Skip to main content

Advertisement

SpringerLink
Log in

Superantigen influence in conjunction with cytokine polymorphism potentiates autoimmunity in systemic lupus erythematosus patients

  • Original Article
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Risk posed by microbial superantigens in triggering or exacerbating SLE in genetically predisposed individuals, thereby altering the response to its treatment strategies, has not been studied. Using streptococcal pyrogenic exotoxin A and staphylococcal enterotoxin B as prototype superantigens, we have demonstrated that they profoundly affect the magnitude of polyclonal T cell response, particularly CD4+ T cells and expression of CD45RA and CD45RO, and cytokine secretion in vitro in SLE patient PBMCs. Also, reduced proportions of FoxP3 expressing CD4+CD25+ T cells were detected in SLE as compared to healthy control PBMCs. Furthermore, polymorphism in IL-10 and TGF-β showed significant association with SLE in our study population. These results indicate that accumulation of superantigen-reactive T cells and cytokine polymorphism may cause disease exacerbation, relapse, or therapeutic resistance in SLE patients. Attempts to contain colonizing and/or superantigen-producing microbial agents in SLE patients in addition to careful monitoring of their therapy may be worthwhile in decreasing disease severity or preventing frequent relapses. The study suggests that superantigen interference in conjunction with cytokine polymorphism may play a role in immune dysregulation, thereby contributing to autoimmunity in SLE. Therefore, changes in T cell phenotypes and cytokine secretion might be good indicators of therapeutic efficacy in these patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol. 2003;56(7):481–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lahita RG. The connective tissue diseases and the overall influence of gender. Int J Fertil Menopausal Stud. 1996;41(2):156–65.

    CAS  PubMed  Google Scholar 

  3. D’Cruz D. Autoimmune diseases associated with drugs, chemicals, and environmental factors. Toxicol Lett. 2000;112–113:421–32.

    Article  PubMed  Google Scholar 

  4. Dooley MA, Hogan SL. Environmental epidemiology and risk factors for autoimmune disease. Curr Opin Rheumatol. 2003;15(2):99–103.

    Article  CAS  PubMed  Google Scholar 

  5. Deapen D, Escalante A, Weinrib L, Horwitz D, Bachman B, Roy-Burman P, Walker A, Mack TM. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 1992;35(3):311–8.

    Article  CAS  PubMed  Google Scholar 

  6. Friedman SM, Posnett DN, Tumang JR, Cole BC, Crow MK. A potential role for microbial superantigens in the pathogenesis of systemic autoimmune disease. Arthritis Rheum. 1991;34(4):468–80.

    Article  CAS  PubMed  Google Scholar 

  7. Fraser JD, Proft T. The bacterial superantigen and superantigen-like proteins. Immunol Rev. 2008;225:226–43.

    Article  CAS  PubMed  Google Scholar 

  8. Sfriso P, Ghirardello A, Botsios C, Tonon M, Zen M, Bassi N, Bassetto F, Doria A. Infections and autoimmunity: the multifaceted relationship. J Leukoc Biol. 2010;87:385–95.

    Article  CAS  PubMed  Google Scholar 

  9. Kissner TL, Ruthel G, Alam S, Ulrich RG, Fernandez S, Saikh KU. Activation of MyD88 signaling upon staphylococcal enterotoxin binding to MHC class II molecules. PLoS One. 2011;6:e15985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Florquin S, Amraoui Z, Goldman M. Persistent production of TH2- type cytokines and polyclonal B cell activation after chronic administration of staphylococcal enterotoxin B in mice. J Autoimmun. 1996;9(5):609–15.

    Article  CAS  PubMed  Google Scholar 

  11. Tumang JR, Zhou JL, Gietl D, Crow MK, Elkon KB, Friedman SM. T helper cell dependent, microbial superantigen-mediated B cell activation in vivo. Autoimmunity. 1996;24(4):247–55.

    Article  CAS  PubMed  Google Scholar 

  12. Friedman SM, Tumang JR, Crow MK. Microbial superantigens as etiopathogenic agents in autoimmunity. Rheum Dis Clin North Am. 1993;19:207–22.

    CAS  PubMed  Google Scholar 

  13. Kotzin BL, Leung DY, Kappler J, Marrack P. Superantigens and their potential role in human disease. Adv Immunol. 1993;54:99–166.

    Article  CAS  PubMed  Google Scholar 

  14. Bette M, Schafer MK, van Rooijen N, Weihe E, Fleischer B. Distribution and kinetics of superantigen-induced cytokine gene expression in mouse spleen. J Exp Med. 1993;178(5):1531–9.

    Article  CAS  PubMed  Google Scholar 

  15. Miethke T, Duschek K, Wahl C, Heeg K, Wagner H. Pathogenesis of the toxic shock syndrome: T cell mediated lethal shock caused by the superantigen TSST-1. Eur J Immunol. 1993;23(7):1494–500.

    Article  CAS  PubMed  Google Scholar 

  16. MacDonald HR, Baschieri S, Lees R. Clonal expansion precedes anergy and death of Vβ8+ peripheral T cells responding to staphylococcal enterotoxin B in vivo. Eur J Immunol. 1991;21:1963.

    Article  CAS  PubMed  Google Scholar 

  17. Baschieri S, Lees RK, Lussow A, MacDonald HR. Clonal anergy to staphylococcal enterotoxin B in vivo: selective effects on T cell subsets and cytokines. Eur J Immunol. 1993;23:2661.

    Article  CAS  PubMed  Google Scholar 

  18. Arend WP, Gabay C. Cytokines in the rheumatic diseases. Rheum Dis Clin North Am. 2004;30(1):41–67.

    Article  PubMed  Google Scholar 

  19. Grainger DJ, Heathcote K, Chiano M, Snieder H, Kemp PR, Metcalfe JC, Carter ND, Spector TD. Genetic control of the circulating concentration of transforming growth factor type beta 1. Hum Mol Genet. 1999;8(1):93–7.

    Article  CAS  PubMed  Google Scholar 

  20. Terry C, Loukaci V, Green F. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem. 2000;275(24):18138–44.

    Article  CAS  PubMed  Google Scholar 

  21. Bidwell J, Keen L, Gallagher G, Kimberly R, Huizinga T, McDermott MF, Oksenberg J, McNicholl J, Pociot F, Hardt C, D’Alfonso S. Cytokine gene polymorphism in human disease: on-line databases. Genes Immun. 1999;1(1):3–19.

    Article  CAS  PubMed  Google Scholar 

  22. Ahmad YA, Bruce IN. Genetic epidemiology: systemic lupus erythematosus. Arthritis Res Ther. 2001;3(6):331–6.

    Article  CAS  Google Scholar 

  23. Magnusson V, Nakken B, Bolstad A, Alarcon-Riquelme M. Cytokine polymorphisms in systemic lupus erythematosus and Sjogren’s syndrome. Scand J Immunol. 2001;54(1–2):55–61.

    Article  CAS  PubMed  Google Scholar 

  24. Lu LY, Cheng HH, Sung PK, Yeh JJ, Shiue YL, Chen A. Single-nucleotide polymorphisms of transforming growth factor-beta1 gene in Taiwanese patients with systemic lupus erythematosus. J Microbiol Immunol Infect. 2004;37(3):145–52.

    CAS  PubMed  Google Scholar 

  25. Boyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Investig. 1968;97:77–89.

    CAS  Google Scholar 

  26. Fuleihan R, Mourad W, Geha RS, Chatila T. Engagement of MHC-class II molecules by staphylococcal exotoxins delivers a co-mitogenic signal to human B cells. J Immunol. 1991;146(5):1661–6.

    CAS  PubMed  Google Scholar 

  27. Leitenberg D, Boutin Y, Lu DD, Bottomly K. Biochemical association of CD45 with the T cell receptor complex: regulation by CD45 isoform and during T cell activation. Immunity. 1999;10(6):701–11.

    Article  CAS  PubMed  Google Scholar 

  28. Davis MM, Boniface JJ, Reich Z, Lyons D, Hamp J, Arden B, Chien Y. Ligand recognition by αβ T cell receptors. Annu Rev Immunol. 1998;16:523–44.

    Article  CAS  PubMed  Google Scholar 

  29. Crispin JC, Martinez A, Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun. 2003;21(3):273–6.

    Article  PubMed  Google Scholar 

  30. Liu MF, Wang CR, Fung LL, Wu CR. Decreased CD4+ CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scand J Immunol. 2004;59(2):98–202.

    Article  Google Scholar 

  31. Sabry A, Sheashaa H, El-Husseini A, Mahmoud K, Eldahshan KF, George SK, Abdel-Khalek E, El-Shafey EM, Abo-Zenah H. Proinflammatory cytokines (TNFalpha and IL-6) in Egyptian patients with SLE: its correlation with disease activity. Cytokine. 2006;35(3–4):148–53.

    Article  CAS  PubMed  Google Scholar 

  32. Kimura A, Naka T, Kishimoto T. IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells. Proc Natl Acad Sci USA. 2007;104(29):12099104.

    Article  Google Scholar 

  33. Zhang B, Zhang X, Tang F, Zhu L, Liu Y. Reduction of forkhead box P3 levels in CD4+CD25high T cells in patients with new-onset systemic lupus erythematosus. Clin Exp Immunol. 2008;153(2):182–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol. 2001;19:225–52.

    Article  CAS  PubMed  Google Scholar 

  35. Al-Mutairi S, Al-Awadhi A, Raghupathy R, Al-Khawari H, Sada P, Al-Herz A, Rawoot P. Lupus patients with pulmonary involvement have a pro-inflammatory cytokines profile. Rheumatol Int. 2007;27(7):621–30.

    Article  CAS  PubMed  Google Scholar 

  36. Ishida H, Muchamuel T, Sakaguchi S, Andrade S, Menon S, Howard M. Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J Exp Med. 1994;179:305–10.

    Article  CAS  PubMed  Google Scholar 

  37. Awad MR, El-Gamel A, Hasleton P, Turner DM, Sinnott PJ, Hutchinson IV. Genotypic variation in the transforming growth factor beta1 gene: association with transforming growth factor production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation. 1998;66(8):1014–20.

    Article  CAS  PubMed  Google Scholar 

  38. Guarnizo-Zuccardi P, Lopez Y, Giraldo M, Garcia N, Rodriguez L, Ramirez L, Uribe O, Garcia L, Vasquez G. Cytokine gene polymorphisms in Colombian patients with systemic lupus erythematosus. Tissue Antigens. 2007;70(5):376–82.

    Article  CAS  PubMed  Google Scholar 

  39. Kurreeman FA, Schonkeren JJ, Heijmans BT, Toes RE, Huizinga TW. Transcription of the IL10 gene reveals allele-specific regulation at the mRNA level. Hum Mol Genet. 2004;13(16):1755–62.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was financially supported in parts by the grants from (1) SERB, Department of Science and Technology [F.No. SR/SO/SH-82/2005], Govt. of India, New Delhi, and (2) the University Grants Commission [F.No. 40-116/2011(SR)], Govt. of India, New Delhi.

Author information

Authors and Affiliations

  1. Department of Microbiology, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi, India

    Sajad Ahmad Dar, Vishnampettai Ganapathysubramanian Ramachandran & Shukla Das

  2. Department of Biology, College of Science, University of Bahrain, Sakhir, Kingdom of Bahrain

    Essam Mohammed Ahmed Janahi

  3. Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

    Shafiul Haque

  4. Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Kingdom of Saudi Arabia

    Naseem Akhter

  5. Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia

    Sajad Ahmad Dar, Shafiul Haque, Arshad Jawed & Mohd Wahid

  6. Department of Dermatology, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi, India

    Sambit Nath Bhattacharya

  7. Department of Biochemistry, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi, India

    Basu Dev Banerjee

Authors
  1. Sajad Ahmad Dar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Essam Mohammed Ahmed Janahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shafiul Haque
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Naseem Akhter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arshad Jawed
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohd Wahid
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vishnampettai Ganapathysubramanian Ramachandran
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sambit Nath Bhattacharya
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Basu Dev Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shukla Das
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shukla Das.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dar, S.A., Janahi, E.M.A., Haque, S. et al. Superantigen influence in conjunction with cytokine polymorphism potentiates autoimmunity in systemic lupus erythematosus patients. Immunol Res 64, 1001–1012 (2016). https://doi.org/10.1007/s12026-015-8768-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-015-8768-4

Keywords

Search

Navigation