Skip to main content

Advertisement

SpringerLink
Log in

Intrathymic Tfh/B Cells Interaction Leads to Ectopic GCs Formation and Anti-AChR Antibody Production: Central Role in Triggering MG Occurrence

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Myasthenia gravis is a typical acetylcholine receptor (AChR) antibody-mediated autoimmune disease in which thymus frequently presents follicular hyperplasia or thymoma. It is now widely accepted that the thymus is probably the site of AChR autosensitization and autoantibody production. However, the exact mechanism that triggers intrathymic AChR antibody production is still unknown. T follicular helper cells, recently identified responsible for B cell maturation and antibody production in the secondary lymphoid organs, were involved in many autoimmune diseases. Newly studies found T follicular helper (Tfh) cells increased in the peripheral blood of myasthenia gravis (MG). Whether it appears in the thymus of MG and its role in the intrathymic B cells help and autoantibody production is unclear. Therefore, this study aims to determine in more detail whether Tfh/B cell interaction exist in MG thymus and to address its role in the ectopic germinal centers (GCs) formation and AChR antibody production. We observed the frequency of Tfh cells and its associated transcription factor Bcl-6, key cytokine IL-21 enhanced both in the thymocytes and peripheral blood mononuclear cells (PBMCs) of MG patients. In parallel, we also showed increased B cells and autoantibody titers in MG peripheral blood and thymus. Confocal microscope results demonstrated Tfh and B cells co-localized within the ectopic GCs in MG thymus, suggesting putative existence of Tfh/B cells interaction. In vitro studies further showed dynamic behavior of Tfh/B cells interaction and Tfh cells induced autoantibody secretion might through its effector cytokine IL-21. Altogether, our data demonstrated that intrathymic Tfh/B cells interaction played a key role in thymic ectopic GCs formation and anti-AChR antibody production, which might trigger MG occurrence.

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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Patrick J, Lindstrom J (1973) Autoimmune response to acetylcholine receptor. Science 180(4088):871–872

    Article  CAS  PubMed  Google Scholar 

  2. Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A (2001) Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7(3):365–368

    Article  CAS  PubMed  Google Scholar 

  3. Higuchi O, Hamuro J, Motomura M, Yamanashi Y (2011) Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol 69(2):418–422

    Article  CAS  PubMed  Google Scholar 

  4. Zhang B, Tzartos JS, Belimezi M, Ragheb S, Bealmear B, Lewis RA, Xiong WC, Lisak RP, Tzartos SJ, Mei L (2012) Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol 69(4):445–451

    Article  PubMed  Google Scholar 

  5. Marx A, Pfister F, Schalke B, Saruhan-Direskeneli G, Melms A, Strobel 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  PubMed  Google Scholar 

  6. Cavalcante P, Le Panse R, Berrih-Aknin S, Maggi L, Antozzi C, Baggi F, Bernasconi P, Mantegazza R (2011) The thymus in myasthenia gravis: site of “innate autoimmunity”? Muscle Nerve 44(4):467–484

    Article  PubMed  Google Scholar 

  7. Spillane J, Hayward M, Hirsch NP, Taylor C, Kullmann DM, Howard RS (2013) Thymectomy: role in the treatment of myasthenia gravis. J Neurol 260(7):1798–1801

    Article  CAS  PubMed  Google Scholar 

  8. Hohlfeld R, Wekerle H (2008) Reflections on the “intrathymic pathogenesis” of myasthenia gravis. J Neuroimmunol 201–202:21–27

    Article  PubMed  Google Scholar 

  9. Le Panse R, Cizeron-Clairac G, Bismuth J, Berrih-Aknin S (2006) Microarrays reveal distinct gene signatures in the thymus of seropositive and seronegative myasthenia gravis patients and the role of CC chemokine ligand 21 in thymic hyperplasia. J Immunol 177(11):7868–7879

    Article  PubMed  PubMed Central  Google Scholar 

  10. Weiss JM, Cufi P, Bismuth J, Eymard B, Fadel E, Berrih-Aknin S, Le Panse R (2013) SDF-1/CXCL12 recruits B cells and antigen-presenting cells to the thymus of autoimmune myasthenia gravis patients. Immunobiology 218(3):373–381

    Article  CAS  PubMed  Google Scholar 

  11. Zhang M, Guo J, Li H, Zhou Y, Tian F, Gong L, Wang X, Li Z, Zhang W (2013) Expression of immune molecules CD25 and CXCL13 correlated with clinical severity of myasthenia gravis. J Mol Neurosci MN 50(2):317–323

    Article  CAS  PubMed  Google Scholar 

  12. Berrih-Aknin SR, Raqheb S, Le Panse R, Lisak RP (2013) Ectopic germinal centers, BAFF and anti-B-cell therapy in myasthenia gravis. Autoimmun Rev 12:885–893

    Article  CAS  PubMed  Google Scholar 

  13. Berrih-Aknin S, Ruhlmann N, Bismuth J, Cizeron-Clairac G, Zelman E, Shachar I, Dartevelle P, de Rosbo NK, Le Panse R (2009) CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myasthenia. Ann Neurol 66(4):521–531

    Article  CAS  PubMed  Google Scholar 

  14. Meraouna A, Cizeron-Clairac G, Le Panse R, Bismuth J, Truffault F, Tallaksen C et al (2006) The chemokine CXCL1 3 is a key molecule in autoimmune myasthenia gravis. Blood 108:432–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cavalcante P, Cufi P, Mantegazza R, Berrih-Aknin S, Bernasconi P, Le Panse R (2013) Etiology of myasthenia gravis: innate immunity signature in pathological thymus. Autoimmun Rev 12(9):863–874

    Article  CAS  PubMed  Google Scholar 

  16. Tangye SG, Ma CS, Brink R, Deenick EK (2013) The good, the bad and the ugly—TFH cells in human health and disease. Nat Rev Immunol 13(6):412–426

    Article  CAS  PubMed  Google Scholar 

  17. Ma CS, Deenick EK (2014) Human T follicular helper (Tfh) cells and disease. Immunol Cell Biol 92(1):64–71

    Article  CAS  PubMed  Google Scholar 

  18. Dong W, Zhu P, Wang Y, Wang Z (2011) Follicular helper T cells in systemic lupus erythematosus: a potential therapeutic target. Autoimmun Rev 10(6):299–304

    Article  CAS  PubMed  Google Scholar 

  19. Zhang X, Ing S, Fraser A, Chen M, Khan O, Zakem J, Davis W, Quinet R (2013) Follicular helper T cells: new insights into mechanisms of autoimmune diseases. Ochsner J 13(1):131–139

    PubMed  PubMed Central  Google Scholar 

  20. Wang J, Shan Y, Jiang Z, Feng J, Li C, Ma L, Jiang Y (2013) High frequencies of activated B cells and T follicular helper cells are correlated with disease activity in patients with new-onset rheumatoid arthritis. Clin Exp Immunol 174(2):212–220

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Luo C, Li Y, Liu W, Feng H, Wang H, Huang X, Qiu L, Ouyang J (2013) Expansion of circulating counterparts of follicular helper T cells in patients with myasthenia gravis. J Neuroimmunol 256(1–2):55–61

    Article  CAS  PubMed  Google Scholar 

  22. Saito R, Onodera H, Tago H, Suzuki Y, Shimizu M, Matsumura Y, Kondo T, Itoyama Y (2005) Altered expression of chemokine receptor CXCR5 on T cells of myasthenia gravis patients. J Neuroimmunol 170(1–2):172–178

    Article  CAS  PubMed  Google Scholar 

  23. Jaretzki A 3rd, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, Sanders DB (2000) Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Ann Thorac Surg 70(1):327–334

    Article  PubMed  Google Scholar 

  24. Lindstrom J (1977) An assay for antibodies to human acetylcholine receptor in serum from patients with myasthenia gravis. Clin Immunol Immunopathol 7(1):36–43

    Article  CAS  PubMed  Google Scholar 

  25. Hunter WM, Greenwood FC (1962) Preparation of iodine-131 labelled human growth hormone of high specific activity. Nature 194:495–496

    Article  CAS  PubMed  Google Scholar 

  26. Yu D, Vinuesa CG (2010) The elusive identity of T follicular helper cells. Trends Immunol 31(10):377–383

    Article  CAS  PubMed  Google Scholar 

  27. Yu D, Rao S, Tsai LM, Lee SK, He Y, Sutcliffe EL, Srivastava M, Linterman M, Zheng L, Simpson N, Ellyard JI, Parish IA, Ma CS, Li QJ, Parish CR, Mackay CR, Vinuesa CG (2009) The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31(3):457–468

    Article  CAS  PubMed  Google Scholar 

  28. Chen M, Guo Z, Ju W, Ryffel B, He X, Zheng SG (2012) The development and function of follicular helper T cells in immune responses. Cell Mol Immunol 9(5):375–379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Asthana D, Fujii Y, Huston GE, Lindstrom J (1993) Regulation of antibody production by helper T cell clones in experimental autoimmune myasthenia gravis is mediated by IL-4 and antigen-specific T cell factors. Clin Immunol Immunopathol 67(3 Pt 1):240–248

    Article  CAS  PubMed  Google Scholar 

  30. Link J, Navikas V, Yu M, Fredrikson S, Osterman PO, Link H (1994) Augmented interferon-gamma, interleukin-4 and transforming growth factor-beta mRNA expression in blood mononuclear cells in myasthenia gravis. J Neuroimmunol 51(2):185–192

    Article  CAS  PubMed  Google Scholar 

  31. Yi Q, Ahlberg R, Pirskanen R, Lefvert AK (1994) Acetylcholine receptor-reactive T cells in myasthenia gravis: evidence for the involvement of different subpopulations of T helper cells. J Neuroimmunol 50(2):177–186

    Article  CAS  PubMed  Google Scholar 

  32. Wang ZY, Okita DK, Howard J Jr, Conti-Fine BM (1997) Th1 epitope repertoire on the alpha subunit of human muscle acetylcholine receptor in myasthenia gravis. Neurology 48(6):1643–1653

    Article  CAS  PubMed  Google Scholar 

  33. Kopf M, Le Gros G, Coyle AJ, Kosco-Vilbois M, Brombacher F (1995) Immune responses of IL-4, IL-5, IL-6 deficient mice. Immunol Rev 148:45–69

    Article  CAS  PubMed  Google Scholar 

  34. Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, Foucat E, Dullaers M, Oh S, Sabzghabaei N, Lavecchio EM, Punaro M, Pascual V, Banchereau J, Ueno H (2011) Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34(1):108–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Aloisi F, Pujol-Borrell R (2006) Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 6(3):205–217

    Article  CAS  PubMed  Google Scholar 

  36. Wang W, Milani M, Ostlie N, Okita D, Agarwal RK, Caspi RR, Conti-Fine BM (2007) C57BL/6 mice genetically deficient in IL-12/IL-23 and IFN-gamma are susceptible to experimental autoimmune myasthenia gravis, suggesting a pathogenic role of non-Th1 cells. J Immunol 178(11):7072–7080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Peters A, Lee Y, Kuchroo VK (2011) The many faces of Th17 cells. Curr Opin Immunol 23(6):702–706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work has been supported by the National Natural Science Foundation of China (grants 31270952, 81171977, 81102217, and 31100620). We thank the Department of Thoracic surgery, Tangdu Hospital, and the Department of Cardiovascular Surgery, Xijing Hospital, for the provision of thymus specimen.

Author information

Authors and Affiliations

  1. Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710038, Shaanxi Province, China

    Xiaoyan Zhang, Shasha Liu, Ting Chang, Jiang Xu, Hong Lin & Zhuyi Li

  2. Department of Immunology, The Fourth Military Medical University, Xi’an, 710032, Shaanxi Province, China

    Xiaoyan Zhang, Shasha Liu, Chunmei Zhang, Yuanjie Sun, Chaojun Song & Kun Yang

  3. Department of Neurology, Lanzhou General Hospital, Lanzhou Command of CPLA, Lanzhou, 730050, Gansu Province, China

    Xiaoyan Zhang

  4. Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710038, Shaanxi Province, China

    Feng Tian

  5. Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, Shaanxi Province, China

    Wei Yi

Authors
  1. Xiaoyan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shasha Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ting Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chunmei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Feng Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuanjie Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chaojun Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wei Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hong Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhuyi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhuyi Li or Kun Yang.

Additional information

Xiaoyan Zhang, Shasha Liu, and Ting Chang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Liu, S., Chang, T. et al. Intrathymic Tfh/B Cells Interaction Leads to Ectopic GCs Formation and Anti-AChR Antibody Production: Central Role in Triggering MG Occurrence. Mol Neurobiol 53, 120–131 (2016). https://doi.org/10.1007/s12035-014-8985-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8985-1

Keywords

Search

Navigation