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The Systemic and Pulmonary Immune Response to Staphylococcal Enterotoxins

Department of Immunology-MC3710, University of Connecticut Heath Center, 263 Farmington Avenue, Farmington, CT 06030, USA
Author to whom correspondence should be addressed.
Received: 21 June 2010 / Accepted: 12 July 2010 / Published: 21 July 2010
(This article belongs to the Special Issue Enterotoxins)


In response to environmental cues the human pathogen Staphylococcus aureus synthesizes and releases proteinaceous enterotoxins. These enterotoxins are natural etiologic entities of severe food poisoning, toxic shock syndrome, and acute diseases. Staphylococcal enterotoxins are currently listed as Category B Bioterrorism Agents by the Center for Disease Control and Prevention. They are associated with respiratory illnesses, and may contribute to exacerbation of pulmonary disease. This likely stems from the ability of Staphylococcal enterotoxins to elicit powerful episodes of T cell stimulation resulting in release of pro-inflammatory cytokines. Here, we discuss the role of the immune system and potential mechanisms of disease initiation and progression.
Keywords: superantigen; T cells; staphylococcal enterotoxins superantigen; T cells; staphylococcal enterotoxins

1. Introduction

Bacterial enterotoxins are proteinaceous toxins primarily ranging between 23–30 kDa that typically enter the body through mucosal sites. Unlike conventional antigens, enterotoxins can bypass antigen processing by binding to a specific groove outside the usual peptide-binding site of Major Histocompatibility class II (MHC II). These enterotoxins are often known as superantigens (SAgs) for their ability to bridge MHC II with the T cell receptor (TCR) unleashing robust T cell activation. In this review, we will examine the specificity of SAgs, their powerful effects on T cells, and their potential to induce strong pulmonary immune responses. The enterotoxins produced by Staphylococcus aureus will be emphasized since this pathogen is an emerging health concern in the living environment, hospitals, and as a co-infection.

2. Mechanism of Action on T Cells

Conventional antigen presentation requires protein processing and peptide binding to MHC I or MHC II followed by interactions with the combined interface of the TCRα and β chains. In contrast, SAg binds directly to the Vβ region of the TCR. Typically a particular SAg has specificity for more than one TCR Vβ chain and this is well documented for enterotoxins derived from Staphylococcus aureus (Table 1). Unlike MHC I and II restricted antigen presentation, both CD4 and CD8 T cells with specific TCR Vβ chains can be activated by SAgs. The oligoclonal nature of such stimulation activates a high proportion of T cells. Hence in human and mice, SAg elicits a powerful T cell response, characterized by robust proliferation and release of effector cytokines. Superantigen-stimulated T cells typically undergo 5–6 rounds of cell division [1] and activation status is clearly indicated by upregulation of surface CD69 [2]. Production of IFN-γ, TNF and other pro-inflammatory cytokines can be detected [1,2]. SEA-stimulated CD8 T cells exhibit cytotoxic killer phenotype that correlates with granzyme B and perforin expression [3]. Therefore, natural SAg responses are similar to artificial triggering by CD3 ligation.
Table 1. T cell receptor Vβ specificity of SE SAgs in mouse and human.
Table 1. T cell receptor Vβ specificity of SE SAgs in mouse and human.
Mouse TCR VβHuman TCR Vβ
SEA1, 3, 10, 11, 171.1, 5.1, 5.2, 5.3, 6.3, 6.4, 6.9, 7.2, 7.3, 7.4, 7.9, 8, 9.1, 16, 18, 21.3, 22, 23.1
SEB3, 7, 8.1, 8.2, 8.3, 171.1, 3.2, 6.4, 12, 13.2, 14, 15.1, 17, 20, 22
SEC13, 8.2, 8.3, 11, 173.2, 6.4, 6.9, 12, 15.1
SEC23, 8.2, 10, 1712, 13.1, 13.2, 14, 15, 17, 20
SEC33, 7, 8.1, 8.25.1, 12
SED3, 7, 8.1, 8.2, 8.3, 11, 171.1, 5.3, 6.9, 7.4, 8.1, 12.1
SEE11, 15, 175.1, 6.1, 6.2, 6.3, 6.4, 6.7, 6.9, 8.1, 16, 18, 21.3
SEG 3, 12, 13.1, 13.2, 13.6, 14, 15
SEH 10
SEI 1.1, 5.1, 5.2, 5.3, 6b, 23.1
SElK 5.1, 5.2, 5.3, 6.7, 21.3, 23
SElL 5.1, 5.2, 5.3, 6.7, 7.9, 9, 16, 22, 23
SElM 5.1, 5.2, 5.3, 6a, 6b, 7.1, 8, 9, 18, 21.3, 23
SElN 5.1, 5.2, 5.3, 9, 20
SElO 5.1, 7.1, 21.3
SElP 5.1, 6, 8, 16, 18, 21.3
SElQ 2.1, 5.1, 5.2, 6.7, 21.3
SElR 3, 5.1, 8, 11, 12, 13.2, 14
SElU 12, 13.2, 14
SES 9, 16
TSST-13, 15, 172.1
Summarized from: [18,124,125,126,127,128].

3. Binding of Staphylococcus aureus Enterotoxins to MHC II and the TCR

The primary peptide sequence of the SEs show significant variation [20], and the three dimensional structure of at least ten of them have been solved by crystallography: SEA [6], SEB [21,22], SEC2 [23], SEC3 [24], SED [10], SEG [25], SEH [26], SEI [27], SEK [28] and TSST-1 [29]. Although differences in SE structure are evident, the similarities are notable despite a lack of primary sequence homology. Staphylococcal enterotoxins are typically ellipsoid with two unequal domains including a B domain, which is the smallest and associated with carbohydrate binding. The characteristic SE disulfide bond is in the domain B and opposes the α-helical cap. The larger A domain contains both the amino and carboxyl ends and the interface between A and B contain α-helices which form a long groove on the back side of the molecule creating a shallow cavity at the top.
The structural basis for SE immunological activity has been revealed by mutagenesis and confirmed by co-crystallization with TCR-β Chain [22,24,26,28,30]. The binding of SE to TCR depends on the shallow cavity at the top of the molecule. This cavity is thought to interact with three loops of the TCR Vβ, and the contact residues are from three distant regions of the primary sequence brought into proximity with each other in the folded protein. These amino acids are not highly conserved and may account for the SE specificity of Vβ. Crystallization of MHC II with SE reveal examples of MHC-peptide dependent binding [31,32,33], MHC-peptide independent binding [34], and finally both types of binding [35,36]. These mutational and functional analyses show structural dependencies concerning how SE activate T cells, which may provide new avenues for averting immune-based diseases mediated by SE. Lastly, recent comprehensive reviews detail the structural features of SAg and SAg like proteins including the properties of SAg binding to MHC and TCR [18,37].

4. How SE Affects Immune T Cell Tolerance

A hallmark of in vivo S. aureus enterotoxin responses is the manifestation peripheral T cell clonal expansion followed by deletion or programmed death of T cells responding to specific SAg [38,39]. This activation-induced cell death (AICD) response can be blocked when the host concomitantly responds to bacterial lipopolysaccharide [40], consistent with the recent finding that heightened IL-6 signaling can also inhibit SEB-induced T cell peripheral deletion [41]. While IL-6 signaling is known to induce naïve T cell survival [42], it was nevertheless shown that gp130 signaling (IL-6 receptor pathway) within SAg-specific T cells themselves does not block AICD [43]. They demonstrated that IL-6 signaling instead impeded Gr-1+ CD8 T cells from synthesizing IFN-γ, a cytokine central in SAg-based T cell tolerance [44]. Atsumi et al., concluded that CD8 T cells synthesizing IFN-γ controlled CD4+ T cell AICD, but the effector molecule was unlikely to be IFN-γ since addition of IFN-γ did not increase cell death [43]. The death effector molecule remains an outstanding question in the S. aureus enterotoxin field, although using non-superantigen systems a combined role for both TNF receptor and CD95 for AICD of T cells has been documented in vitro [45], and in vivo [46].
Although S. aureus enterotoxins induce profound AICD there typically remains a subset of specific T cells that fail to delete [47,48] and their function has been the subject of many studies [49]. Perhaps their durability and anergic phenotype is an outcome of multiple TCR Vβ hits, but this effect is best observed after repeated injections of SEB. For example, three in vivo injections of SEB gives rise to CD4 CD25 T cells expressing Foxp3 protein, which can suppress via dendritic cells by the CD152 pathway [50]. A second study used a similar approach but discovered a novel CD25 negative CD4 T cell population expressing both Foxp3 and GRAIL [51]. Nevertheless, there is in vivo evidence for intrinsic anergy programming in the absence of Tregs after repeated SEB injection [52]. Thus, deletion and autonomous anergy are natural mechanisms that prevent hyper-responsiveness of T cells to S. aureus enterotoxins. An excellent clinical role for these pathways was recently revealed in a model of OVA-induced airway allergy [53]. The authors demonstrated that SEA pre-treatment in neonates enhanced OVA oral tolerance, which conferred protection against intranasal OVA challenge when the mice enter adulthood. The mechanism may involve an increase of CCR9-bearing Tregs but otherwise remains largely elusive. This is an illustrative example of how S. aureus (enterotoxin) can drive clinically beneficial tolerance. There are numerous examples of how SAgs are involved in disease progression [54], but a recent study demonstrated that orally-administered SEB mediated pathology in an adoptive transfer model of inflammatory bowel disease only when Tregs were absent [55]. Importantly, these results show that expansion of specific-TCR Vβ T cells in Chron’s patients may be a function of SAg exacerbating already established disease [56]. Therefore, S. aureus enterotoxins can induce Tregs for useful purposes, and conversely Tregs can also inhibit S. aureus enterotoxin mediated pathology.

5. The Mechanism of How SE Impacts Lung Immune Responses and Disease

The powerful immune response driven by SAgs discussed above poses other significant health risks to humans. Staphylococcal enterotoxins are currently listed on the CDC category B select agent list because of its potential to be used as a biological threat. Perhaps this is most evident by its propensity to rapidly mediate debilitating pulmonary responses after inhalation in people as observed in one known case of an accidental laboratory exposure of SEB [91]. The most recent developments concerning clinical issues, however, are results that link SE to asthma and other respiratory ailments [92]. It stands to reason that if SAgs drive such robust T cell responses in the periphery and intestinal mucosa, then their access to pulmonary sites is all the more serious. In general, this link is based on colonization of S. aureus in nasal polyps (NP) [93], which contain extensive expansion of skewed repertoires of TCR Vβ-possessing T cells [94]. In clinical studies this has been associated with severe upper and lower respiratory disease [95]. In fact, recent data show that some patients with chronic sinusitis/nasal polyposis produce IgE specific to S. aureus enterotoxins [96,97], and there is the same IgE association in some patients suffering from chronic obstructive pulmonary disease [98]. Secondly, the potential disease mechanism of S. aureus enterotoxin in nasal polyps may be the observed high level of IL-6 [99], which is known to contribute to Treg inhibition [100]. This is similar to human airway smooth cells which effectively present SE to T cells [101]. Importantly, human airway smooth cells synthesize IL-6 after CD40 stimulation [102], which is a key T cell based costimulatory pathway. Collectively, these human studies reveal the associated risks with exposure to SAg in pulmonary sites.
A very severe pulmonary illness difficult to study is the human medical condition status asthmaticus. Status asthmaticus is an acute and severe induction of asthma, and is thought to be triggered by a variety of lung irritants [103]. Ultimately, this condition is refractory to standard treatments such as steroids as recently reviewed [103]. Similar to patients experiencing a sudden asthmatic attack, which may occur in hours and be fatal [104], it is possible that disease onset is potentially linked to a role for SE as well as viral infection. A key observation in victims of fatal asthma is the appearance of CD8 T cells in the bronchial airways possessing cytotoxic ability as indicated by expression of perforin [105]. This is similar to a recent study examining peripheral blood responses in patients with mild to severe asthma during periods of exacerbation demonstrating that the patients with severe asthma possessed the highest levels of CD8 memory T cells with a Type 1 cytokine response as opposed to the expected Type 2 cytokine response [106]. New evidence shows that S. aureus which produce enterotoxins A-C can strongly stimulate IL-17 production by human memory T cells but not naïve [107], and this may contribute to toxic cytokine levels. Also, in a postmortem lung study of fatal asthma an increase of CD8 T cells containing cytotoxic abilities in bronchi were detected [105]. Consistent with CD8 T cell function and Type-1 cytokines a new report detected higher levels of nuclear NFκB in lung epithelial and parenchymal cells from patients that had died from fatal asthma compared to control lungs [108]. Lastly, the presence of a skewed TCR Vβ repertoire specific for SE in cells of bronchoalveolar lavage (BAL) from patients with poorly controlled asthma has been observed previously [109]. While these data are consistent with a potential link of SE or SAg playing a role in fatal asthma more proof will be needed and perhaps mouse models can play a role in helping clarify this issue.
In mouse models of SEB intranasal (i.n.) administration, Herz et al., demonstrated that SEB induces allergic airway disease in both BALB/c and C57BL/6 mice in a CD4+ T cell-dependent manner [110]. Importantly, repeated SEB i.n. exposure mediated classic allergic airway disease marked by increased inflammatory cells in BAL capable of producing pro-inflammatory cytokines, and enhanced airway responsiveness to methacholine challenge. This study provided an important link to human asthma and further demonstrated how SE can increase pulmonary inflammation. Further, a mouse expressing human HLA-DR3 extended these observations by showing that the higher dose of SEB dictates disease outcome from eosinophilic to neutrophilic infiltration [111]. The higher SEB i.n. dose (neutrophilic infiltration) caused systemic shock resulting in markedly increased levels of proinflammatory cytokines in serum and expansion of Vβ8 bearing T cells in spleen [112]. In addition, increased gene transcription of IL-5, IL-4, IFN-γ, IL-12 p40 in bronchi, elevated titers of OVA-specific and total IgE in serum, demonstrated that SEB exposure exacerbated or facilitated allergic inflammation in an airway disease mouse model perhaps through a dendritic cell-based process [113,114]. Therefore, SEB i.n. application in mouse provides a valuable research approach to model human pulmonary disease.
Our recent work tested i.n. SEA exposure instead of SEB to examine other potential outcomes of pulmonary immune responses [115]. Histological evidence showed an impressive alveolitis marked by protein leakage as measured in BAL and increased levels of innate cells. Within days histopathology apparently resolved with decreases in protein and cells in BAL, but it is unclear if pathology such as collagen deposition would ensue as a result of this acute response. A striking accumulation of SEA-specific CD8 T cells in lung was evident, which was dependent upon CD4 T cells. Importantly, a concurrent accumulation of CD11c MHC II high cells dramatically increased in lung after i.n. SEA, which were shown to be largely derived from blood [116]. From a mechanistic perspective, it is clear that IFN-γ played a critical role in mediating alveolitis but not protein leakage. Thus, the i.n. SEA model show similarities to acquired respiratory distress syndrome or acute lung injury[117]. In a model of indirect acute lung injury CD4 T cells were specifically recruited to lung in an IL-16 dependent manner after hemorrhagic shock followed by septic challenge [118]. Importantly, these investigators found that Foxp3+ CD4 T regulatory cells played a key role in blocking neutrophil recruitment to lung via an IL-10 dependent process. These studies underscore the need for further investigation of systems that model human acute lung injury or acquired respiratory distress syndrome, which suggest a more prominent role for T cells in disease pathology.

6. Conclusions and Future Avenues of Investigation

Thus, the SE i.n. mouse models demonstrate how SAg stimulation of T cells affect airway, alveolar, and systemic sites of the body after inhalation exposure. Nevertheless, a number of important questions remain with perhaps the most obvious being how does a mitogenic T cell response cause such dramatic changes in the innate immune system as seen in the mouse models and human cases as discussed above. Certainly, it is reasonable to argue that a cytokine storm may play an important role, and there is a solid case for IL-2 being central to this idea. Recently, it was demonstrated that IL-2 deficient mice were resistant to SEB induced toxic shock unless the mice were reconstituted with IL-2 [119]. In addition, Chau et al., demonstrated that toll-like receptor 2 (TLR2) ligands from the Staphylococcal cell wall inhibited SEB-based human T cell activation by reducing IL-2 production. This inhibitory effect resulted from a TLR2/peptidoglycan induction of IL-10, which also functioned in an in vivo mouse model [120]. This shows that IL-2 is central to a T cell-dependent cytokine shock response, but does not necessarily explain how this response conditions cells in the innate immune system. In particular, we found that after a SAg response, cells of the innate immune system possessed greater ability to respond to TLR ligands [121,122]. This conditioning was also evident through TLR pathways cross-talking to TLR non-responsive cells [123]. Therefore, in addition to cytokines it is possible that other factors are involved in accentuating the immune response beside IL-2.
We would like to suggest that another by-product of T cell stimulation such as the generation of endogenous danger-associated molecular patterns (DAMPS) may participate in amplifying a lung damaging response. This is perhaps a “T cell guided” innate response initiated by T cell killing and release of self proteins or lipids that are not normally detected in the steady state but when present are able to trigger inflammasome stimulation or TLR pathways in innate cells. This may produce a cytokine storm that most studies find and may in-turn further push innate cell activation. Second, the type and amount of DAMP generated may also be a biomarker of the magnitude of lung pathology and could perhaps be extrapolated to the seriousness of injury. An important point in this regard is that tissue fluid from the lung would likely have to be analyzed by techniques other than gene microarray since release of the DAMPs would most likely be a product of cell damage. While this idea is speculative it may be a pivot point to ascertain how a T cell mitogen can so potently condition the innate immune system.


  1. Nagashima, T.; Aranamai, T.; Iclozan, C.; Onoe, K. Analysis of T Cell Responses to a Superantigen, Staphylococcal Enterotoxin-B. J. Clin. Exp. Hematopathol. 2004, 44, 25–32. [Google Scholar]
  2. Dauwalder, O.; Thomas, D.; Ferry, T.; Debard, A.L.; Badiou, C.; Vandenesch, F.; Etienne, J.; Lina, G.; Monneret, G. Comparative inflammatory properties of staphylococcal superantigenic enterotoxins SEA and SEG: Implications for septic shock. J. Leukoc. Biol. 2006, 80, 753–758. [Google Scholar]
  3. Li, Z.J.; Omoe, K.; Shinagawa, K.; Yagi, J.; Imanishi, K. Interaction between superantigen and T-cell receptor Vbeta element determines levels of superantigen-dependent cell-mediated cytotoxicity of CD8(+) T cells in induction and effector phases. Microbiol. Immunol. 2009, 53, 451–459. [Google Scholar]
  4. Marrack, P.; Blackman, M.; Kushnir, E.; Kappler, J. The toxicity of staphylococcal enterotoxin B in mice is mediated by T cells. J. Exp. Med. 1990, 171, 455–464. [Google Scholar]
  5. Marrack, P.C.; Kappler, J.W. The staphylococcal enterotoxins and their relatives. Science 1990, 248, 705–711. [Google Scholar]
  6. Schad, E.M.; Zaitseva, I.; Zaitsev, V.N.; Dohlsten, M.; Kalland, T.; Schlievert, P.M.; Ohlendorf, D.H.; Svensson, L.A. Crystal structure of the superantigen staphylococcal enterotoxin type A. EMBO J. 1995, 14, 3292–3301. [Google Scholar]
  7. Holmberg, S.D.; Blake, P.A. Staphylococcal food poisoning in the United States. New facts and old misconceptions. JAMA 1984, 251, 487–489. [Google Scholar] [PubMed]
  8. Bergdoll, M.S.; Borja, C.R.; Avena, R.M. Identification of a new enterotoxin as enterotoxin C. J. Bacteriol. 1965, 90, 1481–1485. [Google Scholar]
  9. Couch, J.L.; Betley, M.J. Nucleotide sequence of the type C3 staphylococcal enterotoxin gene suggests that intergenic recombination causes antigenic variation. J. Bacteriol. 1989, 171, 4507–4510. [Google Scholar]
  10. Sundstrom, M.; Abrahmsen, L.; Antonsson, P.; Mehindate, K.; Mourad, W.; Dohlsten, M. The crystal structure of staphylococcal enterotoxin type D reveals Zn2+-mediated homodimerization. EMBO J. 1996, 15, 6832–6840. [Google Scholar]
  11. Chang, H.C.; Bergdoll, M.S. Purification and some physicochemical properties of staphylococcal enterotoxin D. Biochemistry 1979, 18, 1937–1942. [Google Scholar]
  12. Van den Bussche, R.A.; Lyon, J.D.; Bohach, G.A. Molecular evolution of the staphylococcal and streptococcal pyrogenic toxin gene family. Mol. Phylogenet. Evol. 1993, 2, 281–292. [Google Scholar]
  13. Munson, S.H.; Tremaine, M.T.; Betley, M.J.; Welch, R.A. Identification and characterization of staphylococcal enterotoxin types G and I from Staphylococcus aureus. Infect. Immun. 1998, 66, 3337–3348. [Google Scholar]
  14. Nilsson, H.; Bjork, P.; Dohlsten, M.; Antonsson, P. Staphylococcal enterotoxin H displays unique MHC class II-binding properties. J. Immunol. 1999, 163, 6686–6693. [Google Scholar]
  15. Su, Y.C.; Wong, A.C. Identification and purification of a new staphylococcal enterotoxin, H. Appl. Environ. Microbiol. 1995, 61, 1438–1443. [Google Scholar]
  16. Zhang, S.; Iandolo, J.J.; Stewart, G.C. The enterotoxin D plasmid of Staphylococcus aureus encodes a second enterotoxin determinant (sej). FEMS Microbiol. Lett. 1998, 168, 227–233. [Google Scholar]
  17. Balaban, N.; Rasooly, A. Staphylococcal enterotoxins. Int. J. Food Microbiol. 2000, 61, 1–10. [Google Scholar]
  18. Fraser, J.D.; Proft, T. The bacterial superantigen and superantigen-like proteins. Immunol. Rev. 2008, 225, 226–243. [Google Scholar]
  19. Hudson, K.R.; Robinson, H.; Fraser, J.D. Two adjacent residues in staphylococcal enterotoxins A and E determine T cell receptor Vß specificity. J. Exp. Med. 1993, 177, 175–184. [Google Scholar]
  20. Dinges, M.M.; Orwin, P.M.; Schlievert, P.M. Exotoxins of Staphylococcus aureus. Clin. Microbiol. Rev. 2000, 13, 16–34, table of contents.. [Google Scholar] [CrossRef] [PubMed]
  21. Swaminathan, S.; Furey, W.; Pletcher, J.; Sax, M. Crystal structure of staphylococcal enterotoxin B, a superantigen. Nature 1992, 359, 801–806. [Google Scholar]
  22. Li, H.; Llera, A.; Tsuchiya, D.; Leder, L.; Ysern, X.; Schlievert, P.M.; Karjalainen, K.; Mariuzza, R.A. Three-dimensional structure of the complex between a T cell receptor beta chain and the superantigen staphylococcal enterotoxin B. Immunity 1998, 9, 807–816. [Google Scholar]
  23. Papageorgiou, A.C.; Acharya, K.R.; Shapiro, R.; Passalacqua, E.F.; Brehm, R.D.; Tranter, H. Crystal structure of the superantigen enterotoxin C2 from staphylococcus aureus reveals a zinc binding site. Structure 1995, 3, 769–779. [Google Scholar]
  24. Fields, B.A.; Malchiodi, E.L.; Li, H.; Ysern, X.; Stauffacher, C.V.; Schlievert, P.M.; Karjalainen, K.; Mariuzza, R.A. Crystal structure of a T-cell receptor beta-chain complexed with a superantigen. Nature 1996, 384, 188–192. [Google Scholar]
  25. Fernandez, M.M.; Bhattacharya, S.; De Marzi, M.C.; Brown, P.H.; Kerzic, M.; Schuck, P.; Mariuzza, R.A.; Malchiodi, E.L. Superantigen natural affinity maturation revealed by the crystal structure of staphylococcal enterotoxin G and its binding to T-cell receptor Vbeta8.2. Proteins 2007, 68, 389–402. [Google Scholar]
  26. Hakansson, M.; Petersson, K.; Nilsson, H.; Forsberg, G.; Bjork, P.; Antonsson, P.; Svensson, L.A. The crystal structure of staphylococcal enterotoxin H: Implications for binding properties to MHC class II and TcR molecules. J. Mol. Biol. 2000, 302, 527–537. [Google Scholar]
  27. Fernandez, M.M.; Guan, R.; Swaminathan, C.P.; Malchiodi, E.L.; Mariuzza, R.A. Crystal structure of staphylococcal enterotoxin I (SEI) in complex with a human major histocompatibility complex class II molecule. J. Biol. Chem. 2006, 281, 25356–25364. [Google Scholar]
  28. Gunther, S.; Varma, A.K.; Moza, B.; Kasper, K.J.; Wyatt, A.W.; Zhu, P.; Rahman, A.K.; Li, Y.; Mariuzza, R.A.; McCormick, J.K.; Sundberg, E.J. A novel loop domain in superantigens extends their T cell receptor recognition site. J. Mol. Biol. 2007, 371, 210–221. [Google Scholar]
  29. Acharya, K.R.; Passalacqua, E.F.; Jones, E.Y.; Harlos, K.; Stuart, D.I.; Brehm, R.D.; Tranter, H.S. Structural basis of superantigen action inferred from crystal structure of toxic-shock syndrome toxin-1. Nature 1994, 367, 94–97. [Google Scholar]
  30. Rahman, A.K.; Herfst, C.A.; Moza, B.; Shames, S.R.; Chau, L.A.; Bueno, C.; Madrenas, J.; Sundberg, E.J.; McCormick, J.K. Molecular basis of TCR selectivity, cross-reactivity, and allelic discrimination by a bacterial superantigen: Integrative functional and energetic mapping of the SpeC-Vbeta2.1 molecular interface. J. Immunol. 2006, 177, 8595–8603. [Google Scholar] [PubMed]
  31. Kim, J.; Urban, R.; Strominger, J.; Wiley, D. Toxic shock syndrome toxin-1 complexed with a major histocompatibility molecule HLA-DR1. Science 1994, 266, 1870–1874. [Google Scholar]
  32. Li, Y.; Li, H.; Dimasi, N.; McCormick, J.K.; Martin, R.; Schuck, P.; Schlievert, P.M.; Mariuzza, R.A. Crystal structure of a superantigen bound to the high-affinity, zinc-dependent site on MHC class II. Immunity 2001, 14, 93–104. [Google Scholar]
  33. Petersson, K.; Hakansson, M.; Nilsson, H.; Forsberg, G.; Svensson, L.A.; Liljas, A.; Walse, B. Crystal structure of a superantigen bound to MHC class II displays zinc and peptide dependence. EMBO J. 2001, 20, 3306–3312. [Google Scholar]
  34. Jardetzky, T.S.; Brown, J.H.; Gorga, J.C.; Stern, L.J.; Urban, R.G.; Chi, Y.I.; Stauffacher, C.; Strominger, J.L.; Wiley, D.C. Three-dimensional structure of a human class II histocompatibility molecule complexed with superantigen. Nature 1994, 368, 711–718. [Google Scholar]
  35. Tiedemann, R.E.; Urban, R.J.; Strominger, J.L.; Fraser, J.D. Isolation of HLA-DR1. (staphylococcal enterotoxin A)2 trimers in solution. Proc. Natl. Acad. Sci. USA 1995, 92, 12156–12159. [Google Scholar] [CrossRef]
  36. Tiedemann, R.E.; Fraser, J.D. Cross-linking of MHC class II molecules by staphylococcal enterotoxin A is essential for antigen-presenting cell and T cell activation. J. Immunol. 1996, 157, 3958–3966. [Google Scholar]
  37. Langley, R.; Patel, D.; Jackson, N.; Clow, F.; Fraser, J.D. Staphylococcal superantigen super-domains in immune evasion. Crit. Rev. Immunol. 2010, 30, 149–165. [Google Scholar]
  38. Kawabe, Y.; Ochi, A. Programmed cell death and extrathymic reduction of Vbeta8+ CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B. Nature 1991, 349, 245–248. [Google Scholar]
  39. MacDonald, H.R.; Baschieri, S.; Lees, R.K. Clonal expansion precedes anergy and death of V beta 8+ peripheral T cells responding to staphylococcal enterotoxin B in vivo. Eur. J. Immunol. 1991, 21, 1963–1966. [Google Scholar]
  40. Vella, A.T.; McCormack, J.E.; Linsley, P.S.; Kappler, J.W.; Marrack, P. Lipopolysaccharide interferes with the induction of peripheral T cell death. Immunity 1995, 2, 261–270. [Google Scholar]
  41. Atsumi, T.; Ishihara, K.; Kamimura, D.; Ikushima, H.; Ohtani, T.; Hirota, S.; Kobayashi, H.; Park, S.J.; Saeki, Y.; Kitamura, Y.; Hirano, T. A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J. Exp. Med. 2002, 196, 979–990. [Google Scholar]
  42. Teague, T.K.; Kappler, J.W.; Marrack, P.; Vella, A.T. Interleukin-6 inhibits resting T cells from apoptosis. J. Immunol. 1997, 158, 5791–5796. [Google Scholar]
  43. Atsumi, T.; Sato, M.; Kamimura, D.; Moroi, A.; Iwakura, Y.; Betz, U.A.; Yoshimura, A.; Nishihara, M.; Hirano, T.; Murakami, M. IFN-gamma expression in CD8+ T cells regulated by IL-6 signal is involved in superantigen-mediated CD4+ T cell death. Int. Immunol. 2009, 21, 73–80. [Google Scholar]
  44. Cauley, L.S.; Cauley, K.A.; Shub, F.; Huston, G.; Swain, S.L. Transferable anergy: Superantigen treatment induces CD4+ T cell tolerance that is reversible and requires CD4-CD8- cells and interferon gamma. J. Exp. Med. 1997, 186, 71–81. [Google Scholar]
  45. Zheng, L.; Fisher, G.; Miller, R.E.; Peschon, J.; Lynch, D.H.; Lenardo, M.J. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature 1995, 377, 348–351. [Google Scholar]
  46. Sytwu, H.K.; Liblau, R.S.; McDevitt, H.O. The roles of Fas/APO-1 (CD95) and TNF in antigen-induced programmed cell death in T cell receptor transgenic mice. Immunity 1996, 5, 17–30. [Google Scholar]
  47. McCormack, J.E.; Callahan, J.E.; Kappler, J.; Marrack, P. Profound deletion of mature T cells in vivo by chronic exposure to exogenous superantigen. J. Immunol. 1993, 150, 3785–3792. [Google Scholar]
  48. Miethke, T.; Wahl, C.; Gaus, H.; Heeg, K.; Wagner, H. Exogenous superantigens acutely trigger distinct levels of peripheral T cell tolerance/immunosuppression: Dose-response relationship. Eur. J. Immunol. 1994, 24, 1893–1902. [Google Scholar]
  49. Ivars, F. Superantigen-induced regulatory T cells in vivo. Chem. Immunol. Allergy 2007, 93, 137–160. [Google Scholar]
  50. Feunou, P.; Vanwetswinkel, S.; Gaudray, F.; Goldman, M.; Matthys, P.; Braun, M.Y. Foxp3+CD25+ T regulatory cells stimulate IFN-gamma-independent CD152-mediated activation of tryptophan catabolism that provides dendritic cells with immune regulatory activity in mice unresponsive to staphylococcal enterotoxin B. J. Immunol. 2007, 179, 910–917. [Google Scholar]
  51. Schartner, J.M.; Singh, A.M.; Dahlberg, P.E.; Nettenstrom, L.; Seroogy, C.M. Recurrent superantigen exposure in vivo leads to highly suppressive CD4+CD25+ and CD4+CD25- T cells with anergic and suppressive genetic signatures. Clin. Exp. Immunol. 2009, 155, 348–356. [Google Scholar]
  52. Eroukhmanoff, L.; Oderup, C.; Ivars, F. T-cell tolerance induced by repeated antigen stimulation: Selective loss of Foxp3- conventional CD4 T cells and induction of CD4 T-cell anergy. Eur. J. Immunol. 2009, 39, 1078–1087. [Google Scholar]
  53. Lonnqvist, A.; Ostman, S.; Almqvist, N.; Hultkrantz, S.; Telemo, E.; Wold, A.E.; Rask, C. Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy. Eur. J. Immunol. 2009, 39, 447–456. [Google Scholar]
  54. Proft, T.; Fraser, J.D. Bacterial superantigens. Clin. Exp. Immunol. 2003, 133, 299–306. [Google Scholar]
  55. Heriazon, A.; Zhou, P.; Borojevic, R.; Foerster, K.; Streutker, C.J.; 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. [Google Scholar]
  56. Ibbotson, J.P.; Lowes, J.R. Potential role of superantigen induced activation of cell mediated immune mechanisms in the pathogenesis of Crohn's disease. Gut 1995, 36, 1–4. [Google Scholar]
  57. Cone, L.A.; Woodard, D.R.; Schlievert, P.M.; Tomory, G.S. Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N. Eng. J. Med. 1987, 317, 146–149. [Google Scholar]
  58. Todd, J.; Fishaut, M.; Kapral, F.; Welch, T. Toxic-shock syndrome associated with phage-group-I Staphylococci. Lancet 1978, 2, 1116–1118. [Google Scholar]
  59. White, J.; Herman, A.; Pullen, A.M.; Kubo, R.; Kappler, J.W.; Marrack, P. The Vß-specific superantigen Staphylococcal enterotoxin B: Stimulation of mature T cells and clonal deletion in neonatal mice. Cell 1989, 56, 27–35. [Google Scholar]
  60. Bergdoll, M.S.; Crass, B.A.; Reiser, R.F.; Robbins, R.N.; Davis, J.P. A new staphylococcal enterotoxin, enterotoxin F, associated with toxic shock syndrome isolates. Lancet 1981, 1, 1017–1021. [Google Scholar]
  61. Blomster-Hautamaa, D.A.; Kreiswirth, B.N.; Kornblum, J.S.; Novick, P.P.; Schlievert, P.M. The nucleotide and partial amino acid sequence of toxin shock syndrome toxin-1. J. Biol. Chem. 1986, 261, 15783–15786. [Google Scholar]
  62. Reeves, M.W.; Arko, R.J.; Chandler, F.W.; Bridges, N.B. Affinity purification of staphylococcal toxic shock syndrome toxin 1 and its pathologic effects in rabbits. Infect. Immun. 1986, 51, 431–439. [Google Scholar]
  63. Schwab, J.H.; Brown, R.R.; Anderle, S.K.; Schlievert, P.M. Superantigen can reactivate bacterial cell wall-induced arthritis. J. Immunol. 1993, 150, 4151–4159. [Google Scholar]
  64. Hamad, A.R.; Marrack, P.; Kappler, J.W. Transcytosis of staphylococcal superantigen toxins. J. Exp. Med. 1997, 185, 1447–1454. [Google Scholar]
  65. Peterson, M.L.; Ault, K.; Kremer, M.J.; Klingelhutz, A.J.; Davis, C.C.; Squier, C.A.; Schlievert, P.M. 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. [Google Scholar]
  66. Lappin, E.; Ferguson, A.J. Gram-positive toxic shock syndromes. Lancet. Infect. Dis. 2009, 9, 281–290. [Google Scholar]
  67. Durand, G.; Bes, M.; Meugnier, H.; Enright, M.C.; Forey, F.; Liassine, N.; Wenger, A.; Kikuchi, K.; Lina, G.; Vandenesch, F.; Etienne, J. Detection of new methicillin-resistant Staphylococcus aureus clones containing the toxic shock syndrome toxin 1 gene responsible for hospital- and community-acquired infections in France. J. Clin. Microbiol. 2006, 44, 847–853. [Google Scholar]
  68. Abram, A.C.; Bellian, K.T.; Giles, W.J.; Gross, C.W. Toxic shock syndrome after functional endonasal sinus surgery: An all or none phenomenon? Laryngoscope 1994, 104, 927–931. [Google Scholar] [PubMed]
  69. Jacobson, J.A.; Kasworm, E.M. Toxic shock syndrome after nasal surgery. Case reports and analysis of risk factors. Arch. Otolaryngol. Head Neck Surg. 1986, 112, 329–332. [Google Scholar] [PubMed]
  70. Chu, F.S.; Thadhani, K.; Schantz, E.J.; Bergdoll, M.S. Purification and characterization of staphylococcal enterotoxin A. Biochemistry 1966, 5, 3281–3289. [Google Scholar]
  71. Shupp, J.W.; Jett, M.; Pontzer, C.H. Identification of a transcytosis epitope on staphylococcal enterotoxins. Infect. Immun. 2002, 70, 2178–2186. [Google Scholar]
  72. Bohach, G.A.; Fast, D.J.; Nelson, R.D.; Schlievert, P.M. Staphylococcal and Streptococcal pyrogenic toxins involved in toxic shock syndrom and related illnesses. Crit. Rev. Microbiol. 1990, 17, 251–272. [Google Scholar]
  73. Edwin, C.; Kass, E.H. Identification of functional antigenic segments of toxic shock syndrome toxin 1 by differential immunoreactivity and by differential mitogenic responses of human peripheral blood mononuclear cells, using active toxin fragments. Infect. Immun. 1989, 57, 2230–2236. [Google Scholar]
  74. Kent, T.H. Staphylococcal enterotoxin gastroenteritis in rhesus monkeys. Am. J. Pathol. 1966, 48, 387–407. [Google Scholar]
  75. Barrera, C.A.; Pinchuk, I.V.; Saada, J.I.; Suarez, G.; Bland, D.A.; Beswick, E.; Adegboyega, P.A.; Mifflin, R.C.; Powell, D.W.; Reyes, V.E. Class II MHC-expressing myofibroblasts play a role in the immunopathogenesis associated with staphylococcal enterotoxins. Ann. N. Y. Acad. Sci. 2004, 1029, 313–318. [Google Scholar]
  76. Pinchuk, I.V.; Beswick, E.J.; Saada, J.I.; Suarez, G.; Winston, J.; Mifflin, R.C.; Di Mari, J.F.; Powell, D.W.; Reyes, V.E. Monocyte chemoattractant protein-1 production by intestinal myofibroblasts in response to staphylococcal enterotoxin a: Relevance to staphylococcal enterotoxigenic disease. J. Immunol. 2007, 178, 8097–8106. [Google Scholar]
  77. Leung, D.Y.; Giorno, R.C.; Kazemi, L.V.; Flynn, P.A.; Busse, J.B. Evidence for superantigen involvement in cardiovascular injury due to Kawasaki syndrome. J. Immunol. 1995, 155, 5018–5021. [Google Scholar]
  78. Curtis, N.; Zheng, R.; Lamb, J.R.; Levin, M. Evidence for a superantigen mediated process in Kawasaki disease. Arch. Dis. Child 1995, 72, 308–311. [Google Scholar]
  79. Pietra, B.A.; De Inocencio, J.; Giannini, E.H.; Hirsch, R. TCR V beta family repertoire and T cell activation markers in Kawasaki disease. J. Immunol. 1994, 153, 1881–1888. [Google Scholar]
  80. Leung, D.Y.; Diaz, L.A.; DeLeo, V.; Soter, N.A. Allergic and immunologic skin disorders. JAMA 1997, 278, 1914–1923. [Google Scholar]
  81. Yamashiro, Y.; Nagata, S.; Oguchi, S.; Shimizu, T. Selective increase of V beta 2+ T cells in the small intestinal mucosa in Kawasaki disease. Pediatr. Res. 1996, 39, 264–266. [Google Scholar]
  82. Murono, K.; Fujita, K.; Yoshioka, H. Microbiologic characteristics of exfoliative toxin-producing Staphylococcus aureus. Pediatr. Infect. Dis. J. 1988, 7, 313–315. [Google Scholar]
  83. Ladhani, S.; Joannou, C.L.; Lochrie, D.P.; Evans, R.W.; Poston, S.M. Clinical, microbial, and biochemical aspects of the exfoliative toxins causing staphylococcal scalded-skin syndrome. Clin. Microbiol. Rev. 1999, 12, 224–242. [Google Scholar]
  84. Gentilhomme, E.; Faure, M.; Piemont, Y.; Binder, P.; Thivolet, J. Action of staphylococcal exfoliative toxins on epidermal cell cultures and organotypic skin. J. Dermatol. 1990, 17, 526–532. [Google Scholar]
  85. Leung, D.Y.; Walsh, P.; Giorno, R.; Norris, D.A. A potential role for superantigens in the pathogenesis of psoriasis. J. Invest. Dermatol. 1993, 100, 225–228. [Google Scholar]
  86. Strange, P.; Skov, L.; Lisby, S.; Nielsen, P.L.; Baadsgaard, O. Staphylococcal enterotoxin B applied on intact normal and intact atopic skin induces dermatitis. Arch. Dermatol. 1996, 132, 27–33. [Google Scholar]
  87. Skov, L.; Baadsgaard, O. Bacterial superantigens and inflammatory skin diseases. Clin. Exp. Dermatol. 2000, 25, 57–61. [Google Scholar]
  88. Savinko, T.; Lauerma, A.; Lehtimaki, S.; Gombert, M.; Majuri, M.L.; Fyhrquist-Vanni, N.; Dieu-Nosjean, M.C.; 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. [Google Scholar]
  89. Taskapan, M.O.; Kumar, P. Role of staphylococcal superantigens in atopic dermatitis: From colonization to inflammation. Ann. Allergy Asthma Immunol. 2000, 84, 3–10, quiz 11-12.. [Google Scholar] [CrossRef] [PubMed]
  90. Jackow, C.M.; Cather, J.C.; Hearne, V.; Asano, A.T.; Musser, J.M.; Duvic, M. Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion. Blood 1997, 89, 32–40. [Google Scholar]
  91. Ulrich, R.G.; Sidell, S.; Taylor, T.J.; Wilhelmsen, C.L.; Franz, D.R. Staphylococcal enterotoxin B and related pyrogenic toxins. Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare; Walter Reed Army Medical Center Washington, D.C.: Washington, DC, USA, 1997. Available online: (accessed on 21 July 2010).
  92. Bachert, C.; Patou, J.; Van Cauwenberge, P. The role of sinus disease in asthma. Curr. Opin. Allergy Clin. Immunol. 2006, 6, 29–36. [Google Scholar]
  93. Zhang, N.; Gevaert, P.; van Zele, T.; Perez-Novo, C.; Patou, J.; Holtappels, G.; van Cauwenberge, P.; Bachert, C. An update on the impact of Staphylococcus aureus enterotoxins in chronic sinusitis with nasal polyposis. Rhinology 2005, 43, 162–168. [Google Scholar]
  94. Conley, D.B.; Tripathi, A.; Seiberling, K.A.; Schleimer, R.P.; Suh, L.A.; Harris, K.; Paniagua, M.C.; Grammer, L.C.; Kern, R.C. Superantigens and chronic rhinosinusitis: Skewing of T-cell receptor V beta-distributions in polyp-derived CD4+ and CD8+ T cells. Am. J. Rhinol. 2006, 20, 534–539. [Google Scholar]
  95. Van Cauwenberge, P.; Van Hoecke, H.; Bachert, C. Pathogenesis of chronic rhinosinusitis. Curr. Allergy Asthma Rep. 2006, 6, 487–494. [Google Scholar]
  96. Tripathi, A.; Conley, D.B.; Grammer, L.C.; Ditto, A.M.; Lowery, M.M.; Seiberling, K.A.; Yarnold, P.A.; Zeifer, B.; Kern, R.C. Immunoglobulin E to staphylococcal and streptococcal toxins in patients with chronic sinusitis/nasal polyposis. Laryngoscope 2004, 114, 1822–1826. [Google Scholar]
  97. Suh, Y.J.; Yoon, S.H.; Sampson, A.P.; Kim, H.J.; Kim, S.H.; Nahm, D.H.; Suh, C.H.; Park, H.S. Specific immunoglobulin E for staphylococcal enterotoxins in nasal polyps from patients with aspirin-intolerant asthma. Clin. Exp. Allergy 2004, 34, 1270–1275. [Google Scholar]
  98. 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. [Google Scholar]
  99. Xu, G.; Xia, J.H.; Zhou, H.; Yu, C.Z.; Zhang, Y.; Zuo, K.J.; Shi, J.B.; Li, H.B. Interleukin-6 is essential for Staphylococcal exotoxin B-induced T regulatory cell insufficiency in nasal polyps. Clin. Exp. Allergy 2009, 39, 829–837. [Google Scholar]
  100. Pasare, C.; Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003, 299, 1033–1036. [Google Scholar]
  101. Veler, H.; Hu, A.; Fatma, S.; Grunstein, J.S.; DeStephan, C.M.; Campbell, D.; Orange, J.S.; Grunstein, M.M. Superantigen presentation by airway smooth muscle to CD4+ T lymphocytes elicits reciprocal proasthmatic changes in airway function. J. Immunol. 2007, 178, 3627–3636. [Google Scholar]
  102. Lazaar, A.L.; Amrani, Y.; Hsu, J.; Panettieri, R.A., Jr.; Fanslow, W.C.; Albelda, S.M.; Pure, E. CD40-mediated signal transduction in human airway smooth muscle. J. Immunol. 1998, 161, 3120–3127. [Google Scholar]
  103. Tillie-Leblond, I.; Gosset, P.; Tonnel, A.B. Inflammatory events in severe acute asthma. Allergy 2005, 60, 23–29. [Google Scholar]
  104. Restrepo, R.D.; Peters, J. Near-fatal asthma: Recognition and management. Curr. Opin. Pulmonary Med. 2008, 14, 13–23. [Google Scholar]
  105. O'Sullivan, S.; Cormican, L.; Faul, J.L.; Ichinohe, S.; Johnston, S.L.; Burke, C.M.; Poulter, L.W. Activated, cytotoxic CD8(+) T lymphocytes contribute to the pathology of asthma death. Am. J. Respir. Crit. Care Med. 2001, 164, 560–564. [Google Scholar]
  106. Abdulamir, A.S.; Hafidh, R.R.; Abubakar, F.; Abbas, K.A. Changing survival, memory cell compartment, and T-helper balance of lymphocytes between severe and mild asthma. BMC Immunol. 2008, 9, 73. [Google Scholar]
  107. Islander, U.; Andersson, A.; Lindberg, E.; Adlerberth, I.; Wold, A.E.; Rudin, A. Superantigenic Staphylococcus aureus stimulates production of interleukin-17 from memory but not naive T cells. Infect. Immun. 2010, 78, 381–386. [Google Scholar]
  108. Caramori, G.; Oates, T.; Nicholson, A.G.; Casolari, P.; Ito, K.; Barnes, P.J.; Papi, A.; Adcock, I.M.; Chung, K.F. Activation of NF-kappaB transcription factor in asthma death. Histopathology 2009, 54, 507–509. [Google Scholar]
  109. Hauk, P.J.; Wenzel, S.E.; Trumble, A.E.; Szefler, S.J.; Leung, D.Y. Increased T-cell receptor vbeta8+ T cells in bronchoalveolar lavage fluid of subjects with poorly controlled asthma: a potential role for microbial superantigens. J. Allergy Clin. Immunol. 1999, 104, 37–45. [Google Scholar]
  110. 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. [Google Scholar]
  111. Rajagopalan, G.; Iijima, K.; Singh, M.; Kita, H.; Patel, R.; David, C.S. Intranasal exposure to bacterial superantigens induces airway inflammation in HLA class II transgenic mice. Infect. Immun. 2006, 74, 1284–1296. [Google Scholar]
  112. Rajagopalan, G.; Sen, M.M.; Singh, M.; Murali, N.S.; Nath, K.A.; Iijima, K.; Kita, H.; Leontovich, A.A.; Gopinathan, U.; Patel, R.; David, C.S. Intranasal exposure to staphylococcal enterotoxin B elicits an acute systemic inflammatory response. Shock 2006, 25, 647–656. [Google Scholar]
  113. Hellings, P.W.; Hens, G.; Meyts, I.; Bullens, D.; Vanoirbeek, J.; Gevaert, P.; Jorissen, M.; Ceuppens, J.L.; 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. [Google Scholar]
  114. Huvenne, W.; Callebaut, I.; Plantinga, M.; Vanoirbeek, J.A.; Krysko, O.; Bullens, D.M.; Gevaert, P.; Van Cauwenberge, P.; Lambrecht, B.N.; Ceuppens, J.L.; Bachert, C.; Hellings, P.W. Staphylococcus aureus enterotoxin B facilitates allergic sensitization in experimental asthma. Clin. Exp. Allergy 2010, 40, 1079–1090. [Google Scholar]
  115. Muralimohan, G.; Rossi, R.J.; Guernsey, L.A.; Thrall, R.S.; Vella, A.T. Inhalation of Staphylococcus aureus enterotoxin A induces IFN-gamma and CD8 T cell-dependent airway and interstitial lung pathology in mice. J. Immunol. 2008, 181, 3698–3705. [Google Scholar]
  116. Muralimohan, G.; Rossi, R.J.; Vella, A.T. Recruitment and in situ Renewal Regulate Rapid Accumulation of CD11c+ Cells in the Lung following Intranasal Superantigen Challenge. Int. Arch. Allergy Immunol. 2008, 147, 59–73. [Google Scholar]
  117. Ware, L.B. Pathophysiology of acute lung injury and the acute respiratory distress syndrome. Semin. Respir. Crit. Care Med. 2006, 27, 337–349. [Google Scholar]
  118. Venet, F.; Chung, C.S.; Huang, X.; Lomas-Neira, J.; Chen, Y.; Ayala, A. Lymphocytes in the development of lung inflammation: a role for regulatory CD4+ T cells in indirect pulmonary lung injury. J. Immunol. 2009, 183, 3472–3480. [Google Scholar]
  119. Khan, A.A.; Priya, S.; Saha, B. IL-2 regulates SEB induced toxic shock syndrome in BALB/c mice. PLoS One 2009, 4, e8473. [Google Scholar]
  120. Chau, T.A.; McCully, M.L.; Brintnell, W.; An, G.; Kasper, K.J.; Vines, E.D.; Kubes, P.; Haeryfar, S.M.; McCormick, J.K.; Cairns, E.; Heinrichs, D.E.; Madrenas, J. Toll-like receptor 2 ligands on the staphylococcal cell wall downregulate superantigen-induced T cell activation and prevent toxic shock syndrome. Nat. Med. 2009, 15, 641–648. [Google Scholar]
  121. Muralimohan, G.; Vella, A.T. A role for IFNgamma in differential superantigen stimulation of conventional versus plasmacytoid DCs. Cell Immunol. 2006, 242, 9–22. [Google Scholar]
  122. Rossi, R.J.; Muralimohan, G.; Maxwell, J.R.; Vella, A.T. Staphylococcal enterotoxins condition cells of the innate immune system for Toll-like receptor 4 stimulation. Int. Immunol. 2004, 16, 1751–1760. [Google Scholar]
  123. Yadav, R.; Zammit, D.J.; Lefrancois, L.; Vella, A.T. Effects of LPS-mediated bystander activation in the innate immune system. J. Leukoc. Biol. 2006, 80, 1251–1261. [Google Scholar]
  124. Marrack, P.; Kappler, J. The staphylococcal enterotoxins and their relatives. Science 1990, 248, 705–711. [Google Scholar]
  125. Krakauer, T. Immune response to staphylococcal superantigens. Immunol. Res. 1999, 20, 163–173. [Google Scholar]
  126. Thomas, D.; Chou, S.; Dauwalder, O.; Lina, G. Diversity in Staphylococcus aureus enterotoxins. Chem. Immunol. Allergy 2007, 93, 24–41. [Google Scholar]
  127. Ferry, T.; Thomas, D.; Perpoint, T.; Lina, G.; Monneret, G.; Mohammedi, I.; Chidiac, C.; Peyramond, D.; Vandenesch, F.; Etienne, J. Analysis of superantigenic toxin Vbeta T-cell signatures produced during cases of staphylococcal toxic shock syndrome and septic shock. Clin. Microbiol. Infect. 2008, 14, 546–554. [Google Scholar]
  128. Ono, H.K.; Omoe, K.; Imanishi, K.; Iwakabe, Y.; Hu, D.L.; Kato, H.; Saito, N.; Nakane, A.; Uchiyama, T.; Shinagawa, K. Identification and characterization of two novel staphylococcal enterotoxins, types S and T. Infect. Immun. 2008, 76, 4999–5005. [Google Scholar]
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