Staphylococcus aureus is a common human pathogen, which is regularly part of the normal microflora found in the nose and skin. It represents a significant threat to human health, not in the least because of its capability to produce exotoxins, which have superantigenic properties. These exotoxins, in particular the staphylococcal enterotoxins (SEs), are known to be involved in the modulation and aggravation of airway inflammation. Indeed, recent studies show an important impact of SEs on the natural course of allergic rhinitis, nasal polyposis, asthma and COPD. This review outlines the current knowledge on the influence of SEs on airway inflammation. We highlight, in particular, the recent evidence on their role in asthma.

1.
White J, Herman A, Pullen AM, Kubo R, Kappler JW, Marrack P: The V beta-specific superantigen staphylococcal enterotoxin B: Stimulation of mature T cells and clonal deletion in neonatal mice. Cell 1989;56:27-35.
2.
Fraser J, Arcus V, Kong P, Baker E, Proft T: Superantigens - powerful modifiers of the immune system. Mol Med Today 2000;6:125-132.
3.
Proft T, Fraser JD: Streptococcal superantigens. Chem Immunol Allergy 2007;93:1-23.
4.
Abe J, Takeda T: Characterization of a superantigen produced by Yersinia pseudotuberculosis. Prep Biochem Biotechnol 1997;27:173-208.
5.
Zhao Y, Li Z, Drozd SJ, Guo Y, Mourad W, Li H: Crystal structure of Mycoplasma arthritidis mitogen complexed with HLA-DR1 reveals a novel superantigen fold and a dimerized superantigen-MHC complex. Structure 2004;12:277-288.
6.
Lafon M, Lafage M, Martinez-Arends A, Ramirez R, Vuillier F, Charron D, Lotteau V, Scott-Algara D: Evidence for a viral superantigen in humans. Nature 1992;358:507-510.
7.
Hsiao FC, Lin M, Tai A, Chen G, Huber BT: Cutting edge: Epstein-Barr virus transactivates the HERV-K18 superantigen by docking to the human complement receptor 2 (CD21) on primary B cells. J Immunol 2006;177:2056-2060.
8.
Huber BT, Hsu PN, Sutkowski N: Virus-encoded superantigens. Microbiol Rev 1996;60:473-482.
9.
Townsley-Fuchs J, Neshat MS, Margolin DH, Braun J, Goodglick L: HIV-1 gp120: a novel viral B cell superantigen. Int Rev Immunol 1997;14:325-338.
10.
Kluytmans J, van Belkum A, Verbrugh H: Nasal carriage of Staphylococcus aureus: Epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev 1997;10:505-520.
11.
von Eiff C, Becker K, Machka K, Stammer H, Peters G: Nasal carriage as a source of Staphylococcus aureus bacteremia. Study group. N Engl J Med 2001;344:11-16.
12.
Novick RP: Pathogenecity factors and their regulation; in Fischetti VA, Novick RP, Ferretti JJ, Portnoy DA, Rood JI (eds): Gram-Positive Pathogens. Washington, ASM Press, 2000, pp 345-350.
13.
Jett M, Brinkley W, Neill R, Gemski P, Hunt R: Staphylococcus aureus enterotoxin B challenge of monkeys: correlation of plasma levels of arachidonic acid cascade products with occurrence of illness. Infect Immun 1990;58:3494-3499.
14.
Marrack P, Kappler J: The staphylococcal enterotoxins and their relatives. Science 1990;248:1066.
15.
Rellahan BL, Jones LA, Kruisbeek AM, Fry AM, Matis LA: In vivo induction of anergy in peripheral V beta 8+ T cells by staphylococcal enterotoxin B. J Exp Med 1990;172:1091-1100.
16.
Jarraud S, Peyrat MA, Lim A, Tristan A, Bes M, Mougel C, Etienne J, Vandenesch F, Bonneville M, Lina G: egc, a highly prevalent operon of enterotoxin gene, forms a putative nursery of superantigens in Staphylococcus aureus. J Immunol 2001;166:669-677.
17.
Lindsay JA, Holden MT: Staphylococcus aureus: superbug, super genome? Trends Microbiol 2004;12:378-385.
18.
Thomas D, Chou S, Dauwalder O, Lina G: Diversity in Staphylococcus aureus enterotoxins. Chem Immunol Allergy 2007;93:24-41.
19.
Papageorgiou AC, Tranter HS, Acharya KR: Crystal structure of microbial superantigen staphylococcal enterotoxin B at 1.5 a resolution: implications for superantigen recognition by MHC class II molecules and T-cell receptors. J Mol Biol 1998;277:61-79.
20.
Herrmann T, Accolla RS, MacDonald HR: Different staphylococcal enterotoxins bind preferentially to distinct major histocompatibility complex class II isotypes. Eur J Immunol 1989;19:2171-2174.
21.
Petersson K, Pettersson H, Skartved NJ, Walse B, Forsberg G: Staphylococcal enterotoxin H induces V alpha-specific expansion of T cells. J Immunol 2003;170:4148-4154.
22.
Fraser JD, Proft T: The bacterial superantigen and superantigen-like proteins. Immunol Rev 2008;225:226-243.
23.
Hofer MF, Lester MR, Schlievert PM, Leung DY: Upregulation of IgE synthesis by staphylococcal toxic shock syndrome toxin-1 in peripheral blood mononuclear cells from patients with atopic dermatitis. Clin Exp Allergy 1995;25:1218-1227.
24.
Grumann D, Scharf SS, Holtfreter S, Kohler C, Steil L, Engelmann S, Hecker M, Volker U, Broker BM: Immune cell activation by enterotoxin gene cluster (egc)-encoded and non-egc superantigens from Staphylococcus aureus. J Immunol 2008;181:5054-5061.
25.
Mawhorter SD, Kazura JW, Boom WH: Human eosinophils as antigen-presenting cells: relative efficiency for superantigen- and antigen-induced CD4+ T-cell proliferation. Immunology 1994;81:584-591.
26.
Guan L, Eisenstein TK, Adler MW, Rogers TJ: Inhibition of T cell superantigen responses following treatment with the kappa-opioid agonist U50,488H. J Neuroimmunol 1997;75:163-168.
27.
Zen K, Masuda J, Ogata J: Monocyte-derived macrophages prime peripheral T cells to undergo apoptosis by cell-cell contact via ICAM-1/LFA-1-dependent mechanism. Immunobiology 1996;195:323-333.
28.
Miller EJ, Nagao S, Carr FK, Noble JM, Cohen AB: Interleukin-8 (IL-8) is a major neutrophil chemotaxin from human alveolar macrophages stimulated with staphylococcal enterotoxin A (SEA). Inflamm Res 1996;45:386-392.
29.
Desouza IA, Hyslop S, Franco-Penteado CF, Ribeiro-DaSilva G: Evidence for the involvement of a macrophage-derived chemotactic mediator in the neutrophil recruitment induced by staphylococcal enterotoxin B in mice. Toxicon 2002;40:1709-1717.
30.
Krysko O, Holtappels G, Zhang N, Kubica M, Deswarte K, Derycke L, Claeys S, Hammad H, Brusselle GG, Vandenabeele P, Krysko DV, Bachert C: Alternatively activated macrophages and impaired phagocytosis of S. aureus in chronic rhinosinusitis. Allergy 2011;66:396-403.
31.
Inganas M, Johansson SG, Bennich HH: Interaction of human polyclonal IgE and IgG from different species with protein A from Staphylococcus aureus: demonstration of protein-A-reactive sites located in the fab'2 fragment of human IgG. Scand J Immunol 1980;12:23-31.
32.
Genovese A, Bouvet JP, Florio G, Lamparter-Schummert B, Bjorck L, Marone G: Bacterial immunoglobulin superantigen proteins A and L activate human heart mast cells by interacting with immunoglobulin E. Infect Immun 2000;68:5517-5524.
33.
Huvenne W, Callebaut I, Reekmans K, Hens G, Bobic S, Jorissen M, Bullens DM, Ceuppens JL, Bachert C, Hellings PW: Staphylococcus aureus enterotoxin B augments granulocyte migration and survival via airway epithelial cell activation. Allergy 2010;65:1013-1020.
34.
O'Brien GJ, Riddel G, Elborn JS, Ennis M, Skibinski G: Staphylococcus aureus enterotoxins induce IL-8 secretion by human nasal epithelial cells. Respir Res 2006;7:115.
35.
Schulz H, Karau A, Filsinger S, Schoels M, Kabelitz D, Richter R, Hansch GM: Tubular epithelial cells as accessory cells for superantigen-induced T cell activation. Exp Nephrol 1998;6:67-73.
36.
Peterson ML, Ault K, Kremer MJ, Klingelhutz AJ, Davis CC, Squier CA, Schlievert PM: The innate immune system is activated by stimulation of vaginal epithelial cells with Staphylococcus aureus and toxic shock syndrome toxin 1. Infect Immun 2005;73:2164-2174.
37.
Mandron M, Aries MF, Brehm RD, Tranter HS, Acharya KR, Charveron M, Davrinche C: Human dendritic cells conditioned with Staphylococcus aureus enterotoxin B promote Th2 cell polarization. J Allergy Clin Immunol 2006;117:1141-1147.
38.
Sha Q, Truong-Tran AQ, Plitt JR, Beck LA, Schleimer RP: Activation of airway epithelial cells by Toll-like receptor agonists. Am J Respir Cell Mol Biol 2004;31:358-364.
39.
Leyden JJ, Marples RR, Kligman AM: Staphylococcus aureus in the lesions of atopic dermatitis. Br J Dermatol 1974;90:525-530.
40.
Breuer K, Kapp A, Werfel T: Bacterial infections and atopic dermatitis. Allergy 2001;56:1034-1041.
41.
Schlievert PM, Strandberg KL, Lin YC, Peterson ML, Leung DY: Secreted virulence factor comparison between methicillin-resistant and methicillin-sensitive Staphylococcus aureus, and its relevance to atopic dermatitis. J Allergy Clin Immunol 2010;125:39-49.
42.
Leung DY, Harbeck R, Bina P, Reiser RF, Yang E, Norris DA, Hanifin JM, Sampson HA: 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.
43.
Hauk PJ, Hamid QA, Chrousos GP, Leung DY: Induction of corticosteroid insensitivity in human PBMCs by microbial superantigens. J Allergy Clin Immunol 2000;105:782-787.
44.
Schlievert PM, Case LC, Strandberg KL, Abrams BB, Leung DY: Superantigen profile of Staphylococcus aureus isolates from patients with steroid-resistant atopic dermatitis. Clin Infect Dis 2008;46:1562-1567.
45.
Laouini D, Kawamoto S, Yalcindag A, Bryce P, Mizoguchi E, Oettgen H, Geha RS: Epicutaneous sensitization with superantigen induces allergic skin inflammation. J Allergy Clin Immunol 2003;112:981-987.
46.
Savinko T, Lauerma A, Lehtimaki S, Gombert M, Majuri ML, Fyhrquist-Vanni N, Dieu-Nosjean MC, Kemeny L, Wolff H, Homey B, Alenius H: Topical superantigen exposure induces epidermal accumulation of CD8+ T cells, a mixed Th1/Th2-type dermatitis and vigorous production of IgE antibodies in the murine model of atopic dermatitis. J Immunol 2005;175:8320-8326.
47.
Le Loir Y, Baron F, Gautier M: Staphylococcus aureus and food poisoning. Genet Mol Res 2003;2:63-76.
48.
Ganeshan K, Neilsen CV, Hadsaitong A, Schleimer RP, Luo X, Bryce PJ: Impairing oral tolerance promotes allergy and anaphylaxis: a new murine food allergy model. J Allergy Clin Immunol 2009;123:231-238.
49.
Heriazon A, Zhou P, Borojevic R, Foerster K, Streutker CJ, Ng T, Croitoru K: Regulatory T cells modulate staphylococcal enterotoxin B-induced effector T-cell activation and acceleration of colitis. Infect Immun 2009;77:707-713.
50.
Tilahun AY, Holz M, Wu T-T, David CS, Rajagopalan G: Interferon gamma-dependent intestinal pathology contributes to the lethality in bacterial superantigen-induced toxic shock syndrome. PLoS One 2011;6:e16764.
51.
Hamad AR, Marrack P, Kappler JW: Transcytosis of staphylococcal superantigen toxins. J Exp Med 1997;185:1447-1454.
52.
Shupp JW, Jett M, Pontzer CH: Identification of a transcytosis epitope on staphylococcal enterotoxins. Infect Immun 2002;70:2178-2186.
53.
Rajagopalan G, Smart MK, Murali N, Patel R, David CS: Acute systemic immune activation following vaginal exposure to staphylococcal enterotoxin B - implications for menstrual shock. J Reprod Immunol 2007;73:51-59.
54.
Shiomori T, Yoshida S, Miyamoto H, Makishima K: Relationship of nasal carriage of Staphylococcus aureus to pathogenesis of perennial allergic rhinitis. J Allergy Clin Immunol 2000;105:449-454.
55.
Rossi RE, Monasterolo G: Prevalence of serum IgE antibodies to the Staphylococcus aureus enterotoxins (SAE, SEB, SEC, SED, TSST-1) in patients with persistent allergic rhinitis. Int Arch Allergy Immunol 2004;133:261-266.
56.
Okano M, Hattori H, Yoshino T, Sugata Y, Yamamoto M, Fujiwara T, Satoskar AA, Satoskar AR, Nishizaki K: Nasal exposure to staphylococcal enterotoxin enhances the development of allergic rhinitis in mice. Clin Exp Allergy 2005;35:506-514.
57.
Bachert C, Gevaert P, Holtappels G, Cuvelier C, van Cauwenberge P: Nasal polyposis: from cytokines to growth. Am J Rhinol 2000;14:279-290.
58.
van Zele T, Gevaert P, Watelet JB, Claeys G, Holtappels G, Claeys C, van Cauwenberge P, Bachert C: Staphylococcus aureus colonization and IgE antibody formation to enterotoxins is increased in nasal polyposis. J Allergy ClinImmunol 2004;114:981-983.
59.
Tripathi A, Kern R, Conley DB, Seiberling K, Klemens JC, Harris KE, Suh L, Huang J, Grammer LC: Staphylococcal exotoxins and nasal polyposis: analysis of systemic and local responses. Am J Rhinol 2005;19:327-333.
60.
Zhang N, Holtappels G, Gevaert P, Patou J, Dhaliwal B, Gould H, Bachert C: Mucosal tissue polyclonal IgE is functional in response to allergen and SEB. Allergy 2011;66:141-148.
61.
Bachert C, Zhang N, Patou J, van Zele T, Gevaert P: Role of staphylococcal superantigens in upper airway disease. Curr Opin Allergy Clin Immunol 2008;8:34-38.
62.
Bachert C, Zhang N, Holtappels G, De Lobel L, van Cauwenberge P, Liu S, Lin P, Bousquet J, van Steen K: Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma. J Allergy Clin Immunol 2010;126:962-968, 968 e961-e966.
63.
Gevaert P, Calus L, van Zele T, Blomme K, De Ruyck N, Bauters W, Hellings P, Brusselle G, De Bacquer D, van Cauwenberge P, Bachert C: Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol 2013;131:110-116 e111.
64.
Bachert C, Gevaert P, Howarth P, Holtappels G, van Cauwenberge P, Johansson SG: Ige to Staphylococcus aureus enterotoxins in serum is related to severity of asthma. J Allergy Clin Immunol 2003;111:1131-1132.
65.
Perez-Novo CA, Kowalski ML, Kuna P, Ptasinska A, Holtappels G, van Cauwenberge P, Gevaert P, Johannson S, Bachert C: Aspirin sensitivity and IgE antibodies to Staphylococcus aureus enterotoxins in nasal polyposis: studies on the relationship. Int Arch Allergy Immunol 2004;133:255-260.
66.
Hellings PW, Hens G, Meyts I, Bullens D, Vanoirbeek J, Gevaert P, Jorissen M, Ceuppens JL, Bachert C: Aggravation of bronchial eosinophilia in mice by nasal and bronchial exposure to Staphylococcus aureus enterotoxin B. Clin Exp Allergy 2006;36:1063-1071.
67.
Barnes PJ: Intrinsic asthma: not so different from allergic asthma but driven by superantigens? Clin Exp Allergy 2009;39:1145-1151.
68.
Herz U, Ruckert R, Wollenhaupt K, Tschernig T, Neuhaus-Steinmetz U, Pabst R, Renz H: Airway exposure to bacterial superantigen (SEB) induces lymphocyte-dependent airway inflammation associated with increased airway responsiveness - a model for non-allergic asthma. Eur J Immunol 1999;29:1021-1031.
69.
Bachert C, van Steen K, Zhang N, Holtappels G, Cattaert T, Maus B, Buhl R, Taube C, Korn S, Kowalski M, Bousquet J, Howarth P: Specific IgE against Staphylococcus aureus enterotoxins: an independent risk factor for asthma. J Allergy Clin Immunol 2012;130:376-381 e378.
70.
Bachert C, Zhang N: Chronic rhinosinusitis and asthma: novel understanding of the role of IgE ‘above atopy'. J Intern Med 2012;272:133-143.
71.
Semic-Jusufagic A, Bachert C, Gevaert P, Holtappels G, Lowe L, Woodcock A, Simpson A, Custovic A: Staphylococcus aureus sensitization and allergic disease in early childhood: population-based birth cohort study. J Allergy Clin Immunol 2007;119:930-936.
72.
Hollams E, Hales B, Bachert C, Huvenne W, Parsons F, de Klerk N, Serralha M, Holt B, Ahlstedt S, Thomas W, Sly P, Holt PG: Th2-associated immunity to bacteria in asthma in teenagers and susceptibility to asthma. Eur Respir J 2010;36:509-516.
73.
Holt PG, Strickland DH, Wikstrom ME, Jahnsen FL: Regulation of immunological homeostasis in the respiratory tract. Nat Rev Immunol 2008;8:142-152.
74.
Rohde G, Gevaert P, Holtappels G, Borg I, Wiethege A, Arinir U, Schultze-Werninghaus G, Bachert C: Increased IgE-antibodies to Staphylococcus aureus enterotoxins in patients with COPD. Respir Med 2004;98:858-864.
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.