Superantigens and pseudosuperantigens of gram-positive cocci

Fleischer, Bernhard; Gerlach, Dieter; Fuhrmann, Andreas; Schmidt, Karl‐Hermann

doi:10.1007/bf00216783

Cited by 39 publications

(29 citation statements)

References 83 publications

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“…One of the major concerns regarding SEB in aerosol form is its ability to produce severe lung damage. Enterotoxin-producing S. aureus strains are associated with toxic shock syndrome, which includes systemic and respiratory complications such as cardiomyopathy, renal failure, electrolyte imbalances, disseminated intravascular coagulation, encephalopathy, and adult respiratory distress syndrome (2,13,18,25,31). Since in past studies SEB aerosol exposure was shown to induce lethal pulmonary lesions in nonhuman primates, we sought to examine whether aerosol delivery of SEB to the HLA-DQ8 mice induced respiratory damage (35,39).…”

Section: Resultsmentioning

confidence: 99%

“…Staphylococcus aureus and group A streptococci are responsible for a wide range of mild to life-threatening infections, including scarlet fever, pharyngitis, dermatitis, infectious arthritis, and toxic shock syndrome (2,13,18,25,31). These pathogenic bacteria use several virulence mechanisms to enhance their toxicity after infection, including the M protein, diffusible enzymes (e.g., DNase), and streptolysin.…”

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confidence: 99%

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Human Leukocyte Antigen-DQ8 Transgenic Mice: a Model To Examine the Toxicity of Aerosolized Staphylococcal Enterotoxin B

et al. 2005

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Staphylococcal enterotoxins (SEs) belong to a large group of bacterial exotoxins that cause severe immunopathologies, especially when delivered as an aerosol. SEs elicit the release of lethal amounts of cytokines by binding to major histocompatibility complex (MHC) class II and cross-linking susceptible T-cell receptors. Efforts to develop effective therapeutic strategies to protect against SEs delivered as an aerosol have been hampered by the lack of small animal models that consistently emulate human responses to these toxins. Here, we report that human leukocyte antigen-DQ8 (HLA-DQ8) transgenic (Tg) mice, but not littermate controls, succumbed to lethal shock induced by SEB aerosols without potentiation. Substantial amounts of perivascular edema and inflammatory infiltrates were noted in the lungs of Tg mice, similar to the pathology observed in nonhuman primates exposed by aerosol to SEB. Furthermore, the observed pathologies and lethal shock correlated with an upsurge in proinflammatory cytokine mRNA gene expression in the lungs and spleens, as well as with marked increases in the levels of proinflammatory circulating cytokines in the Tg mice. Unlike the case for littermate controls, telemetric evaluation showed significant hypothermia in Tg mice exposed to lethal doses of SEB. Taken together, these results show that this murine model will allow for the examination of therapeutics and vaccines developed specifically against SEB aerosol exposure and possibly other bacterial superantigens in the context of human MHC class II receptors.Staphylococcus aureus and group A streptococci are responsible for a wide range of mild to life-threatening infections, including scarlet fever, pharyngitis, dermatitis, infectious arthritis, and toxic shock syndrome (2, 13, 18, 25, 31). These pathogenic bacteria use several virulence mechanisms to enhance their toxicity after infection, including the M protein, diffusible enzymes (e.g., DNase), and streptolysin. Furthermore, many strains of S. aureus produce bacterial superantigens (BSAgs), which exert a series of critical, negative immunological effects on the host. Specifically, BSAgs bind to major histocompatibility complex (MHC) class II molecules and form a ternary complex with receptive variable ␤ chains of T-cell antigen receptors. After binding, BSAg-stimulated T cells are eliminated by a Fas/Fas-ligand-mediated apoptosis or, alternatively, enter a state of specific nonresponsiveness (anergy), which may last for several months. Furthermore, BSAgs may exacerbate subclinical viral infections by removing activated T cells from their normal role in clearing invasive organisms.Mice are naturally insensitive to BSAg-induced lethal shock (23,24,32). In order to overcome the natural insensitivity of mice to staphylococcal enterotoxins (SEs), sublethal amounts of lipopolysaccharide (LPS) have been used to potentiate the lethal effects of BSAgs (7,32). Although the exact mechanism of LPS induction is not known, it has been shown that lethality is dependent on the expression of mo...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Human Leukocyte Antigen-DQ8 Transgenic Mice: a Model To Examine the Toxicity of Aerosolized Staphylococcal Enterotoxin B

et al. 2005

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“…It is the immune system and not LPS that kills the host. There are many other microbial pathogens that are able to activate the immune system nonspecifically, which is often referred to as “polyclonal lymphocyte activation.”79 Some of these products are known in immunology as “superantigens.”80–82 The immunobiology of superantigens is complex and is beyond the scope of this paper. However, many of them are pyrogenic substances, 83 and therefore capable of activating APR.…”

Section: Host Defense In Febrile Illnessmentioning

confidence: 99%

Neurohormonal Host Defense in Endotoxin Shock

Berczi

1998

Annals of the New York Academy of Sciences

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Lipopolysaccharide (LPS) of gram-negative bacteria is capable of activating the immune system of higher animals, which may lead to cytokine-induced lethal shock and death. LPS has little toxicity for the frog and fish, but it kills the horseshoe crab instantly by causing intravascular blood coagulation. The response to LPS evolved from simple reactions in lower animals into an intense reaction in mammals that involves a massive immune activation leading to a profound neuroendocrine and metabolic response. This is now known as the acute-phase response (APR). During APR, LPS-binding proteins (LBP) are produced by the liver in rapidly increasing quantities under the influence of interleukin-6, glucocorticoids, and catecholamines. After combination with LPS, LPB is capable of activating monocyte-macrophages and granulocytes via the CD14 surface receptor. Other receptors (CD18, 80-kDa receptor) allow for direct action by LPS of phagocytes, B and T lymphocytes, and other cells. Numerous other acute-phase proteins are produced in the liver, including C-reactive protein, complement components, fibrinogen, enzyme inhibitors, and anti-inflammatory proteins. Similar responses may be stimulated by subtoxic doses of LPS or by detoxified LPS, which manifest in endotoxin tolerance. Tolerant animals and man show increased resistance to LPS, to infections, and to various noxious insults. Infection and various forms of tissue injury are also capable of causing APR. There is much evidence to indicate that APR, which manifests in febrile illness, is an efficient host defense reaction. It is an emergency response in cases where specific immunity fails to protect the host. Therefore, the neuroimmunoregulatory network converts the immune system to a less specific, but rapid and more efficient response, APR. The hypothesis is presented that intestinal LPS serves to amplify the APR in response to various insults, which contribute to host defense, regeneration, and healing.

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“…Streptococcal pyrogenic exotoxins have been shown to act as superantigens that activate T lymphocytes expressing certain T cell receptor V β regions [1]. These may include potentially autoreactive T cells and superantigens have therefore been implicated in the aetiology of autoimmune diseases [2].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-12 alone can not enhance the expression of the cutaneous lymphocyte associated antigen (CLA) by superantigen-stimulated T lymphocytes

Sigmundsdóttir

Guðjónsson

Valdimarsson

2003

Clinical and Experimental Immunology

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It has been reported that bacterial superantigens induce interleukin (IL)-12 dependent expression of the cutaneous lymphocyte associated antigen (CLA) and that this may be relevant to the association between certain skin diseases and infections including psoriasis and streptococcal tonsillitis. We have confirmed that the streptococcal pyrogenic superantigen C (SpeC) increases CLA expression by both CD4+ and CD8+ T cells when PBMCs are incubated in medium enriched with fetal calf serum (FCS). However, such an increase could not be induced in medium enriched with human serum (HS) even when recombinant IL-12 was added to the PBMCs cultures. Strikingly, CD4+ T cells incubated with SpeC in HS showed a marked reduction in CLA expression, which was not due to apoptosis. In contrast, SpeC did induce T cell proliferation and expression of CD25, CD54 and CD103 in the presence of HS indicating that the absence of SpeC induced CLA expression in HS was not due to SpeC inhibitors. Although addition of low amounts of lipopolysaccharide endotoxin (LPS) caused a highly significant increase in CLA expression in the absence of SpeC in cultures enriched with HS, a combination of LPS and SpeC did not increase CLA expression beyond that induced by LPS alone. The superantigen-induced CLA expression in FCS was partially inhibited by anti-IL-12 but not by anti-IL-18 or antibodies to transforming growth factor (TGF)-beta. It is concluded that IL-12 alone can not increase CLA expression but requires the help of other factor(s) present in FCS but not in HS. Although LPS can induce CLA expression it does not seem to be the factor that interacts with IL-12 to induce superantigen-mediated CLA expression in cultures enriched with FCS.

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Superantigens and pseudosuperantigens of gram-positive cocci

Cited by 39 publications

References 83 publications

Human Leukocyte Antigen-DQ8 Transgenic Mice: a Model To Examine the Toxicity of Aerosolized Staphylococcal Enterotoxin B

Human Leukocyte Antigen-DQ8 Transgenic Mice: a Model To Examine the Toxicity of Aerosolized Staphylococcal Enterotoxin B

Neurohormonal Host Defense in Endotoxin Shock

Interleukin-12 alone can not enhance the expression of the cutaneous lymphocyte associated antigen (CLA) by superantigen-stimulated T lymphocytes

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