IC50) of peripheral-blood mononuclear cell (PBMC) proliferation in vitro. Results: The levels of plasma anti-SEB or TSST-1 IgE in the severe patients were significantly higher than those in the mild to moderate patients (p < 0.05 and p < 0.01, respectively). When stimulated with concanavalin A in vitro, PBMCs in the severe patients exhibited low sensitivity to the suppressive efficacy of tacrolimus (FK506) as compared to the mild to moderate patients (p < 0.01). Furthermore, there was a significant correlation between the IC50s of FK506 and plasma anti-TSST-1 IgE levels (p < 0.01). Conclusions: We showed that PBMCs in severe AD patients exhibited lower sensitivity to FK506, and had higher plasma levels of anti-TSST-1 IgE as compared to the mild AD patients. SAgs appear to be one of the causes of decreased PBMC sensitivity to FK506, and therefore an alternative treatment would be useful based on the individual drug sensitivity data and anti-TSST-1 IgE levels.

1.
Leung DYM, Harbeck R, Bina P: 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.
2.
Leyden JE, Marples RR, Kligman AM: Staphylococcus aureus in the lesions of atopic dermatitis. Br J Dermatol 1974;90:525–530.
3.
Dinges MM, Orwin PM, Schlievert PM: Exotoxins of Staphylococcus aureus. Clin Microbiol Rev 2000;13:16–34.
4.
Lever R, Hadley K, Downey D, Mackie R: Staphylococcal colonization in atopic dermatitis and the effect of topical mupirocin therapy. Br J Dermatol 1988;119:189–198.
5.
Neuber K, Konig W: Effects of Staphylococcus aureus cell wall products (teichonic acid, peptidoglycan) and enterotoxin B in immunoglobulin (IgE, IgA, IgG) synthesis and CD23 expression in patients with atopic dermatitis. Immunology 1992;75:23–28.
6.
Leung DYM, Hauk P, Strickland I, Traverd JB, et al: The role of superantigens in human disease: therapeutic implications for the treatment of skin diseases. Br J Dermatol 1998;139:17–29.
7.
Zollner TM, Wichelhaus TA, Hartung A, et al: Colonization with superantigen-producing Staphylococcus aureus is associated with increased severity of atopic dermatitis. Clin Exp Allergy 2000;30:994–1000.
8.
Hauk PJ, Hamid QA, Chrousos GP, et al: Induction of corticosteroid insensitivity in human PBMCs by microbial superantigens. J Allergy Clin Immunol 2000;105:782–787.
9.
Uchiyama T, Yan XJ, Imanishi K, et al: Bacterial superantigens – mechanism of T cell activation by the superantigens and their role in the pathogenesis of infectious diseases. Microbiol Immunol 1994;38:245–256.
10.
Llwelyn MC, Cohen J: Superantigens: microbial agents that corrupt immunity. Lancet Infect Dis 2002;2:156–162.
11.
Florquin S, Aaldering L: Superantigens: a tool to gain new insight into cellular immunity. Res Immunol 1997;148:373–386.
12.
Takahashi M, Takahata M, Shinohara M, et al: Effect of superantigen and lipopolysaccharide on induction of CD80 through apoptosis of human monocytes. Infect Immun 2001;69:3652–3657.
13.
Monday SR, Bohach GA: Properties of Staphylococcus aureus enterotoxins and toxic shock syndrome toxin-1; in Alouf JE, Freer JH (eds): The Comprehensive Sourcebook of Bacterial Protein Toxins. London, Academic Press, 1999, pp 589–610.
14.
Leung DYM, Meissner HC, Fulton DR, et al: Superantigens in Kawasaki syndrome. Clin Immunol Immunopathol 1995;77:119–126.
15.
Paliard X, West SG, Lafferty JA, et al: Evidence for the effects of a superantigen in rheumatoid arthritis. Science 1991;253:325–329.
16.
Hauk PJ, Wenzel SE, Trumble AE, et al: Increased T cell receptor vbeta8+ T cells in bronchoalveolar lavage fruid of subjects with poorly controlled asthma: a potential role for microbial superantigens. J Allergy Clin Immunol 1999;104:37–45.
17.
Shiomori T, Yoshida S, Miyamoto H: Relation ship of nasal carriage of Staphylococcal aureus to pathogenesis of perennial allergic rhinitis. J Allergy Clin Immunol 2000;105:449–454.
18.
Leung DYM, Travers JB, Giorno R, et al: Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis. J Clin Invest 1995;96:2106–2112.
19.
Tada J, Toy Y, Akiyama H, et al: Presence of specific IgE antibody to staphylococcal enterotoxins in patients with atopic dermatitis. Eur J Dermatol 1996;6:552–554.
20.
Bunikowski R, Mielke M, Skarabis H, et al: Prevalence and role of serum IgE antibodies to the Staphylococcus aureus-derived superantigens SEA and SEB in children with atopic dermatitis. J Allergy Clin Immunol 1999;103:119–124.
21.
Sohn MH, Kim CH, Kim WK, et al: Effect of staphylococcal enterotoxin B on specific antibody production in children with atopic dermatitis. Allergy Asthma Proc 2003;24:67–71.
22.
Furue M, Furukawa F, Hide M, Takehara K: Guidelines for therapy for atopic dermatitis. Jpn J Dermatol 2004;114:135–142.
23.
Hirano T, Oka K, Takeuchi H, et al: Clinical significance of glucocorticoid pharmacodynamics assessed by antilymphocyte action in kidney transplantation. Marked difference between prednisolone and methylprednisolone. Transplantation 1994;57:1341–1348.
24.
Miwa K, Fukuyama M, Sakai R, et al: Sensitive enzyme-linked immunosorbent assays for detection of bacterial superantigens and antibodies against them in human plasma. Microbiol Immunol 2000;44:519–523.
25.
Matsui K, Nishikawa A, Suto H, et al: Comparative study of Staphylococcus aureus isolated from lesion and no-lesional skin of atopic dermatitis patients. Microbiol Immunol 2000;44:945–947.
26.
Bunikowski R, Mielke ME, Skarabis H, et al: Evidence for disease-promoting effect of Staphylococcus aureus-derived exotoxins in atopic dermatitis. J Allergy Clin Immunol 2000;105:814–819.
27.
Breuer K, Wittmann M, Bosche B, et al: Severe atopic dermatitis is associated with sensitization to staphylococcal enterotoxin S (SEB). Allergy 2000;55:551–555.
28.
Nomura I, Tanaka H, Tomita H, et al: Evaluation of the staphylococcal exotoxins and their specific IgE in childhood atopic dermatitis. J Allergy Clin Immunol 1999;104:441–446.
29.
Yoshino T, Asada H, Sano S, et al: Impaired responses of peripheral blood mononuclear cells to staphylococcal superantigen in patients with severe atopic dermatitis: a role of T cell apoptosis. J Invest Dermatol 2000;114:281–288.
30.
Konig B, Neuber K, Konig W: Responsiveness of peripheral blood mononuclear cells from normal and atopic donors to microbial superantigens. Int Arch Allergy Immunol 1995;106:124–133.
31.
Yudate T, Yamada H, Tezuka T: Role of staphylococcal enterotoxins in pathogenesis of atopic dermatitis: growth and expression of T cell receptor V beta of peripheral blood mononuclear cells stimulated by enterotoxins A and B. J Dermatol Sci 1996;13:63–70.
32.
Cambell DE, Kemp AS: Proliferation and production of interferon-gamma (IFN-gamma) and IL-4 in response to Staphylococus aureus and staphylococcal superantigen in childhood atopic dermatitis. Clin Exp Immunol 1997;107:392–397.
33.
Tanaka M, Aiba S, Takahashi K, et al: Reduced proliferative responses of peripheral blood mononuclear cells specifically to Candida albicans antigen in patients with atopic dermatitis – comparison with their normal reactivity to bacterial superantigens. Arch Dermatol Res 1996;288:495–499.
34.
Florquin S, Amraoui Z, Goldman M: T cells made deficient in interleukin-2 production by exposure to staphylococcal enterotoxin B in vivo are primed for interferon-gamma and interleukin-10 secretion. Eur J Immunol 1995;25:1148–1153.
35.
Gimeno R, Codony-Servet J, Plaza M, et al: Stat1 implication in the immune response to superantigens in vivo. J Immunol 1996;156:1378–1386.
36.
Schols D, Jones D, Roncarolo MG: Unique cytokine production profile of anergic human T cells in SCID-hu mice after staphylococcal enterotoxin B administration. J Immunol 1995;154:3204–3212.
37.
Plaza R, Vidal S, Rodriguez JL, et al: Implication of STAT1 and STAT3 transcription factors in the response to superantigens. Cytokine 2004;25:1–10.
38.
Fleischer AB: Treatment of atopic dermatitis: role of tacrolimus ointment as a topical non-corticosteroidal therapy. J Allergy Clin Immunol 1999;104:S126–S130.
39.
Hisatomi A, Mitamura T, Kimura M, et al: Comparison of FK506 (tacrolimus) and glucocorticoid ointment on dermal atrophogenecity in rats. J Toxicol Pathol 1997;10:97–102.
40.
Paller A, Eichenfield LF, Leung DY, et al: A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001;44 (1 suppl):S47–S57.
41.
Hirano T, Oka K, Takeuchi H, et al: Immunosuppressant pharmacodynamics on lymphocytes from healthy subjects and patients with chronic renal failure, nephrosis, and psoriasis. Clin Pharmacol Ther 1997;62:652–664.
42.
Li LB, Goleva E, Hall CF, et al: Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway. J Allergy Clin Immunol 2004;114:1059–1069.
43.
Sakuma S, Higashi Y, Sato N, et al: Tacrolimus suppressed the production of cytokines involved in atopic dermatitis by direct stimulation of the human PBMC system. (Comparison with steroids). Int Immunopharmacol 2001;1:1219–1226.
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.