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

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• 作者：Xiaoyan Zhang ; Shasha Liu ; Ting Chang ; Jiang Xu ; Chunmei Zhang…
• 关键词：Myasthenia gravis ; Follicular helper T cells ; Thymus ; Anti ; acetylcholine receptor antibody ; Germinal centers
• 刊名：Molecular Neurobiology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：53
• 期：1
• 页码：120-131
• 全文大小：5,101 KB
• 参考文献：1.Patrick J, Lindstrom J (1973) Autoimmune response to acetylcholine receptor. Science 180(4088):871–872CrossRef PubMed
  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):365–368CrossRef PubMed
  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):418–422CrossRef PubMed
  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):445–451CrossRef PubMed
  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):875–884CrossRef PubMed
  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):467–484CrossRef PubMed
  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):1798–1801CrossRef PubMed
  8.Hohlfeld R, Wekerle H (2008) Reflections on the “intrathymic pathogenesis” of myasthenia gravis. J Neuroimmunol 201–202:21–27CrossRef PubMed
  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):7868–7879CrossRef PubMed PubMedCentral
  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):373–381CrossRef PubMed
  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):317–323CrossRef PubMed
  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 12:885–893CrossRef PubMed
  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):521–531CrossRef PubMed
  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 108:432–440CrossRef PubMed PubMedCentral
  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):863–874CrossRef PubMed
  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):412–426CrossRef PubMed
  17.Ma CS, Deenick EK (2014) Human T follicular helper (Tfh) cells and disease. Immunol Cell Biol 92(1):64–71CrossRef PubMed
  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):299–304CrossRef PubMed
  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):131–139PubMed PubMedCentral
  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):212–220PubMed PubMedCentral
  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):55–61CrossRef PubMed
  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):172–178CrossRef PubMed
  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):327–334CrossRef PubMed
  24.Lindstrom J (1977) An assay for antibodies to human acetylcholine receptor in serum from patients with myasthenia gravis. Clin Immunol Immunopathol 7(1):36–43CrossRef PubMed
  25.Hunter WM, Greenwood FC (1962) Preparation of iodine-131 labelled human growth hormone of high specific activity. Nature 194:495–496CrossRef PubMed
  26.Yu D, Vinuesa CG (2010) The elusive identity of T follicular helper cells. Trends Immunol 31(10):377–383CrossRef PubMed
  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):457–468CrossRef PubMed
  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):375–379CrossRef PubMed PubMedCentral
  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):240–248CrossRef PubMed
  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):185–192CrossRef PubMed
  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):177–186CrossRef PubMed
  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):1643–1653CrossRef PubMed
  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 148:45–69CrossRef PubMed
  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):108–121CrossRef PubMed PubMedCentral
  35.Aloisi F, Pujol-Borrell R (2006) Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 6(3):205–217CrossRef PubMed
  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):7072–7080CrossRef PubMed PubMedCentral
  37.Peters A, Lee Y, Kuchroo VK (2011) The many faces of Th17 cells. Curr Opin Immunol 23(6):702–706CrossRef PubMed PubMedCentral
  
• 作者单位：Xiaoyan Zhang (1) (2) (3)
  Shasha Liu (1) (2)
  Ting Chang (1)
  Jiang Xu (1)
  Chunmei Zhang (2)
  Feng Tian (4)
  Yuanjie Sun (2)
  Chaojun Song (2)
  Wei Yi (5)
  Hong Lin (1)
  Zhuyi Li (1)
  Kun Yang (2)
  
  1. Department of Neurology, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710038, Shaanxi Province, People’s Republic of China
  2. Department of Immunology, The Fourth Military Medical University, Xi’an, 710032, Shaanxi Province, People’s Republic of China
  3. Department of Neurology, Lanzhou General Hospital, Lanzhou Command of CPLA, Lanzhou, 730050, Gansu Province, People’s Republic of China
  4. Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710038, Shaanxi Province, People’s Republic of China
  5. Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032, Shaanxi Province, People’s Republic of China
  
• 刊物主题：Neurosciences; Neurobiology; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1559-1182

文摘

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.