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Superantigens and Their Association with Dermatological Inflammatory Diseases

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Superantigens and Their Association with Dermatological Inflammatory Diseases Acta Derm Venereol 2000; 80: 321± 328 REVIEW Superantigens and their Association with Dermatological In¯ ammatory Diseases: Facts and Hypotheses UTA JAPPE Department of Microbiology, Skin Research Center, University of Leeds, Leeds, UK Superantigens have been suggested to play an important role MECHANISMS OF ACTION OF SUPERANTIGENS in the pathogenesis of several in¯ ammatory skin diseases as Common and distinct features of different SAgs well as systemic diseases such as atopic dermatitis, psoriasis, vasculitis, T-cell lymphoma and autoimmune diseases. A SAg binds as an unprocessed protein to non-polymorphic Infections often precede the onset and relapse of these regions of major histocompatibility complex (MHC) class II diseases, and antibiotic treatment with or without additional molecules on the surface of antigen-presenting cells, which are glucocorticosteroids and immunoglobulins is occasionally regions different from the antigen binding groove (2). SAgs successful. Superantigens are microbial proteins that are can interact with a large number of T-cells, which all share able to stimulate up to 20% of the naõÈ ve T-cell population in particular sequences within the variable region of the b-chain a non-speci® c way. They are produced by Gram-positive and (Vb) of the T-cell receptor (TCR) and, thereby, stimulate up -negative bacteria as well as by viruses, parasites and yeasts. to 20% of the naõÈ ve T-cell population. Although SAgs are The importance of the pathogenic role of superantigens is mitogenic for T-cells, the term ``mitogen’’ should not be used determined by the potency to induce in¯ ammation by as a synonym. ``Mitogens’’ induce polyclonal T-cell stimula- extensive cytokine release after T-cell stimulation and/or tion by using pathways different to those of SAgs; for T-cell-mediated cytotoxicity and, thereby, tissue damage. example they act independently to Vb-components of the TCR (3). Furthermore, superantigens may be able to induce auto- Most SAgs are of microbial origin (Table I). In order to immune processes by stimulation of autoreactive T-cells as understand SAg effects on the immune system, several well as autoantibody production by stimulation of B-cells. investigations have concentrated on the characterization of Among the diseases associated with superantigens, atopic their molecular structure and attempted to relate this to their dermatitis, guttate and chronic plaque psoriasis, as well as function. Despite considerable differences in the primary Kawasaki disease, are by far the best-characterized. Never- sequence of SAgs there are remarkable similarities between theless, con¯ icting results have been obtained and formal their overall folded structures, suggesting a common ancestral proof of a pathogenic role of superantigens in these diseases origin. For example, staphylococcal enterotoxin (SE) B and is still lacking. The aim of this review is to summarize the toxic shock syndrome toxin 1 (TSST-1) show only 20 ± 30% data on superantigens in terms of their distribution in identity and yet have a similar conformational structure, microorganisms, their interactions with the adaptive immune which is of consequence for their binding to receptor system and their contribution to skin pathology. Key words: molecules (4, 5). superantigens; skin disease; Vb repertoire. (Accepted August 30, 2000.) MHC dependence and human leucocyte antigen preference of Acta Derm Venereol 2000; 80: 321± 328. SAgs Uta Jappe, Department of Dermatology, University of MHC class II molecules serve as SAg receptors. SAgs are Heidelberg, Voû straû e 2, D-69115, Heidelberg, Germany. bifunctional molecules: the amino-terminal site has a high E-mail: [email protected] af® nity for binding to the a-chain of the MHC class II molecule, whereas the carboxy-terminal site is responsible for a strong binding to the TCR. In cases of direct SAg ± T-cell interactions of which, for example, SEC and SEE are capable, higher doses of SAgs are needed to activate T-cells independently of MHC (6). The fact that the MHC- Superantigens (SAgs) are potent virulence factors which independent pathway seems not to lead to apoptosis indicates stimulate several immunological processes and play a role that MHC involvement and MHC independence induce in the maintenance of in¯ ammation. The term ``super- different immune reactions. In addition to differences in antigen’’ was coined in 1989 by White et al. (1) to describe MHC restriction, differences in the binding af® nity of SAgs to a murine self-antigen which is not presented via the MHC class II molecules are also affected by allelic variations conventional pathway. This review considers the role of in these molecules as well as by cellular factors that SAgs in clinical conditions. It will be necessary to give profoundly modulate SAg responses. The majority of some basic information on the structure and effects of staphylococcal SAgs interact better with human leukocyte these molecules in order to illuminate their potential antigen (HLA)-DR than HLA-DQ or HLA-DP, and several impact on the pathogenesis of dermatological in¯ amma- streptococcal SAgs prefer HLA-DQ (7, 8). A given SAg has tory diseases. diverse effects in different individuals with distinct MHC class # 2000 Taylor & Francis. ISSN 0001-555 5 Acta Derm Venereol 80 322 U. Jappe Table I. Microorganisms and their SAgs Gram-positive bacteria Gram-negative bacteria Viruses Parasites Fungi/yeasts Toxic shock syndrome Yersinia pseudotuberculosi s- Mouse mammary tumour Toxoplasma gondii Candida albicans toxin-1 derived mitogen virus 1, 3, 6, 7, 9, 43 (superantigen in mice) (some evidence) Staphylococcal enterotoxin types A and B Mouse mammary tumour Heligmosomoides polygyrus Cryptococcus A ± E; G ± I Y. enterocolitica virus strain SW Theileria annulata neoformans Exfoliative toxin Mycoplasma arthritidis Rabies virus-associated Plasmodium (some evidence) Streptococcal mitogenic mitogen superantigen (murine malaria) exotoxin Z Mitogenic factors from Cytomegalovirus-associated LMWS group G streptococci superantigen 17 kD mitogen epsilon Pseudomonas aeroginosa HIV-1 gp 120 S. pyogenes mitogen-2 Clostridium perfringens superantigen S. pyogenes cytoplasmic (some evidence) HIV-1 Nef protein membrane-associated Mycobacteria tuberculosis Epstein ± Barr virus protein (CAP) (some evidence) (some evidence) S. pyogenes secretion-type CAP S. pyogenes exotoxin A ± J Streptococcal superantigen A Streptococcal M protein 5, 6, 18, 19, 24 Borrelia burgdorferi (some evidence) II haplotypes (9). It has been shown that expression of as well as nuclear factor w B binding proteins (13). SAg certain MHC class II haplotypes, which bind speci® c SAgs, is reactions with T-cells may have a number of outcomes, associated with the development of severe manifestations and leading to different clinical symptoms. They may induce toxic shock compared to individuals expressing haplotypes anergy, in¯ ammation, cytotoxicity, deletion of T-cells and with lower af® nity for the same SAgs (10). autoimmunity (11, 14, 15). Vb preference of SAgs SAgs and autoimmunity There are &30 Vb phenotypes in humans. Depending on the SAgs seem to be involved in the development of autoimmune particular host, a given type of Vb sequence may be expressed diseases by different mechanisms. T-cell clones that manifest frequently or not at all on the T-cells. Individuals who have cross-reactivity towards endogenous host and microbial relatively higher frequencies of T-cells expressing Vb elements epitopes, and that normally exist either anergized or in that can interact with a particular SAg will be most likely to very low numbers in the blood of healthy individuals, may be develop stronger responses to this SAg than individuals who have ampli® ed according to their Vb type, and may migrate to the a lower frequency of these T-cells in their repertoire (11). Speci® c target tissue containing the autoantigen, a mechanism patterns of Vb expansion or Vb depletion serve as ® ngerprints for believed to play an important role for streptococcal M- a particular SAg. Although, for example, SEA and SEE show proteins in the pathogenesis of rheumatic fever (16, 17). 490% homology they have distinct patterns of human Vb Certain individuals with autoimmune diseases show an speci® city. increase in T-cells bearing selected Vb elements in affected organs or peripheral blood (18). SAgs have been shown to stimulate not only selective T- In¯ uences of other factors on SAg effects cell expansion but also autoantibody production by bridging The biological effects of SAgs also may be potentiated by the MHC class II molecule of B-cells with the TCR on T-cells environmental factors, for example other bacterial components, (19). Whether deletion or autoimmunity occurs, however, will as has been shown for streptolysin and Streptococcus pyogenes be dependent on the dose and persistence of the SAg in the exotoxin A. Simultaneous bacterial and viral infections have host and is likely to be affected by the magnitude of the been documented to potentiate SAg effects, for example Varizella cytokine response (20). zoster and staphylococcal infections (12). SAgs and the conventional pathway of antigenic stimulation HOST EFFECTS OF SUPERANTIGENS TSST-1 is a SAg and can also be immunogenic, leading to the production of neutralizing anti-TSST-1-IgG antibodies General effects (21). In patients with atopic dermatitis anti-toxin-IgE The toxicity of bacterial SAgs is mediated by their potent T- antibodies are detectable, which indicates: (i) that SAgs cell-stimulating activity, which leads to abnormally high play a role in the pathogenesis of atopic dermatitis; and (ii) levels of cytokines, for example tumour necrosis factor that they are also processed as antigens (22). It has been (TNF), interleukins (IL)-1, -2 and -6 and interferon (IFN)-c, shown that SAgs stimulate B-cells to increase production of Acta Derm Venereol 80 Superantigens and dermatological in¯ ammatory diseases 323 allergen-speci® c IgE, e.g. against pollen. Furthermore, it was streptococcal infection was recognized as early as the 1960s demonstrated that TSST-1 induces the expression of B7.2 on (28).
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