葡萄球菌肠毒素超抗原抑制性肽与减毒突变体的构建和功能研究
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摘要
超抗原是一种具有强大免疫刺激功能的新型蛋白质抗原,业已证明超抗原参与多种疾病的发病过程。金黄色葡萄球菌(金葡菌)肠毒素超抗原家族涉及的疾病谱非常广泛,并且也是一种失能型的生物战剂,一直是比较活跃的研究领域。已取得的研究进展提示我们,目前针对金葡菌肠毒素超抗原所致疾病除了临床对症支持治疗外,尚无很好的针对超抗原的治疗手段,因此,从其超抗原特性入手,寻找有效控制肠毒素毒性作用的方法,可以进一步为相关疾病的防治研究和生物武器防护提供新的手段。
SEA、SEB、SEC和SED是常见的毒性作用较强的金葡菌肠毒素,国内外对其研究内容大多数是利用其超抗原免疫活性进行抗肿瘤临床治疗等,针对超抗原的活性本身来研究超抗原相关疾病的防治手段较少。目前的研究主要是针对肠毒素的免疫识别区域设计小分子多肽和构建并筛选肠毒素的减毒突变体,从这两方面研究抑制肠毒素超抗原的活性的手段。但是大多数研究都是对单一种类的肠毒素研究,针对多种肠毒素的广谱抑制性手段的研究很少。
基于上述问题,我们针对葡萄球菌肠毒素同源序列设计了9条小分子多肽,通过细胞模型筛选具有广谱抑制性的多肽分子,并运用动物模型检测筛选到的抑制性多肽对动物的保护作用,研究抑制性肽与MHCⅡ类分子的亲和力,预测抑制性肽的空间结构,探讨其广谱抑制活性的机制;同时构建了SED减毒突变体,并检测了该突变体的促人PBMC增殖活性、MHCⅡ类分子结合活性和TCRVβ特异性。主要研究内容和结果包括以下几方面:
1.抑制性多肽的设计和合成,对金葡菌肠毒素家族的序列进行比较,选择具有同源性的保守序列设计多肽,共设计了9条多肽。
2.建立人外周血单个核细胞的细胞模型,检测9条合成多肽对超抗原的抑制效应。主要从多肽对SEs刺激人PBMC的增殖和分泌IL-2、IFN-γ、TNF-β的抑制效应进行检测,筛选具有广谱抑制性效应的多肽,试验结果显示多肽P72对SEA、SEB和SEC超抗原活性具有明显抑制作用,其他8条多肽对SEs的抑制作用不明显。确证试验显示P72对PHA、ConA的促PBMC增殖活性无抑制作用。
3.建立8周龄雌性BALB/c小鼠感染性休克的动物模型,以脂多糖(LPS)和D-氨基半乳糖(D-GalN)致敏小鼠,再用不同剂量的SE进行攻击,获得了此条件下SEA、SEB和SEC的最低致死剂量。利用该动物模型检测多肽P72对SEA、SEB和SEC攻击小鼠的保护效果,结果显示P72对SEA、SEB和SEC致休克效应具有显著的保护作用。
4.竞争结合实验检测抑制性多肽P72与MHCⅡ类分子的结合活性,结果显示多肽P72不能与SEA、SEB和SEC有效竞争结合Raji细胞上的MHCⅡ类分子,提示P72可能不是通过与MHCⅡ类分子结合产生的抑制活性。
5.对抑制性多肽P72的空间结构进行预测,将P72在SEA、SEB、SEC的同源序列的空间结构进行对比,结果显示3种超抗原与P72同源的序列在空间结构上具有高度的相似性。
6.构建了SEDN23A/H26R突变体。并对突变体蛋白进行纯化、定量和免疫印迹分析。检测了SEDN23A/H26R突变体促T淋巴细胞增殖的活性,结果显示其促增殖活性比SED显著降低;以竞争实验检测SEDN23A/H26R突变体与MHCⅡ类分子的结合活性,并用流式细胞仪检测突变体TCRVβ特异性变化。结果:突变体SEDN23A/H26R与MHCⅡ类分子的亲合力未发生变化,但刺激人TCRVβ5+T细胞水平显著降低。
综上,本研究设计并筛选到了1条广谱抑制性多肽P72,P72能够在体外和体内显著抑制SEA、SEB、SEC的超抗原活性,证实了P72可能不是通过与MHCⅡ类分子结合对SEs产生的抑制作用;发现N23、H26位氨基酸残基可能是SED与人TCRVβ5结合的关键位点;研究结果丰富了对SEs超抗原免疫识别机制的认识,为细菌性超抗原相关疾病的防治以及生物武器防护技术的研究提供了新的手段。
The family of staphylococcal enterotoxins (SEs), including SEA-E, SEG,SEH and SEI, has been known to contribute to a broad spectrum of diseases ranging from tissue infections to life-threating speticemia and toxic shock syndromes, and from Kawasaki’s syndrome to atopic dermatitis, even multisystem vasculitis. Moreover, SEs are also manufactured as bio-logical warfare agents and used on military actions. SEA, SEB, SEC and SED are common SEs and possess the high toxicity among SE family. In recent years, much attention has been paid to the study on immunizing treatment of the diseases caused by SEs. Inhibitory peptides and mutants were designed and proved to be effective in antagonising SEs. Because the SEs are comprised of so many toxins, development of the broad-spectrum inhibitory peptides may be a promising method for antagonising SEs. Moreover, more researches were concerned about the SEA, SEB and SEC, so few studis on fighting with SED were carried out. This study is designed to explore the above issues. The main content and results of this study are as follows:
Firstly, nine low-molecular peptides were designed on the basis of high conservative re-gions of amino acid sequences and structures of the SEs. All peptides with more than 95% purity were constructed by solid-phase synthesis and can be used in the subsequent study. Secondly, we constructed the human PBMC cellular models. Lymphocyte proliferation assay and detection of IL-2, IFN-γand TNF-βby ELISA were used to screen the inhibi-tory peptides. The results indicated peptide P72 possessed a broad-spectrum antagonist activ-ity against superantigen SEA, SEB and SEC. However, the other eight peptides had no inhib-iting activity. The viability studies indicated that the PBMCs remained similar livability, with or without the addition of peptide P72, and the peptide P72 didn’t influence the activation of PHA and ConA stimulating proliferation of PBMCs.
Thirdly, the“two-hit”animal model with combination of LPS and the SEs was carried out in the murine experiments. The minimal doses of superantigen that had been shown to cause 100% lethality were obtained. Peptide P72 on the biological activity of SEs was de-tected by this animal model, the results showed P72 can completely protect most of the mice for each toxin tested.
Fourthly, we detected the ability of the peptide P72 binding to MHC classⅡmolecules by competition assay and found that the P72 could not bind to MHC classⅡmolecules, which indicated that the inhibitory activity of P72 may not due to binding to MHC classⅡmolecules.
Fifthly, we compared the amino acid sequences between P72 and SEs, and constructed the three-dimension structure of P72. The results showed three-dimensional domains of the peptide P72 from SEA, SEB and SEC were quite similar.
Finally, a SED mutant was constructed and named SEDN23A/H26R. We detected the mito-gen activity of SEDN23A/H26R and found that its mitogen activity decreased significantly. Fur-thermore, competition assay was used to detect the ability of mutant SEDN23A/H26R binding to MHCⅡ. The TCRVβspecificity of the mutant was then determined with FACS. The results showed that residue N23 played an important role on SED interacting with human TCRVβ5. Residue H26 was probably an active site of SED binding to other human TCRVβ.
In conclusion, our results indicate that P72 possesses a broad-spectrum antagonist activ-ity against superantigen SEA, SEB and SEC. Inhibitory activity of P72 may not due to bind-ing to MHC classⅡm olecules. N23 and H26 on SED are the important residues involved SED interacting with TCRVβ.SEDN23A/H26R with lower mitogen activity may be used to manufacture the attenuated vaccine. Our study might enrich understanding the mechanism of immune response arised by superantigens, and provide new methods for developing counter-measure to fight with SEs-related deseases and biological weapons.
SEA、SEB、SEC和SED是常见的毒性作用较强的金葡菌肠毒素,国内外对其研究内容大多数是利用其超抗原免疫活性进行抗肿瘤临床治疗等,针对超抗原的活性本身来研究超抗原相关疾病的防治手段较少。目前的研究主要是针对肠毒素的免疫识别区域设计小分子多肽和构建并筛选肠毒素的减毒突变体,从这两方面研究抑制肠毒素超抗原的活性的手段。但是大多数研究都是对单一种类的肠毒素研究,针对多种肠毒素的广谱抑制性手段的研究很少。
基于上述问题,我们针对葡萄球菌肠毒素同源序列设计了9条小分子多肽,通过细胞模型筛选具有广谱抑制性的多肽分子,并运用动物模型检测筛选到的抑制性多肽对动物的保护作用,研究抑制性肽与MHCⅡ类分子的亲和力,预测抑制性肽的空间结构,探讨其广谱抑制活性的机制;同时构建了SED减毒突变体,并检测了该突变体的促人PBMC增殖活性、MHCⅡ类分子结合活性和TCRVβ特异性。主要研究内容和结果包括以下几方面:
1.抑制性多肽的设计和合成,对金葡菌肠毒素家族的序列进行比较,选择具有同源性的保守序列设计多肽,共设计了9条多肽。
2.建立人外周血单个核细胞的细胞模型,检测9条合成多肽对超抗原的抑制效应。主要从多肽对SEs刺激人PBMC的增殖和分泌IL-2、IFN-γ、TNF-β的抑制效应进行检测,筛选具有广谱抑制性效应的多肽,试验结果显示多肽P72对SEA、SEB和SEC超抗原活性具有明显抑制作用,其他8条多肽对SEs的抑制作用不明显。确证试验显示P72对PHA、ConA的促PBMC增殖活性无抑制作用。
3.建立8周龄雌性BALB/c小鼠感染性休克的动物模型,以脂多糖(LPS)和D-氨基半乳糖(D-GalN)致敏小鼠,再用不同剂量的SE进行攻击,获得了此条件下SEA、SEB和SEC的最低致死剂量。利用该动物模型检测多肽P72对SEA、SEB和SEC攻击小鼠的保护效果,结果显示P72对SEA、SEB和SEC致休克效应具有显著的保护作用。
4.竞争结合实验检测抑制性多肽P72与MHCⅡ类分子的结合活性,结果显示多肽P72不能与SEA、SEB和SEC有效竞争结合Raji细胞上的MHCⅡ类分子,提示P72可能不是通过与MHCⅡ类分子结合产生的抑制活性。
5.对抑制性多肽P72的空间结构进行预测,将P72在SEA、SEB、SEC的同源序列的空间结构进行对比,结果显示3种超抗原与P72同源的序列在空间结构上具有高度的相似性。
6.构建了SEDN23A/H26R突变体。并对突变体蛋白进行纯化、定量和免疫印迹分析。检测了SEDN23A/H26R突变体促T淋巴细胞增殖的活性,结果显示其促增殖活性比SED显著降低;以竞争实验检测SEDN23A/H26R突变体与MHCⅡ类分子的结合活性,并用流式细胞仪检测突变体TCRVβ特异性变化。结果:突变体SEDN23A/H26R与MHCⅡ类分子的亲合力未发生变化,但刺激人TCRVβ5+T细胞水平显著降低。
综上,本研究设计并筛选到了1条广谱抑制性多肽P72,P72能够在体外和体内显著抑制SEA、SEB、SEC的超抗原活性,证实了P72可能不是通过与MHCⅡ类分子结合对SEs产生的抑制作用;发现N23、H26位氨基酸残基可能是SED与人TCRVβ5结合的关键位点;研究结果丰富了对SEs超抗原免疫识别机制的认识,为细菌性超抗原相关疾病的防治以及生物武器防护技术的研究提供了新的手段。
The family of staphylococcal enterotoxins (SEs), including SEA-E, SEG,SEH and SEI, has been known to contribute to a broad spectrum of diseases ranging from tissue infections to life-threating speticemia and toxic shock syndromes, and from Kawasaki’s syndrome to atopic dermatitis, even multisystem vasculitis. Moreover, SEs are also manufactured as bio-logical warfare agents and used on military actions. SEA, SEB, SEC and SED are common SEs and possess the high toxicity among SE family. In recent years, much attention has been paid to the study on immunizing treatment of the diseases caused by SEs. Inhibitory peptides and mutants were designed and proved to be effective in antagonising SEs. Because the SEs are comprised of so many toxins, development of the broad-spectrum inhibitory peptides may be a promising method for antagonising SEs. Moreover, more researches were concerned about the SEA, SEB and SEC, so few studis on fighting with SED were carried out. This study is designed to explore the above issues. The main content and results of this study are as follows:
Firstly, nine low-molecular peptides were designed on the basis of high conservative re-gions of amino acid sequences and structures of the SEs. All peptides with more than 95% purity were constructed by solid-phase synthesis and can be used in the subsequent study. Secondly, we constructed the human PBMC cellular models. Lymphocyte proliferation assay and detection of IL-2, IFN-γand TNF-βby ELISA were used to screen the inhibi-tory peptides. The results indicated peptide P72 possessed a broad-spectrum antagonist activ-ity against superantigen SEA, SEB and SEC. However, the other eight peptides had no inhib-iting activity. The viability studies indicated that the PBMCs remained similar livability, with or without the addition of peptide P72, and the peptide P72 didn’t influence the activation of PHA and ConA stimulating proliferation of PBMCs.
Thirdly, the“two-hit”animal model with combination of LPS and the SEs was carried out in the murine experiments. The minimal doses of superantigen that had been shown to cause 100% lethality were obtained. Peptide P72 on the biological activity of SEs was de-tected by this animal model, the results showed P72 can completely protect most of the mice for each toxin tested.
Fourthly, we detected the ability of the peptide P72 binding to MHC classⅡmolecules by competition assay and found that the P72 could not bind to MHC classⅡmolecules, which indicated that the inhibitory activity of P72 may not due to binding to MHC classⅡmolecules.
Fifthly, we compared the amino acid sequences between P72 and SEs, and constructed the three-dimension structure of P72. The results showed three-dimensional domains of the peptide P72 from SEA, SEB and SEC were quite similar.
Finally, a SED mutant was constructed and named SEDN23A/H26R. We detected the mito-gen activity of SEDN23A/H26R and found that its mitogen activity decreased significantly. Fur-thermore, competition assay was used to detect the ability of mutant SEDN23A/H26R binding to MHCⅡ. The TCRVβspecificity of the mutant was then determined with FACS. The results showed that residue N23 played an important role on SED interacting with human TCRVβ5. Residue H26 was probably an active site of SED binding to other human TCRVβ.
In conclusion, our results indicate that P72 possesses a broad-spectrum antagonist activ-ity against superantigen SEA, SEB and SEC. Inhibitory activity of P72 may not due to bind-ing to MHC classⅡm olecules. N23 and H26 on SED are the important residues involved SED interacting with TCRVβ.SEDN23A/H26R with lower mitogen activity may be used to manufacture the attenuated vaccine. Our study might enrich understanding the mechanism of immune response arised by superantigens, and provide new methods for developing counter-measure to fight with SEs-related deseases and biological weapons.
引文
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44. Labrecque-N; Thibodeau-J; Sekaly-RP. Interactions between staphylo-coccal superanti-gens and MHC class II molecules. Semin-Immunol. 1993; 5(1): 23-32.
45. Barik-S. Site-directed mutagenesis in vitro by megaprimer PCR. Meth-ods-Mol-Biol. 1996; 57: 203-15.
46. Ke-SH; Madison-EL. Rapid and efficient site-directed mutagenesis by single-tube 'megaprimer' PCR method. Nucleic-Acids-Res. 1997 15; 25(16): 3371-2.
47. Barik-S. Mutagenesis and gene fusion by megaprimer PCR. Meth-ods-Mol-Biol. 1997; 67: 173-82
48. J.萨姆布鲁克,E.F.弗里奇,T.曼尼阿蒂斯。分子克隆实验指南。科学出版社,北京,第二版,1992。
49. F.奥斯伯,R.布伦特,R.E.金斯顿,等。精编分子生物学实验指南.科学出版社,北京,第一版,1998。
50.姜永强.超抗原与超抗原疫苗.国外医学免疫学分册. 1998,21(5):264-68
51. Dellabona-P; Peccoud-J; Kappler-J; et al. Superantigens interact with MHC class II molecules outside of the antigen groove. Cell. 1990; 62(6): 1115-21.
52. Wen-R; Blackman-MA; Woodland-D. Variable influence of MHC polymorphism on the recognition of bacterial superantigens by T cells. J-Immunol. 1995; 155(4): 1884-92.
53. Karp-DR; Long-EO. Identification of HLA-DR1 beta chain residues critical for binding staphylococcal enterotoxins A and E. J-Exp-Med. 1992; 175(2): 415-24.
54. Mollick-JA; Chintagumpala-M; Cook-RG; et al. Staphylococcal exotoxin activation of T cells. Role of exotoxin-MHC class II binding affinity and class II isotype. J-Immunol.1991; 146(2): 463-8.
55. Majumdar-G; Beachey-EH; Tomai-M; et al. Differential signal requirements in T-cell activation by mitogen and superantigen. Cell-Signal. 1990; 2(6): 521-30.
56. Carlsson-R; Fischer-H; Sjogren-HO. Binding of staphylococcal entero-toxin A to acces-sory cells is a requirement for its ability to activate human T cells. J-Immunol. 1988; 140(8): 2484-8.
1. Dinges MM, Orwin PM, Schlievert PM. Exotoxins of staphylococcus aureus. Clin Microbiol Rev 2000;13:16–34.
2. Orwin PM, Leung DY, Donahue HL, Novick RP, Schlievert PM. Bio-chemical and biological properties of staphylococcal enterotoxin K. In fect Immun 2001;69:360–6.
3. Orwin PM, Fitzgerald JR, Leung DY, Gutierrez JA, Bohach GA, Schlievert PM. Characterization of staphylococcus aureus enterotoxin L. Infect Immun 2003;71: 2916–9
4. Omoe K, Hu DL, Takahashi-Omoe H, Nakane A, Shinagawa K. Identifi-cation and characterization of a new staphylococcal enterotoxinrelated putative toxin encoded by two kinds of plasmids. Infect Immun 2003;71:6088–94.
5. Alouf JE, Müller-Alouf H. Staphylococcal and streptococcal superanti-gens: molecular, biological and clinical aspects. Int J Med Microbiol. 2003;292(7-8):429-40.
6. Fluer FS. Staphylococcal toxin of toxic shock syndrome. Zh Mikrobiol Epidemiol Immunobiol. 2007; Sep-Oct: 106-14
7. Hussain A, Robinson G, Malkin J, Duthie M, Kearns A, Perera N.Purpura fulminans in a child secondary to Panton-Valentine leukocidin-producing staphylococcus aureus. J Med Microbiol. 2007; 56: 1407-9
8. Yarwood JM, Leung DY, Schlievert PM. Evidence for the involvement of bacterial superantigens in psoriasis, atopic dermatitis, and Kawasaki syndrome. FEMS- Micro-biol-Lett. 2000; 192: 1.
9. Cohen-Tervaert-JW; Popa-ER; Bos-NA.The role of superantigens in vas-culitis. Curr-Opin-Rheumatol. 1999; 11: 24.
10. Bunikowski-R; Mielke-M-E; Skarabis-H; et al. Evidence for a dis-ease-promoting ef-fect of staphylococcus aureus-derived exotoxins in atopic dermatitis. J-Allergy-Clin-Immunol. 2000; 105: 814.
11. Bachert C, Zhang N, Patou J, van Zele T, Gevaert P.Role of staphylococ-cal superan-tigens in upper airway disease.Curr Opin Allergy Clin Immu-nol. 2008; 8: 34-8
12. Herman A, Kappler JW, Marrack P, Pullen AM. Superantigens: mecha-nism of T-cell stimulation and role in immune responses. Annu Rev Im-munol. 1991; 9: 745–72.
13. Zhang S,landolo JJ,Stewart GC,et a1.The enterotoxln D plasmid of Staphylococcusaureus encodes a second enterotoxin determ inant(sej).FEMS Mierobiol Lett 1998,168(2):227-233.
14. Munson SH,Tremaine MT,Betley MJ,et a1.Identification and characterization of staphylococcal entemtoxin types G and I from Staphylococcns aureus.Infect lmmun 1998,66(7):3337-3348.
15. Jarraud S,Peyrat MA,Lim A. et a1.egc, a highly prevalent operon of enterotoxin gene, forms a putative nursery of superantigens in Staphylococcus aureus..J lmmunol 2001,166(1):669-677.
16. Orwin PM,Leung DY,Donahue HL,et a1.Biochemical properties of staphylococcal entemtoxin K.Infect lmmunol 200l, 69:360-366.
17. Lindsay JA,Ruin A,Ross HF,et a1.The gene for toxic shock toxin is carried by a family of mobile pathogenicity islands in Staphylococcus aureus.Mol Mierobiol 1998,29(2):527-543.
18. Holmberg SD, Blake PA. Staphylococcal food poisoning in the United States. New facts and old misconceptions. JAMA 1984; 251: 487–9.
19. Eisenberg MS, Gaarslev K, Brown W, Horwitz M, Hill D. Staphylococcal food poi-soning aboard a commercial aircraft. Lancet 1975; 2: 595–9.
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37. Reiser RF, Hinzman SJ, Bergdoll MS. Production of toxic shock syndrome toxin-1 by Staphylococcus aureus restricted to endogenous air in tampons. J Clin Microbiol 1987; 25: 1450–2.
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44. Labrecque-N; Thibodeau-J; Sekaly-RP. Interactions between staphylo-coccal superanti-gens and MHC class II molecules. Semin-Immunol. 1993; 5(1): 23-32.
45. Barik-S. Site-directed mutagenesis in vitro by megaprimer PCR. Meth-ods-Mol-Biol. 1996; 57: 203-15.
46. Ke-SH; Madison-EL. Rapid and efficient site-directed mutagenesis by single-tube 'megaprimer' PCR method. Nucleic-Acids-Res. 1997 15; 25(16): 3371-2.
47. Barik-S. Mutagenesis and gene fusion by megaprimer PCR. Meth-ods-Mol-Biol. 1997; 67: 173-82
48. J.萨姆布鲁克,E.F.弗里奇,T.曼尼阿蒂斯。分子克隆实验指南。科学出版社,北京,第二版,1992。
49. F.奥斯伯,R.布伦特,R.E.金斯顿,等。精编分子生物学实验指南.科学出版社,北京,第一版,1998。
50.姜永强.超抗原与超抗原疫苗.国外医学免疫学分册. 1998,21(5):264-68
51. Dellabona-P; Peccoud-J; Kappler-J; et al. Superantigens interact with MHC class II molecules outside of the antigen groove. Cell. 1990; 62(6): 1115-21.
52. Wen-R; Blackman-MA; Woodland-D. Variable influence of MHC polymorphism on the recognition of bacterial superantigens by T cells. J-Immunol. 1995; 155(4): 1884-92.
53. Karp-DR; Long-EO. Identification of HLA-DR1 beta chain residues critical for binding staphylococcal enterotoxins A and E. J-Exp-Med. 1992; 175(2): 415-24.
54. Mollick-JA; Chintagumpala-M; Cook-RG; et al. Staphylococcal exotoxin activation of T cells. Role of exotoxin-MHC class II binding affinity and class II isotype. J-Immunol.1991; 146(2): 463-8.
55. Majumdar-G; Beachey-EH; Tomai-M; et al. Differential signal requirements in T-cell activation by mitogen and superantigen. Cell-Signal. 1990; 2(6): 521-30.
56. Carlsson-R; Fischer-H; Sjogren-HO. Binding of staphylococcal entero-toxin A to acces-sory cells is a requirement for its ability to activate human T cells. J-Immunol. 1988; 140(8): 2484-8.
1. Dinges MM, Orwin PM, Schlievert PM. Exotoxins of staphylococcus aureus. Clin Microbiol Rev 2000;13:16–34.
2. Orwin PM, Leung DY, Donahue HL, Novick RP, Schlievert PM. Bio-chemical and biological properties of staphylococcal enterotoxin K. In fect Immun 2001;69:360–6.
3. Orwin PM, Fitzgerald JR, Leung DY, Gutierrez JA, Bohach GA, Schlievert PM. Characterization of staphylococcus aureus enterotoxin L. Infect Immun 2003;71: 2916–9
4. Omoe K, Hu DL, Takahashi-Omoe H, Nakane A, Shinagawa K. Identifi-cation and characterization of a new staphylococcal enterotoxinrelated putative toxin encoded by two kinds of plasmids. Infect Immun 2003;71:6088–94.
5. Alouf JE, Müller-Alouf H. Staphylococcal and streptococcal superanti-gens: molecular, biological and clinical aspects. Int J Med Microbiol. 2003;292(7-8):429-40.
6. Fluer FS. Staphylococcal toxin of toxic shock syndrome. Zh Mikrobiol Epidemiol Immunobiol. 2007; Sep-Oct: 106-14
7. Hussain A, Robinson G, Malkin J, Duthie M, Kearns A, Perera N.Purpura fulminans in a child secondary to Panton-Valentine leukocidin-producing staphylococcus aureus. J Med Microbiol. 2007; 56: 1407-9
8. Yarwood JM, Leung DY, Schlievert PM. Evidence for the involvement of bacterial superantigens in psoriasis, atopic dermatitis, and Kawasaki syndrome. FEMS- Micro-biol-Lett. 2000; 192: 1.
9. Cohen-Tervaert-JW; Popa-ER; Bos-NA.The role of superantigens in vas-culitis. Curr-Opin-Rheumatol. 1999; 11: 24.
10. Bunikowski-R; Mielke-M-E; Skarabis-H; et al. Evidence for a dis-ease-promoting ef-fect of staphylococcus aureus-derived exotoxins in atopic dermatitis. J-Allergy-Clin-Immunol. 2000; 105: 814.
11. Bachert C, Zhang N, Patou J, van Zele T, Gevaert P.Role of staphylococ-cal superan-tigens in upper airway disease.Curr Opin Allergy Clin Immu-nol. 2008; 8: 34-8
12. Herman A, Kappler JW, Marrack P, Pullen AM. Superantigens: mecha-nism of T-cell stimulation and role in immune responses. Annu Rev Im-munol. 1991; 9: 745–72.
13. Zhang S,landolo JJ,Stewart GC,et a1.The enterotoxln D plasmid of Staphylococcusaureus encodes a second enterotoxin determ inant(sej).FEMS Mierobiol Lett 1998,168(2):227-233.
14. Munson SH,Tremaine MT,Betley MJ,et a1.Identification and characterization of staphylococcal entemtoxin types G and I from Staphylococcns aureus.Infect lmmun 1998,66(7):3337-3348.
15. Jarraud S,Peyrat MA,Lim A. et a1.egc, a highly prevalent operon of enterotoxin gene, forms a putative nursery of superantigens in Staphylococcus aureus..J lmmunol 2001,166(1):669-677.
16. Orwin PM,Leung DY,Donahue HL,et a1.Biochemical properties of staphylococcal entemtoxin K.Infect lmmunol 200l, 69:360-366.
17. Lindsay JA,Ruin A,Ross HF,et a1.The gene for toxic shock toxin is carried by a family of mobile pathogenicity islands in Staphylococcus aureus.Mol Mierobiol 1998,29(2):527-543.
18. Holmberg SD, Blake PA. Staphylococcal food poisoning in the United States. New facts and old misconceptions. JAMA 1984; 251: 487–9.
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