Skip to main content

Advertisement

Log in

Detection of Microbiota from Human Thymus of Myasthenia Gravis

  • Original Article
  • Published:
Indian Journal of Surgery Aims and scope Submit manuscript

Abstract

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies directed against different components of the neuromuscular junction (NMJ), and pathogenic mechanism associated thymic pathologies. Microbiota invading thymus is hypothesized to trigger human autoimmune response by providing antigens to produce NMJ antibodies and clinical manifestations of myasthenia gravis. There are many reports of microbial nucleic acid isolation and protein expression and even a few studies of viable microbes isolated from the human thymus. However, high-resolution investigation of microbial infectious agents from the human thymus that may contribute to myasthenia gravis is very limited. To investigate potential microbial infection within human thymus tissue samples, we performed quantitative real-time PCR of the bacterial 16S ribosomal RNA (rRNA) and fungal 18S rRNA gene analysis on (1) a total of 23 abnormal thymus including 13 thymomas and 4 thymus hyperplasias obtained from MG patients and 6 thymoma-nonMG patients who underwent thymectomy. (2) Another 14 normal thymus were selected as control from patients who underwent congenital heart disease surgery. Results show that a wide range of bacteria agents are exhibited in the thymus, rather than fungus. And an intriguing new observation that shows the microbiota displayed differences among MG patients, thymoma-nonMG patients, and normal thymus as judged from the taxonomic profiles in these three groups. Compared with the normal thymus group, the Klebsiella and Escherichia coli show higher abundance in MG patient group. The thymus harbors bacteria agents and Klebsiella and Escherichia coli may be potential pathogens associated with MG. Further investigations are needed to elucidate the possible associations of Klebsiella and E. coli and MG.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Marx A, Pfister F, Schalke B, Saruhan-Direskeneli G, Melms A, Ströbel P (2013) The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun Rev 12(9):875–884

    Article  CAS  Google Scholar 

  2. Vincent A (2002) Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol 2(10):797–804

    Article  CAS  Google Scholar 

  3. Cavalcante P et al (2010) Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus. Ann Neurol 67(6):726–738

    PubMed  Google Scholar 

  4. Iwasa K, Yoshikawa H, Hamaguchi T, Sakai K, Shinohara-Noguchi M, Samuraki M, Takahashi K, Yanase D, Ono K, Ishida C, Yoshita M, Nakamura H, Yamada M (2018) Time-series analysis: variation of anti-acetylcholine receptor antibody titer in myasthenia gravis is related to incidence of mycoplasma pneumoniae and influenza virus infections. Neurol Res 40(2):102–109

    Article  CAS  Google Scholar 

  5. Rennspiess D, Pujari S, Keijzers M, Abdul-Hamid MA, Hochstenbag M, Dingemans AM, Kurz AK, Speel EJ, Haugg A, Pastrana DV, Buck CB, de Baets MH, zur Hausen A (2015) Detection of human polyomavirus 7 in human thymic epithelial tumors. J Thorac Oncol 10(2):360–366

    Article  CAS  Google Scholar 

  6. Cufi P, Dragin N, Ruhlmann N, Weiss JM, Fadel E, Serraf A, Berrih-Aknin S, le Panse R (2014) Central role of interferon-beta in thymic events leading to myasthenia gravis. J Autoimmun 52:44–52

    Article  CAS  Google Scholar 

  7. Savino W (2006) The thymus is a common target organ in infectious diseases. PLoS Pathog 2(6):e62

    Article  Google Scholar 

  8. Nunes-Alves C, Nobrega C, Behar SM, Correia-Neves M (2013) Tolerance has its limits: how the thymus copes with infection. Trends Immunol 34(10):502–510

    Article  CAS  Google Scholar 

  9. Stefansson K, Dieperink ME, Richman DP, Gomez CM, Marton LS (1985) Sharing of antigenic determinants between the nicotinic acetylcholine receptor and proteins in Escherichia coli, Proteus vulgaris, and Klebsiella pneumoniae. Possible role in the pathogenesis of myasthenia gravis. N Engl J Med 312(4):221–225

    Article  CAS  Google Scholar 

  10. Lu Y, Li X, Liu S, Zhang Y, Zhang D (2018) Toll-like receptors and inflammatory bowel disease. Front Immunol 9:72

    Article  Google Scholar 

  11. Roszyk E, Puszczewicz M (2017) Role of human microbiome and selected bacterial infections in the pathogenesis of rheumatoid arthritis. Reumatologia 55(5):242–250

    Article  Google Scholar 

  12. Marino E et al (2017) Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nat Immunol 18(5):552–562

    Article  CAS  Google Scholar 

  13. Brito VN, Souto PC, Cruz-Höfling MA, Ricci LC, Verinaud L (2003) Thymus invasion and atrophy induced by Paracoccidioides brasiliensis in BALB/c mice. Med Mycol 41(2):83–87

    CAS  PubMed  Google Scholar 

  14. Zhan X, Stamova B, Jin LW, DeCarli C, Phinney B, Sharp FR (2016) Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology 87(22):2324–2332

    Article  CAS  Google Scholar 

  15. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Peña AG, Goodrich JK, Gordon JI, Huttley GA, Kelley ST, Knights D, Koenig JE, Ley RE, Lozupone CA, McDonald D, Muegge BD, Pirrung M, Reeder J, Sevinsky JR, Turnbaugh PJ, Walters WA, Widmann J, Yatsunenko T, Zaneveld J, Knight R (2010) QIIME allows analysis of high-throughput community sequencing data. Nat Methods 7(5):335–336

    Article  CAS  Google Scholar 

  16. Stach SC et al (2015) Placental transfer of IgG antibodies specific to Klebsiella and Pseudomonas LPS and to group B Streptococcus in twin pregnancies. Scand J Immunol 81(2):135–141

    Article  CAS  Google Scholar 

  17. Altman SPN, Tino-de-Franco M, Carbonare CB, Palmeira P, Carbonare SB (2017) Placental and colostral transfer of antibodies reactive with enteropathogenic Escherichia coli intimins alpha, beta, or gamma. J Pediatr 93(6):568–575

    Article  Google Scholar 

  18. Finne J, Leinonen M, Makela PH (1983) Antigenic similarities between brain components and bacteria causing meningitis. Implications for vaccine development and pathogenesis. Lancet 2(8346):355–357

    Article  CAS  Google Scholar 

  19. Bogdanos DP, Sakkas LI (2017) From microbiome to infectome in autoimmunity. Curr Opin Rheumatol 29(4):369–373

    Article  CAS  Google Scholar 

  20. Schwimmbeck PL, Yu DT, Oldstone MB (1987) Autoantibodies to HLA B27 in the sera of HLA B27 patients with ankylosing spondylitis and Reiter's syndrome. Molecular mimicry with Klebsiella pneumoniae as potential mechanism of autoimmune disease. J Exp Med 166(1):173–181

    Article  CAS  Google Scholar 

  21. Nobrega C, Nunes-Alves C, Cerqueira-Rodrigues B, Roque S, Barreira-Silva P, Behar SM, Correia-Neves M (2013) T cells home to the thymus and control infection. J Immunol 190(4):1646–1658

    Article  CAS  Google Scholar 

  22. Radovich M, Pickering CR, Felau I, Ha G, Zhang H, Jo H, Hoadley KA, Anur P, Zhang J, McLellan M, Bowlby R, Matthew T, Danilova L, Hegde AM, Kim J, Leiserson MDM, Sethi G, Lu C, Ryan M, Su X, Cherniack AD, Robertson G, Akbani R, Spellman P, Weinstein JN, Hayes DN, Raphael B, Lichtenberg T, Leraas K, Zenklusen JC, Fujimoto J, Scapulatempo-Neto C, Moreira AL, Hwang D, Huang J, Marino M, Korst R, Giaccone G, Gokmen-Polar Y, Badve S, Rajan A, Ströbel P, Girard N, Tsao MS, Marx A, Tsao AS, Loehrer PJ, Ally A, Appelbaum EL, Auman JT, Balasundaram M, Balu S, Behera M, Beroukhim R, Berrios M, Blandino G, Bodenheimer T, Bootwalla MS, Bowen J, Brooks D, Carcano FM, Carlsen R, Carvalho AL, Castro P, Chalabreysse L, Chin L, Cho J, Choe G, Chuah E, Chudamani S, Cibulskis C, Cope L, Cordes MG, Crain D, Curley E, Defreitas T, Demchok JA, Detterbeck F, Dhalla N, Dienemann H, Edenfield WJ, Facciolo F, Ferguson ML, Frazer S, Fronick CC, Fulton LA, Fulton RS, Gabriel SB, Gardner J, Gastier-Foster JM, Gehlenborg N, Gerken M, Getz G, Heiman DI, Hobensack S, Holbrook A, Holt RA, Hoyle AP, Hutter CM, Ittmann M, Jefferys SR, Jones CD, Jones SJM, Kasaian K, Kim J, Kimes PK, Lai PH, Laird PW, Lawrence MS, Lin P, Liu J, Lolla L, Lu Y, Ma Y, Maglinte DT, Mallery D, Mardis ER, Marra MA, Martin J, Mayo M, Meier S, Meister M, Meng S, Meyerson M, Mieczkowski PA, Miller CA, Mills GB, Moore RA, Morris S, Mose LE, Muley T, Mungall AJ, Mungall K, Naresh R, Newton Y, Noble MS, Owonikoko T, Parker JS, Paulaskis J, Penny R, Perou CM, Perrin C, Pihl T, Radenbaugh A, Ramalingam S, Ramirez N, Rieker R, Roach J, Sadeghi S, Saksena G, Schein JE, Schmidt HK, Schumacher SE, Shelton C, Shelton T, Shi Y, Shih J, Sica G, Silveira HCS, Simons JV, Sipahimalani P, Skelly T, Sofia HJ, Soloway MG, Stuart J, Sun Q, Tam A, Tan D, Tarnuzzer R, Thiessen N, van den Berg DJ, Vasef MA, Veluvolu U, Voet D, Walter V, Wan Y, Wang Z, Warth A, Weis CA, Weisenberger DJ, Wilkerson MD, Wise L, Wong T, Wu HT, Wu Y, Yang L, Zhang J, Zmuda E (2018) The integrated genomic landscape of thymic epithelial tumors. Cancer Cell 33(2):244–258 e10

    Article  CAS  Google Scholar 

  23. Meyer M, Höls AK, Liersch B, Leistner R, Gellert K, Schalke B, Marx A, Niedobitek G (2011) Lack of evidence for Epstein-Barr virus infection in myasthenia gravis thymus. Ann Neurol 70(3):515–518

    Article  Google Scholar 

  24. Hale JS, Fink PJ (2009) Back to the thymus: peripheral T cells come home. Immunol Cell Biol 87(1):58–64

    Article  CAS  Google Scholar 

  25. Nobrega C, Roque S, Nunes-Alves C, Coelho A, Medeiros I, Castro AG, Appelberg R, Correia-Neves M (2010) Dissemination of mycobacteria to the thymus renders newly generated T cells tolerant to the invading pathogen. J Immunol 184(1):351–358

    Article  CAS  Google Scholar 

  26. Villegas JA, Gradolatto A, Truffault F, Roussin R, Berrih-Aknin S, le Panse R, Dragin N (2018) Cultured human thymic-derived cells display medullary thymic epithelial cell phenotype and functionality. Front Immunol 9:1663

    Article  Google Scholar 

  27. Bach JF (2018) The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat Rev Immunol 18(2):105–120

    Article  CAS  Google Scholar 

  28. Cordiglieri C, Marolda R, Franzi S, Cappelletti C, Giardina C, Motta T, Baggi F, Bernasconi P, Mantegazza R, Cavalcante P (2014) Innate immunity in myasthenia gravis thymus: pathogenic effects of toll-like receptor 4 signaling on autoimmunity. J Autoimmun 52:74–89

    Article  CAS  Google Scholar 

  29. Gu L et al (2018) Toll like receptor 4 signaling licenses the cytosolic transport of lipopolysaccharide from bacterial outer membrane vesicles. Shock

  30. Ramos-Fransi A, Rojas-García R, Segovia S, Márquez-Infante C, Pardo J, Coll-Cantí J, Jericó I, Illa I, Myasthenia NMD-ES Study Group (2015) Myasthenia gravis: descriptive analysis of life-threatening events in a recent nationwide registry. Eur J Neurol 22(7):1056–1061

    Article  CAS  Google Scholar 

  31. Mendes-da-Cruz DA, de Meis J, Cotta-de-Almeida V, Savino W (2003) Experimental Trypanosoma cruzi infection alters the shaping of the central and peripheral T-cell repertoire. Microbes Infect 5(10):825–832

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (81571173).

Author information

Authors and Affiliations

Authors

Contributions

L.-Q.X., Z.-H.L. and H.Y. conceived and designed this study. Z.-B.L., H.-Y.M., Y.L., S.-M.Y., and W.-L.J. conducted the experiment. Z.-B.L. performed data analysis and wrote the manuscript. H.Y. contributed to editing of the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Huan Yang.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee for Human Research, Central South University (reference number: 201703107) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 845 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Z., Li, Y., Meng, H. et al. Detection of Microbiota from Human Thymus of Myasthenia Gravis. Indian J Surg 82, 1100–1106 (2020). https://doi.org/10.1007/s12262-020-02202-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12262-020-02202-1

Keywords

Navigation