- Email: [email protected]
Atopic dermatitis and the immune system: The role of superantigens and bacteria
SUPPORTED
BY AN EDUCATIONAL GRANT FROM NOVARTIS PHARMA AND NOVARTIS PHARMACEUTICALS CORPORATION
AG
Atopic dermatitis and the immune system: The role of superantigens and bacteria Donald Y. M. Leung, MD, PhD Denver, Colorado
P
opulation studies indicate that the prevalence of atopic dermatitis (AD) has been steadily increasing since World War II. It now affects 10% to 15% of children in many parts of the world.1 The basis of this rapid increase in prevalence is unknown. However, it is generally thought to be related to changes in our environment because there is great worldwide variation in the prevalence of AD even among populations with common genetic backgrounds. Several factors can trigger AD, including irritants, foods, aeroallergens, and infection.2 However, there has been widespread interest in the potential role of Staphylococcus aureus in the pathogenesis of AD because most patients are colonized with this microbe and it secretes potent toxins that trigger skin inflammation. More than 90% of patients with AD have S aureus on their skin.3 The importance of S aureus colonization in AD is supported by the observation that not only patients with impetiginized AD, but also AD patients without superinfection, show clinical response to combined treatment with antistaphylococcal antibiotics and topical corticosteroids.4-6 One longitudinal study demonstrated that S aureus only infrequently colonized the noneczematous skin of infants with AD.7 This suggests that S aureus colonization is a secondary phenomenon, not present when AD begins during infancy. However, once colo-
From the Division of Allergy-Immunology, National Jewish Medical and Research Center. This article is part of a supplement sponsored by Novartis Pharma AG and Novartis Pharmaceuticals Corporation. Supported in part by National Institutes of Health grants AR41256 and RR00051. Presented at the International Consensus Conference on Atopic Dermatitis, November 5-6, 1999, Rome, Italy. Disclosure: Dr Leung is a paid consultant to Novartis Pharmaceutical Corporation. Reprint requests: Donald Leung, MD, PhD, National Jewish Medical and Research Center, Head, Division of Allergy-Immunology, 1400 Jackson St (K926), Denver, CO 80206. E-mail: [email protected]. J Am Acad Dermatol 2001;45:S13-6. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/0/117024 doi:10.1067/mjd.2001.117024
nized with S aureus, the skin disease can become much more severe.
IMMUNOBIOLOGY OF SUPERANTIGENS Recent studies suggest that one strategy by which S aureus exacerbates or maintains skin inflammation in AD is by secreting superantigens, which stimulate massive activation of T cells and macrophages.8 Superantigens refer to a group of microbial antigens that differ in several respects from nominal peptide antigens. Although superantigens, like peptide antigens, are presented by class II major histocompatibility complex (MHC) molecules, they do not engage the MHC peptide-antigen binding groove. Instead, the intact (unprocessed) superantigen binds to the lateral walls of the peptide-antigen binding groove. An important distinguishing feature between superantigens and conventional peptide antigens is that superantigens stimulate T cells almost solely through the Vβ portion of the T-cell receptor (TCR). Conventional peptide antigens frequently require recognition by all 5 variable elements (ie, Vβ, Dβ, Jβ, Vα, and Jα) of the TCR. Therefore the responding frequency to a nominal peptide antigen is usually much less than 1 in 1000. In contrast, because the number of Vβ genes is limited, the frequency of T cells responding to these molecules exceeds that of nominal peptide antigens by several orders of magnitude, hence the term superantigen.
EFFECTS OF SUPERANTIGENS IN AD Several lines of investigation support a role for superantigens in AD (Table I). First, more than half of patients with AD have S aureus isolates cultured from their skin that secrete superantigens, such as staphylococcal enterotoxins (SE) A or B and toxic shock syndrome toxin-1 (TSST-1).9-11 Second, most patients with AD make specific immunoglobulin (IgE) antibodies directed against the staphylococcal toxins found on their skin. Basophils and mast cells from patients with antitoxin IgE release histamine on exposure to the relevant toxin, but not in response to toxins to which they had no specific IgE. Third, microgram amounts of SEB applied to the skin can induce the eczematoid skin changes of S13
S14 Leung
Table I. Evidence for role of staphylococcal superantigens in AD • Atopic skin is associated with an overgrowth of S aureus. • The majority of S aureus isolates from AD skin produce superantigens. • AD severity correlates with presence of IgE antibodies to superantigens. • Superantigens augment allergen-induced skin inflammation by activating infiltrating mononuclear cells and inducing mast cell degranulation. • Superantigens induce dermatitis on application to skin by patch testing. • Patients recovering from toxic shock syndrome develop chronic eczema. • Superantigens induce the skin-homing receptor on T cells. • PBMCs from AD, as compared with normal controls, have higher proliferative responses to superantigens. PBMC, Peripheral blood mononuclear cell.
erythema and induration in unaffected atopic or normal skin. Interestingly, only nanogram amounts of superantigens are needed to trigger skin inflammation in vivo when keratinocytes express human leukocyte antigen from the DR region (HLADR).12,13 Fourth, superantigens induce T-cell expression of the skin homing receptor CLA via stimulation of interleukin 12 (IL-12) production.14 In the case of AD, we have proposed that staphylococcal superantigens secreted at the skin surface could penetrate inflamed skin and stimulate epidermal Langerhans’ cells or macrophages to produce IL-1, tumor necrosis factor (TNF), and IL-12. Local production of IL-1 and TNF induces the expression of E-selectin on vascular endothelium, allowing an initial influx of CLA+ memory/effector cells. Local secretion of IL-12 could increase CLA expression on those T cells activated by allergen or superantigen and thereby increase their efficiency of T-cell recirculation to the skin. IL-12 secreted by toxinstimulated Langerhans’ cells, which migrate to skin-associated lymph nodes (and serve as antigenpresenting cells therein), could also up-regulate the expression of CLA, thereby creating additional skinhoming memory-effector T cells. This concept is supported by our recent observation that the presence of superantigens on the skin lesions of AD predicted the expansion of appropriate (superantigenassociated) TCR-Vβ–bearing T cells in the skin lesions, as well as the circulating CLA+ skin-homing memory T-cell subset.15,16 Together, these mechanisms would tend to markedly amplify the initial cutaneous inflammation in AD and create conditions favoring staphylococcal skin colonization.
J AM ACAD DERMATOL JULY 2001
Finally, peripheral blood mononuclear cells (PBMCs) from children with AD have also been reported to have significantly higher proliferation and IL-4 responses to both S aureus and SEB, but diminished production of interferon gamma (IFN-γ) in response to S aureus and SEB.17 These investigators suggested that impaired IFN-γ production to S aureus in vivo may result in failure to eradicate this organism from the skin. Persistence on the skin could contribute to inflammation by causing continued T-cell and macrophage activation. Recent studies by Bratton et al18 have demonstrated that staphylococcal superantigens induce the production of granulocyte-macrophage colony-stimulating factor, resulting in inhibition of monocyte-macrophage apoptosis, perpetuating the chronicity of this inflammatory skin disease.
ASSOCIATION OF SUPERANTIGENS WITH DISEASE SEVERITY It is well established that exacerbation of AD is frequently associated with S aureus infection.19 Relevant to this, several recent articles have reported a correlation between the presence of IgE anti-superantigens and the severity of AD.10,11 This correlation is strongest when patients produce IgE against staphylococcal superantigens that are found on the skin surface of patients with AD. In this situation, superantigens being continuously secreted on the skin surface may be constantly triggering mediator/cytokine release from IgE-bearing mast cells and macrophages. With the use of a humanized murine model of skin inflammation, S aureus toxin plus allergen also has been found to have an additive effect on allergeninduced cutaneous inflammation.20 These observations are consistent with our recent report that superantigens augment allergen-induced IgE responses, which suggests that these potent molecules have an adjuvant effect on T-cell–mediated responses by cross-linking HLA-DR with the TCR.21 Topical corticosteroids are the mainstay of antiinflammatory therapy in the management of chronic AD. However, patients vary greatly in their response to corticosteroid therapy. The observation that combined treatment of AD with antibiotics and corticosteroids is more effective than corticosteroids alone suggests that S aureus secretes products that can induce corticosteroid insensitivity.4,5 Recently, we made the interesting observation that when T cells are stimulated with superantigens, as compared with other stimuli, they become insensitive to the immunosuppressive effects of corticosteroids.22 This may be clinically important because use of antibiotics is known to inhibit superantigen production by S aureus.
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
Leung S15
Corticosteroids exert their biologic effects by binding to a specific intracellular protein, that is, the glucocorticoid receptor. Cloning of the human glucocorticoid receptor gene has revealed that alternative splicing of the glucocorticoid receptor pre-messenger RNA generates two homologous isoforms, termed glucocorticoid receptor α and glucocorticoid receptor β.3 These two protein isoforms have in common the same first 727 NH2-terminal amino acids, and thus both contain the DNA binding domains. Glucocorticoid receptor β is the steroidactivated transcription factor that, in the hormonebound state, modulates the expression of corticosteroid-sensitive genes. Glucocorticoid receptor β differs from glucocorticoid receptor α only in its COOH terminus, by replacement of the last 50 amino acids of the latter with a unique 15 amino acid sequence. This difference renders glucocorticoid receptor β unable to bind glucocorticoid hormones and antagonizes the activity of glucocorticoid receptor α. Interestingly, superantigens have recently been found to be a potent inducer of glucocorticoid receptor β expression in T cells and may account for their ability to induce corticosteroid insensitivity.22
Indeed, several studies have demonstrated increased adherence of S aureus to keratinocytes from atopic skin.24,25 Gram-positive bacteria other than S aureus did not have this characteristic. The surface molecules responsible for adherence of S aureus to tissue sites are termed “adhesins.” During the past few years, several important staphylococcal adhesins have been identified, which are responsible for the initial interactions between S aureus and epithelial cells from different tissues. These include fibronectin-binding proteins A and B, clumping factors A and B (which are fibrinogen-binding proteins), and collagen adhesins.26 Importantly, it is well established that the tissue ligands for some of these staphylococcal adhesins, that is, fibronectin and collagen, are up-regulated by proinflammatory cytokines such as TNF-α and T-cell growth factor β. Fibrinogen and other plasma proteins, including fibronectin, can exudate into inflamed skin of patients with excoriated AD. In the future, it will be important to determine the role of these molecules in the attachment of S aureus to atopic skin and the way in which expression of their tissue ligands is modulated.
MECHANISMS FOR INCREASED S AUREUS COLONIZATION
I thank Maureen Sandoval for her assistance in the preparation of the manuscript.
The observation that a variety of staphylococcal toxins can induce skin inflammation suggests that it is important to develop new strategies for eliminating the entire S aureus organism from the skin of patients with AD. Currently, the mechanisms leading to increased S aureus colonization in AD are unknown. However, a number of processes could contribute. These include disruption of skin barrier function from scratching with exudation of plasma proteins, exposure of inflamed underlying skin from scratching, loss of certain innate antibacterial activities from changes in lipid composition or β-defensin levels, and reduced immune responses needed for eradication and defense against bacteria, as well as changes in skin surface pH values toward alkalinity. None of these factors is mutually exclusive. The initial event in colonization requires “adherence” of S aureus to the skin, and if it results in firm attachment of S aureus to skin surfaces, there is an increased risk for subsequent infection. Interestingly, treatment with topical corticosteroids alone can reduce S aureus counts on lesions of AD, although not as effectively as the combination of topical antibiotics and corticosteroids.24 Corticosteroids have no direct antibiotic effects on the growth of cultured S aureus. Thus it is very likely that inflamed skin expresses increased attachment sites for S aureus, which promote colonization of S aureus.
REFERENCES 1. Williams H, Robertson C, Stewart A, Ait-Khaled N, Anabwani G, Anderson R, et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood. J Allergy Clin Immunol 1999;103:125-38. 2. Leung DYM, Tharp M, Boguniewicz M. Atopic dermatitis. In: Freeberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, et al, editors. Dermatology in general medicine. New York: McGraw-Hill; 1998. p. 1464-80. 3. Leyden JJ, Marples RR, Kligman AM. Staphylococcus aureus in the lesions of atopic dermatitis. Br J Dermatol 1974;90:525-30. 4. Leyden JJ, Kligman AM. The case for steroid-antibiotic combinations. Br J Dermatol 1977;96:179-87. 5. Wachs GN, Maibach HI. Co-operative double-blind trial of an antibiotic/corticoid combination in impetiginized atopic dermatitis. Br J Dermatol 1976;95:323-8. 6. Ramsay CA, Savoie JM, Gilbert M, Gidon J, Kidson P. The treatment of atopic dermatitis with topical fusidic acid and hydrocortisone acetate. J Eur Acad Dermatol Venereol 1996;7(Suppl 1):S15-S22. 7. Seymour JL, Keswick BH, Milligan MC, Jordan WP, Hanifin JM. Clinical and microbial effects of cloth, cellulose core, and cellulose core/absorbent gel diapers in atopic dermatitis. Pediatrician 1987;14(Suppl 1):39-43. 8. Kotzin BL, Leung DYM, Kappler J, Marrack P. Superantigens and their potential role in human disease. Adv Immunol 1993;54:99166. 9. Leung DYM, 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;92:1374-80.
S16 Leung
10. Bunikowski R, Mielke M, Skarabis H, Herz U, Bergmann RL, Wahn U, 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; 103:119-24. 11. Nomura I, Tanaka K, Tomita H, Katsunuma T, Ohya Y, Ikeda N, et al. Evaluation of the staphylococcal exotoxins and their specific IgE in childhood atopic dermatitis. J Allergy Clin Immunol 1999;104:441-6. 12. Skov L, Olsen JV, Giorno R,Trumble A, Schlievert PM, Baadsgaard O, et al. Application of staphylococcal enterotoxin B on normal and atopic skin induces upregulation of T cells via a superantigen-mediated mechanism. J Allergy Clin Immunol 2000;105: 820-6. 13. Travers JB, Hamid QA, Norris DA, Kuhn C, Giorno RC, Schlievert PM, et al. Enhanced cutaneous reactivity to superantigenic toxins in psoriasis: evidence for involvement of epidermal HLA-DR. J Clin Invest 1999;104:1181-9. 14. Leung DYM, Gately M, Trumble A, Ferguson-Darnell B, Schlievert PM, Picker LJ. Bacterial superantigens induce T cell expression of the skin-selective homing receptor, the cutaneous lymphocyteassociated antigen, via stimulation of interleukin 12 production. J Exp Med 1995;181:747-53. 15. Bunikowski R, Mielke MEA, Skarabis H, Worm M, Anagnostopoulos J, Kolde G, et al. Evidence for a disease promoting effect of S aureus-derived exotoxins in atopic dermatitis. J Allergy Clin Immunol 2000;105:814-9. 16. Strickland I, Hauk PJ, Trumble AE, Picker LJ, Leung DYM. Evidence for superantigen involvement in skin homing of T cells in atopic dermatitis. J Invest Dermatol 1999;112:249-53. 17. Campbell DE, Kemp AS. Proliferation and production of interferon-gamma (IFN-gamma) and IL-4 in response to Staphylococcus aureus and staphylococcal superantigen in childhood atopic dermatitis. Clin Exp Immunol 1997;107:392-7. 18. Bratton DL, May KR, Kailey JM, Doherty DE, Leung DYM. Staphylococcal toxic shock syndrome toxin-1 inhibits monocyte apoptosis. J Allergy Clin Immunol 1999;103:895-900. 19. Hanifin JM, Rogge JL. Staphylococcal infections in patients with atopic dermatitis. Arch Dermatol 1977;113:1383-6. 20. Herz U, Schnoy N, Borelli S, Weigl L, Kasbohrer U, Daser A, et al. A human-SCID mouse model for allergic immune response bacterial superantigen enhances skin inflammation and suppresses IgE production. J Invest Dermatol 1998;110:224-31. 21. Hofer MF, Harbeck RJ, Schlievert PM, Leung DYM. Staphylococcal toxins augment specific IgE responses by atopic patients exposed to allergen. J Invest Dermatol 1999; 112:171-6. 22. Hauk PJ, Hamid QA, Chrousos GP, Leung DYM. Induction of corticosteroid insensitivity in human peripheral blood mononuclear cells by microbial superantigens. J Allergy Clin Immunol 2000;105:782-7.
J AM ACAD DERMATOL JULY 2001
23. Bamberger CM, Bamberger AM, de Castro M, Chrousos GP. Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest 1995;95:243541. 24. Stalder JF, Fleury M, Sourisse M, Rostin M, Pheline F, Litoux P. Local steroid therapy and bacterial skin flora in atopic dermatitis. Br J Dermatol 1994;131:536-40. 25. Cho S-H, Strickland PT, Tomkinson A, Fehringer AP, Gelfand EW, Leung DYM. Preferential binding of Staphylococcus aureus to sites of allergic skin inflammation using a murine model [abstract]. J Allergy Clin Immunol 2000;105:S166. Abstract 504. 26. Foster TJ, Höök M. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol 1998;6:484-8.
DISCUSSION Dr Saurat: What is the relationship at the molecular level between the decrease in the glucocorticoid-receptor effectiveness and superantigen? Dr Leung: We actually do not know exactly what the basis is. We know that superantigens induce the alternative splicing event that regulates how much αversus β-glucocorticoid receptor you have, and it causes overexpression of the β-form, which is an isoform of the steroid receptor that is not associated with steroid binding. So, we think that this is one mechanism by which superantigens alter steroid response. Dr Stingl: The two microorganisms that most greatly aggravate AD are S aureus and herpes simplex virus (eczema herpeticum). My question concerns the mechanism by which you get this great increase in skin inflammation in eczema herpeticum. When herpesviruses affect keratinocytes, is it known whether proteins or peptides are generated that also may have superantigenic properties? Dr Leung: That is a very interesting question. It is not known, but in the herpes family, the EpsteinBarr virus and cytomegalovirus have been identified to have superantigens. But I do not know specifically about herpes simplex.
BY AN EDUCATIONAL GRANT FROM NOVARTIS PHARMA AND NOVARTIS PHARMACEUTICALS CORPORATION
AG
Atopic dermatitis and the immune system: The role of superantigens and bacteria Donald Y. M. Leung, MD, PhD Denver, Colorado
P
opulation studies indicate that the prevalence of atopic dermatitis (AD) has been steadily increasing since World War II. It now affects 10% to 15% of children in many parts of the world.1 The basis of this rapid increase in prevalence is unknown. However, it is generally thought to be related to changes in our environment because there is great worldwide variation in the prevalence of AD even among populations with common genetic backgrounds. Several factors can trigger AD, including irritants, foods, aeroallergens, and infection.2 However, there has been widespread interest in the potential role of Staphylococcus aureus in the pathogenesis of AD because most patients are colonized with this microbe and it secretes potent toxins that trigger skin inflammation. More than 90% of patients with AD have S aureus on their skin.3 The importance of S aureus colonization in AD is supported by the observation that not only patients with impetiginized AD, but also AD patients without superinfection, show clinical response to combined treatment with antistaphylococcal antibiotics and topical corticosteroids.4-6 One longitudinal study demonstrated that S aureus only infrequently colonized the noneczematous skin of infants with AD.7 This suggests that S aureus colonization is a secondary phenomenon, not present when AD begins during infancy. However, once colo-
From the Division of Allergy-Immunology, National Jewish Medical and Research Center. This article is part of a supplement sponsored by Novartis Pharma AG and Novartis Pharmaceuticals Corporation. Supported in part by National Institutes of Health grants AR41256 and RR00051. Presented at the International Consensus Conference on Atopic Dermatitis, November 5-6, 1999, Rome, Italy. Disclosure: Dr Leung is a paid consultant to Novartis Pharmaceutical Corporation. Reprint requests: Donald Leung, MD, PhD, National Jewish Medical and Research Center, Head, Division of Allergy-Immunology, 1400 Jackson St (K926), Denver, CO 80206. E-mail: [email protected]. J Am Acad Dermatol 2001;45:S13-6. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/0/117024 doi:10.1067/mjd.2001.117024
nized with S aureus, the skin disease can become much more severe.
IMMUNOBIOLOGY OF SUPERANTIGENS Recent studies suggest that one strategy by which S aureus exacerbates or maintains skin inflammation in AD is by secreting superantigens, which stimulate massive activation of T cells and macrophages.8 Superantigens refer to a group of microbial antigens that differ in several respects from nominal peptide antigens. Although superantigens, like peptide antigens, are presented by class II major histocompatibility complex (MHC) molecules, they do not engage the MHC peptide-antigen binding groove. Instead, the intact (unprocessed) superantigen binds to the lateral walls of the peptide-antigen binding groove. An important distinguishing feature between superantigens and conventional peptide antigens is that superantigens stimulate T cells almost solely through the Vβ portion of the T-cell receptor (TCR). Conventional peptide antigens frequently require recognition by all 5 variable elements (ie, Vβ, Dβ, Jβ, Vα, and Jα) of the TCR. Therefore the responding frequency to a nominal peptide antigen is usually much less than 1 in 1000. In contrast, because the number of Vβ genes is limited, the frequency of T cells responding to these molecules exceeds that of nominal peptide antigens by several orders of magnitude, hence the term superantigen.
EFFECTS OF SUPERANTIGENS IN AD Several lines of investigation support a role for superantigens in AD (Table I). First, more than half of patients with AD have S aureus isolates cultured from their skin that secrete superantigens, such as staphylococcal enterotoxins (SE) A or B and toxic shock syndrome toxin-1 (TSST-1).9-11 Second, most patients with AD make specific immunoglobulin (IgE) antibodies directed against the staphylococcal toxins found on their skin. Basophils and mast cells from patients with antitoxin IgE release histamine on exposure to the relevant toxin, but not in response to toxins to which they had no specific IgE. Third, microgram amounts of SEB applied to the skin can induce the eczematoid skin changes of S13
S14 Leung
Table I. Evidence for role of staphylococcal superantigens in AD • Atopic skin is associated with an overgrowth of S aureus. • The majority of S aureus isolates from AD skin produce superantigens. • AD severity correlates with presence of IgE antibodies to superantigens. • Superantigens augment allergen-induced skin inflammation by activating infiltrating mononuclear cells and inducing mast cell degranulation. • Superantigens induce dermatitis on application to skin by patch testing. • Patients recovering from toxic shock syndrome develop chronic eczema. • Superantigens induce the skin-homing receptor on T cells. • PBMCs from AD, as compared with normal controls, have higher proliferative responses to superantigens. PBMC, Peripheral blood mononuclear cell.
erythema and induration in unaffected atopic or normal skin. Interestingly, only nanogram amounts of superantigens are needed to trigger skin inflammation in vivo when keratinocytes express human leukocyte antigen from the DR region (HLADR).12,13 Fourth, superantigens induce T-cell expression of the skin homing receptor CLA via stimulation of interleukin 12 (IL-12) production.14 In the case of AD, we have proposed that staphylococcal superantigens secreted at the skin surface could penetrate inflamed skin and stimulate epidermal Langerhans’ cells or macrophages to produce IL-1, tumor necrosis factor (TNF), and IL-12. Local production of IL-1 and TNF induces the expression of E-selectin on vascular endothelium, allowing an initial influx of CLA+ memory/effector cells. Local secretion of IL-12 could increase CLA expression on those T cells activated by allergen or superantigen and thereby increase their efficiency of T-cell recirculation to the skin. IL-12 secreted by toxinstimulated Langerhans’ cells, which migrate to skin-associated lymph nodes (and serve as antigenpresenting cells therein), could also up-regulate the expression of CLA, thereby creating additional skinhoming memory-effector T cells. This concept is supported by our recent observation that the presence of superantigens on the skin lesions of AD predicted the expansion of appropriate (superantigenassociated) TCR-Vβ–bearing T cells in the skin lesions, as well as the circulating CLA+ skin-homing memory T-cell subset.15,16 Together, these mechanisms would tend to markedly amplify the initial cutaneous inflammation in AD and create conditions favoring staphylococcal skin colonization.
J AM ACAD DERMATOL JULY 2001
Finally, peripheral blood mononuclear cells (PBMCs) from children with AD have also been reported to have significantly higher proliferation and IL-4 responses to both S aureus and SEB, but diminished production of interferon gamma (IFN-γ) in response to S aureus and SEB.17 These investigators suggested that impaired IFN-γ production to S aureus in vivo may result in failure to eradicate this organism from the skin. Persistence on the skin could contribute to inflammation by causing continued T-cell and macrophage activation. Recent studies by Bratton et al18 have demonstrated that staphylococcal superantigens induce the production of granulocyte-macrophage colony-stimulating factor, resulting in inhibition of monocyte-macrophage apoptosis, perpetuating the chronicity of this inflammatory skin disease.
ASSOCIATION OF SUPERANTIGENS WITH DISEASE SEVERITY It is well established that exacerbation of AD is frequently associated with S aureus infection.19 Relevant to this, several recent articles have reported a correlation between the presence of IgE anti-superantigens and the severity of AD.10,11 This correlation is strongest when patients produce IgE against staphylococcal superantigens that are found on the skin surface of patients with AD. In this situation, superantigens being continuously secreted on the skin surface may be constantly triggering mediator/cytokine release from IgE-bearing mast cells and macrophages. With the use of a humanized murine model of skin inflammation, S aureus toxin plus allergen also has been found to have an additive effect on allergeninduced cutaneous inflammation.20 These observations are consistent with our recent report that superantigens augment allergen-induced IgE responses, which suggests that these potent molecules have an adjuvant effect on T-cell–mediated responses by cross-linking HLA-DR with the TCR.21 Topical corticosteroids are the mainstay of antiinflammatory therapy in the management of chronic AD. However, patients vary greatly in their response to corticosteroid therapy. The observation that combined treatment of AD with antibiotics and corticosteroids is more effective than corticosteroids alone suggests that S aureus secretes products that can induce corticosteroid insensitivity.4,5 Recently, we made the interesting observation that when T cells are stimulated with superantigens, as compared with other stimuli, they become insensitive to the immunosuppressive effects of corticosteroids.22 This may be clinically important because use of antibiotics is known to inhibit superantigen production by S aureus.
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
Leung S15
Corticosteroids exert their biologic effects by binding to a specific intracellular protein, that is, the glucocorticoid receptor. Cloning of the human glucocorticoid receptor gene has revealed that alternative splicing of the glucocorticoid receptor pre-messenger RNA generates two homologous isoforms, termed glucocorticoid receptor α and glucocorticoid receptor β.3 These two protein isoforms have in common the same first 727 NH2-terminal amino acids, and thus both contain the DNA binding domains. Glucocorticoid receptor β is the steroidactivated transcription factor that, in the hormonebound state, modulates the expression of corticosteroid-sensitive genes. Glucocorticoid receptor β differs from glucocorticoid receptor α only in its COOH terminus, by replacement of the last 50 amino acids of the latter with a unique 15 amino acid sequence. This difference renders glucocorticoid receptor β unable to bind glucocorticoid hormones and antagonizes the activity of glucocorticoid receptor α. Interestingly, superantigens have recently been found to be a potent inducer of glucocorticoid receptor β expression in T cells and may account for their ability to induce corticosteroid insensitivity.22
Indeed, several studies have demonstrated increased adherence of S aureus to keratinocytes from atopic skin.24,25 Gram-positive bacteria other than S aureus did not have this characteristic. The surface molecules responsible for adherence of S aureus to tissue sites are termed “adhesins.” During the past few years, several important staphylococcal adhesins have been identified, which are responsible for the initial interactions between S aureus and epithelial cells from different tissues. These include fibronectin-binding proteins A and B, clumping factors A and B (which are fibrinogen-binding proteins), and collagen adhesins.26 Importantly, it is well established that the tissue ligands for some of these staphylococcal adhesins, that is, fibronectin and collagen, are up-regulated by proinflammatory cytokines such as TNF-α and T-cell growth factor β. Fibrinogen and other plasma proteins, including fibronectin, can exudate into inflamed skin of patients with excoriated AD. In the future, it will be important to determine the role of these molecules in the attachment of S aureus to atopic skin and the way in which expression of their tissue ligands is modulated.
MECHANISMS FOR INCREASED S AUREUS COLONIZATION
I thank Maureen Sandoval for her assistance in the preparation of the manuscript.
The observation that a variety of staphylococcal toxins can induce skin inflammation suggests that it is important to develop new strategies for eliminating the entire S aureus organism from the skin of patients with AD. Currently, the mechanisms leading to increased S aureus colonization in AD are unknown. However, a number of processes could contribute. These include disruption of skin barrier function from scratching with exudation of plasma proteins, exposure of inflamed underlying skin from scratching, loss of certain innate antibacterial activities from changes in lipid composition or β-defensin levels, and reduced immune responses needed for eradication and defense against bacteria, as well as changes in skin surface pH values toward alkalinity. None of these factors is mutually exclusive. The initial event in colonization requires “adherence” of S aureus to the skin, and if it results in firm attachment of S aureus to skin surfaces, there is an increased risk for subsequent infection. Interestingly, treatment with topical corticosteroids alone can reduce S aureus counts on lesions of AD, although not as effectively as the combination of topical antibiotics and corticosteroids.24 Corticosteroids have no direct antibiotic effects on the growth of cultured S aureus. Thus it is very likely that inflamed skin expresses increased attachment sites for S aureus, which promote colonization of S aureus.
REFERENCES 1. Williams H, Robertson C, Stewart A, Ait-Khaled N, Anabwani G, Anderson R, et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood. J Allergy Clin Immunol 1999;103:125-38. 2. Leung DYM, Tharp M, Boguniewicz M. Atopic dermatitis. In: Freeberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, et al, editors. Dermatology in general medicine. New York: McGraw-Hill; 1998. p. 1464-80. 3. Leyden JJ, Marples RR, Kligman AM. Staphylococcus aureus in the lesions of atopic dermatitis. Br J Dermatol 1974;90:525-30. 4. Leyden JJ, Kligman AM. The case for steroid-antibiotic combinations. Br J Dermatol 1977;96:179-87. 5. Wachs GN, Maibach HI. Co-operative double-blind trial of an antibiotic/corticoid combination in impetiginized atopic dermatitis. Br J Dermatol 1976;95:323-8. 6. Ramsay CA, Savoie JM, Gilbert M, Gidon J, Kidson P. The treatment of atopic dermatitis with topical fusidic acid and hydrocortisone acetate. J Eur Acad Dermatol Venereol 1996;7(Suppl 1):S15-S22. 7. Seymour JL, Keswick BH, Milligan MC, Jordan WP, Hanifin JM. Clinical and microbial effects of cloth, cellulose core, and cellulose core/absorbent gel diapers in atopic dermatitis. Pediatrician 1987;14(Suppl 1):39-43. 8. Kotzin BL, Leung DYM, Kappler J, Marrack P. Superantigens and their potential role in human disease. Adv Immunol 1993;54:99166. 9. Leung DYM, 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;92:1374-80.
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DISCUSSION Dr Saurat: What is the relationship at the molecular level between the decrease in the glucocorticoid-receptor effectiveness and superantigen? Dr Leung: We actually do not know exactly what the basis is. We know that superantigens induce the alternative splicing event that regulates how much αversus β-glucocorticoid receptor you have, and it causes overexpression of the β-form, which is an isoform of the steroid receptor that is not associated with steroid binding. So, we think that this is one mechanism by which superantigens alter steroid response. Dr Stingl: The two microorganisms that most greatly aggravate AD are S aureus and herpes simplex virus (eczema herpeticum). My question concerns the mechanism by which you get this great increase in skin inflammation in eczema herpeticum. When herpesviruses affect keratinocytes, is it known whether proteins or peptides are generated that also may have superantigenic properties? Dr Leung: That is a very interesting question. It is not known, but in the herpes family, the EpsteinBarr virus and cytomegalovirus have been identified to have superantigens. But I do not know specifically about herpes simplex.