IMMUNE NETWORK

  • 제16권4호
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  • Pages.219-232
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  • 2016
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
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Follicular Helper T (Tfh) Cells in Autoimmune Diseases and Allograft Rejection

  • Yun-Hui Jeon (Department of Biological Sciences, Seoul National University Graduate School) ;
  • Youn Soo Choi (Transplant Research Institute, Department of Medicine, Seoul National University College of Medicine)
  • 투고 : 2016.06.08
  • 심사 : 2016.08.02
  • 발행 : 2016.08.31
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⟨ 이전 논문 다음 논문 ⟩

초록

Production of high affinity antibodies for antigens is a critical component for the immune system to fight off infectious pathogens. However, it could be detrimental to our body when the antigens that B cells recognize are of self-origin. Follicular helper T, or Tfh, cells are required for the generation of germinal center reactions, where high affinity antibody-producing B cells and memory B cells predominantly develop. As such, Tfh cells are considered as targets to prevent B cells from producing high affinity antibodies against self-antigens, when high affinity autoantibodies are responsible for immunopathologies in autoimmune disorders. This review article provides an overview of current understanding of Tfh cells and discusses it in the context of animal models of autoimmune diseases and allograft rejections for generation of novel therapeutic interventions.

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과제정보

This work was supported by Research Resettlement Fund for the new faculty of Seoul National University (to YSC) and research grants SNU invitation program for distinguished scholar (to YSC) and SNUH Research Fund (03-2016-0060) (to YSC).

참고문헌

  1. Murphy, K. 2012. Janeway's Immunobiology. Garland Science. 8th ed. 
  2. Kyewski, B., and L. Klein. 2006. A central role for central tolerance. Annu. Rev. Immunol. 24: 571-606.  https://doi.org/10.1146/annurev.immunol.23.021704.115601
  3. Hardy, R. R., and K. Hayakawa. 2001. B cell development pathways. Annu. Rev. Immunol. 19: 595-621.  https://doi.org/10.1146/annurev.immunol.19.1.595
  4. Sandel, P. C., and J. G. Monroe. 1999. Negative selection of immature B cells by receptor editing or deletion is determined by site of antigen encounter. Immunity 10: 289-299.  https://doi.org/10.1016/S1074-7613(00)80029-1
  5. Goodnow, C. C., S. Adelstein, and A. Basten. 1990. The need for central and peripheral tolerance in the B cell repertoire. Science 248: 1373-1379.  https://doi.org/10.1126/science.2356469
  6. Lim, P. L., and M. Zouali. 2006. Pathogenic autoantibodies: emerging insights into tissue injury. Immunol. Lett. 103: 17-26.  https://doi.org/10.1016/j.imlet.2005.10.023
  7. Baumgarth, N., Y. S. Choi, K. Rothaeusler, Y. Yang, and L. A. Herzenberg. 2008. B cell lineage contributions to antiviral host responses. Curr. Top. Microbiol. Immunol. 319: 41-61. 
  8. Baumgarth, N. 2013. Innate-like B cells and their rules of engagement. Adv. Exp. Med. Biol. 785: 57-66.  https://doi.org/10.1007/978-1-4614-6217-0_7
  9. Cerutti, A., M. Cols, and I. Puga. 2013. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat. Rev. Immunol. 13: 118-132.  https://doi.org/10.1038/nri3383
  10. Victora, G. D., and M. C. Nussenzweig. 2012. Germinal centers. Annu. Rev. Immunol. 30: 429-457.  https://doi.org/10.1146/annurev-immunol-020711-075032
  11. Zhu, J., H. Yamane, and W. E. Paul. 2010. Differentiation of effector CD4 T cell populations (*). Annu. Rev. Immunol. 28: 445-489.  https://doi.org/10.1146/annurev-immunol-030409-101212
  12. Crotty, S. 2011. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29: 621-663.  https://doi.org/10.1146/annurev-immunol-031210-101400
  13. Johnston, R. J., A. C. Poholek, D. DiToro, I. Yusuf, D. Eto, B. Barnett, A. L. Dent, J. Craft, and S. Crotty. 2009. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325: 1006-1010.  https://doi.org/10.1126/science.1175870
  14. Nurieva, R. I., Y. Chung, G. J. Martinez, X. O. Yang, S. Tanaka, T. D. Matskevitch, Y. H. Wang, and C. Dong. 2009. Bcl6 mediates the development of T follicular helper cells. Science 325: 1001-1005.  https://doi.org/10.1126/science.1176676
  15. Yu, D., S. Rao, L. M. Tsai, S. K. Lee, Y. He, E. L. Sutcliffe, M. Srivastava, M. Linterman, L. Zheng, N. Simpson, J. I. Ellyard, I. A. Parish, C. S. Ma, Q. J. Li, C. R. Parish, C. R. Mackay, and C. G. Vinuesa. 2009. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31: 457-468.  https://doi.org/10.1016/j.immuni.2009.07.002
  16. Baumjohann, D., S. Preite, A. Reboldi, F. Ronchi, K. M. Ansel, A. Lanzavecchia, and F. Sallusto. 2013. Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype. Immunity 38: 596-605.  https://doi.org/10.1016/j.immuni.2012.11.020
  17. Ballesteros-Tato, A., B. Leon, B. A. Graf, A. Moquin, P. S. Adams, F. E. Lund, and T. D. Randall. 2012. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36: 847-856.  https://doi.org/10.1016/j.immuni.2012.02.012
  18. Vinuesa, C. G., M. A. Linterman, D. Yu, and I. C. MacLennan. 2016. Follicular Helper T Cells. Annu. Rev. Immunol. 34: 335-368.  https://doi.org/10.1146/annurev-immunol-041015-055605
  19. Plotkin, S. A. 2008. Vaccines: correlates of vaccine-induced immunity. Clin. Infect. Dis. 47: 401-409.  https://doi.org/10.1086/589862
  20. Sherer, Y., A. Gorstein, M. J. Fritzler, and Y. Shoenfeld. 2004. Autoantibody explosion in systemic lupus erythematosus: more than 100 different antibodies found in SLE patients. Semin. Arthritis Rheum. 34: 501-537.  https://doi.org/10.1016/j.semarthrit.2004.07.002
  21. Basso, K., C. Schneider, Q. Shen, A. B. Holmes, M. Setty, C. Leslie, and R. la-Favera. 2012. BCL6 positively regulates AID and germinal center gene expression via repression of miR-155. J. Exp. Med. 209: 2455-2465.  https://doi.org/10.1084/jem.20121387
  22. Kosco-Vilbois, M. H. 2003. Are follicular dendritic cells really good for nothing? Nat. Rev. Immunol. 3: 764-769.  https://doi.org/10.1038/nri1179
  23. MacLennan, I. C. 1994. Germinal centers. Annu. Rev. Immunol. 12: 117-139.  https://doi.org/10.1146/annurev.iy.12.040194.001001
  24. Romagnani, S. 2000. T-cell subsets (Th1 versus Th2). Ann. Allergy Asthma Immunol. 85: 9-18.  https://doi.org/10.1016/S1081-1206(10)62426-X
  25. Andoh, A., A. Masuda, M. Yamakawa, Y. Kumazawa, and T. Kasajima. 2000. Absence of interleukin-4 enhances germinal center reaction in secondary immune response. Immunol. Lett. 73: 35-41. 
  26. Schaerli, P., K. Willimann, A. B. Lang, M. Lipp, P. Loetscher, and B. Moser. 2000. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192: 1553-1562.  https://doi.org/10.1084/jem.192.11.1553
  27. Chtanova, T., S. G. Tangye, R. Newton, N. Frank, M. R. Hodge, M. S. Rolph, and C. R. Mackay. 2004. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J. Immunol. 173: 68-78.  https://doi.org/10.4049/jimmunol.173.1.68
  28. Kim, C. H., H. W. Lim, J. R. Kim, L. Rott, P. Hillsamer, and E. C. Butcher. 2004. Unique gene expression program of human germinal center T helper cells. Blood 104: 1952-1960. 
  29. Rasheed, A. U., H. P. Rahn, F. Sallusto, M. Lipp, and G. Muller. 2006. Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression. Eur. J. Immunol. 36: 1892-1903.  https://doi.org/10.1002/eji.200636136
  30. Kroenke, M. A., D. Eto, M. Locci, M. Cho, T. Davidson, E. K. Haddad, and S. Crotty. 2012. Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J. Immunol. 188: 3734-3744.  https://doi.org/10.4049/jimmunol.1103246
  31. Achenbach, P., K. Koczwara, A. Knopff, H. Naserke, A. G. Ziegler, and E. Bonifacio. 2004. Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes. J. Clin. Invest 114: 589-597.  https://doi.org/10.1172/JCI200421307
  32. Shlomchik, M., M. Mascelli, H. Shan, M. Z. Radic, D. Pisetsky, A. Marshak-Rothstein, and M. Weigert. 1990. Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J. Exp. Med. 171: 265-292.  https://doi.org/10.1084/jem.171.1.265
  33. van Es, J. H., F. H. Gmelig Meyling, W. R. van de Akker, H. Aanstoot, R. H. Derksen, and T. Logtenberg. 1991. Somatic mutations in the variable regions of a human IgG anti-double-stranded DNA autoantibody suggest a role for antigen in the induction of systemic lupus erythematosus. J. Exp. Med. 173: 461-470.  https://doi.org/10.1084/jem.173.2.461
  34. Grammer, A. C., R. Slota, R. Fischer, H. Gur, H. Girschick, C. Yarboro, G. G. Illei, and P. E. Lipsky. 2003. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. J. Clin. Invest 112: 1506-1520.  https://doi.org/10.1172/JCI200319301
  35. Hoyer, B. F., K. Moser, A. E. Hauser, A. Peddinghaus, C. Voigt, D. Eilat, A. Radbruch, F. Hiepe, and R. A. Manz. 2004. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J. Exp. Med. 199: 1577-1584.  https://doi.org/10.1084/jem.20040168
  36. Sanchez, M., Z. Misulovin, A. L. Burkhardt, S. Mahajan, T. Costa, R. Franke, J. B. Bolen, and M. Nussenzweig. 1993. Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta. J. Exp. Med. 178: 1049-1055.  https://doi.org/10.1084/jem.178.3.1049
  37. Heyman, B. 2000. Regulation of antibody responses via antibodies, complement, and Fc receptors. Annu. Rev. Immunol. 18: 709-737.  https://doi.org/10.1146/annurev.immunol.18.1.709
  38. Pone, E. J., H. Zan, J. Zhang, A. Al-Qahtani, Z. Xu, and P. Casali. 2010. Toll-like receptors and B-cell receptors synergize to induce immunoglobulin class-switch DNA recombination: relevance to microbial antibody responses. Crit. Rev. Immunol. 30: 1-29.  https://doi.org/10.1615/CritRevImmunol.v30.i1.10
  39. Pelanda, R., U. Braun, E. Hobeika, M. C. Nussenzweig, and M. Reth. 2002. B cell progenitors are arrested in maturation but have intact VDJ recombination in the absence of Ig-alpha and Ig-beta. J. Immunol. 169: 865-872.  https://doi.org/10.4049/jimmunol.169.2.865
  40. Soni, C., E. B. Wong, P. P. Domeier, T. N. Khan, T. Satoh, S. Akira, and Z. S. Rahman. 2014. B cell-intrinsic TLR7 signaling is essential for the development of spontaneous germinal centers. J. Immunol. 193: 4400-4414.  https://doi.org/10.4049/jimmunol.1401720
  41. Clingan, J. M., and M. Matloubian. 2013. B Cell-intrinsic TLR7 signaling is required for optimal B cell responses during chronic viral infection. J. Immunol. 191: 810-818.  https://doi.org/10.4049/jimmunol.1300244
  42. Domeier, P. P., S. B. Chodisetti, C. Soni, S. L. Schell, M. J. Elias, E. B. Wong, T. K. Cooper, D. Kitamura, and Z. S. Rahman. 2016. IFN-gamma receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity. J. Exp. Med. 213: 715-732.  https://doi.org/10.1084/jem.20151722
  43. Cantin, E., B. Tanamachi, H. Openshaw, J. Mann, and K. Clarke. 1999. Gamma interferon (IFN-gamma) receptor null-mutant mice are more susceptible to herpes simplex virus type 1 infection than IFN-gamma ligand null-mutant mice. J. Virol. 73: 5196-5200.  https://doi.org/10.1128/JVI.73.6.5196-5200.1999
  44. Kjerrulf, M., D. Grdic, L. Ekman, K. Schon, M. Vajdy, and N. Y. Lycke. 1997. Interferon-gamma receptor-deficient mice exhibit impaired gut mucosal immune responses but intact oral tolerance. Immunology 92: 60-68.  https://doi.org/10.1046/j.1365-2567.1997.00312.x
  45. Vinuesa, C. G., M. C. Cook, C. Angelucci, V. Athanasopoulos, L. Rui, K. M. Hill, D. Yu, H. Domaschenz, B. Whittle, T. Lambe, I. S. Roberts, R. R. Copley, J. I. Bell, R. J. Cornall, and C. C. Goodnow. 2005. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435: 452-458.  https://doi.org/10.1038/nature03555
  46. Leppek, K., J. Schott, S. Reitter, F. Poetz, M. C. Hammond, and G. Stoecklin. 2013. Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs. Cell 153: 869-881.  https://doi.org/10.1016/j.cell.2013.04.016
  47. Vogel, K. U., S. L. Edelmann, K. M. Jeltsch, A. Bertossi, K. Heger, G. A. Heinz, J. Zoller, S. C. Warth, K. P. Hoefig, C. Lohs, F. Neff, E. Kremmer, J. Schick, D. Repsilber, A. Geerlof, H. Blum, W. Wurst, M. Heikenwalder, M. Schmidt-Supprian, and V. Heissmeyer. 2013. Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation. Immunity 38: 655-668.  https://doi.org/10.1016/j.immuni.2012.12.004
  48. Choi, Y. S., R. Kageyama, D. Eto, T. C. Escobar, R. J. Johnston, L. Monticelli, C. Lao, and S. Crotty. 2011. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 34: 932-946.  https://doi.org/10.1016/j.immuni.2011.03.023
  49. Nurieva, R. I., Y. Chung, D. Hwang, X. O. Yang, H. S. Kang, L. Ma, Y. H. Wang, S. S. Watowich, A. M. Jetten, Q. Tian, and C. Dong. 2008. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29: 138-149.  https://doi.org/10.1016/j.immuni.2008.05.009
  50. Lee, S. K., D. G. Silva, J. L. Martin, A. Pratama, X. Hu, P. P. Chang, G. Walters, and C. G. Vinuesa. 2012. Interferon-gamma excess leads to pathogenic accumulation of follicular helper T cells and germinal centers. Immunity 37: 880-892.  https://doi.org/10.1016/j.immuni.2012.10.010
  51. Pisitkun, P., J. A. Deane, M. J. Difilippantonio, T. Tarasenko, A. B. Satterthwaite, and S. Bolland. 2006. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312: 1669-1672.  https://doi.org/10.1126/science.1124978
  52. Bubier, J. A., T. J. Sproule, O. Foreman, R. Spolski, D. J. Shaffer, H. C. Morse, III, W. J. Leonard, and D. C. Roopenian. 2009. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc. Natl. Acad. Sci. U. S. A. 106: 1518-1523.  https://doi.org/10.1073/pnas.0807309106
  53. Wei, L., A. Laurence, K. M. Elias, and J. J. O'Shea. 2007. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J. Biol. Chem. 282: 34605-34610.  https://doi.org/10.1074/jbc.M705100200
  54. Zotos, D., J. M. Coquet, Y. Zhang, A. Light, K. D'Costa, A. Kallies, L. M. Corcoran, D. I. Godfrey, K. M. Toellner, M. J. Smyth, S. L. Nutt, and D. M. Tarlinton. 2010. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 207: 365-378.  https://doi.org/10.1084/jem.20091777
  55. Ozaki, K., R. Spolski, C. G. Feng, C. F. Qi, J. Cheng, A. Sher, H. C. Morse, III, C. Liu, P. L. Schwartzberg, and W. J. Leonard. 2002. A critical role for IL-21 in regulating immunoglobulin production. Science 298: 1630-1634.  https://doi.org/10.1126/science.1077002
  56. Watanabe-Fukunaga, R., C. I. Brannan, N. G. Copeland, N. A. Jenkins, and S. Nagata. 1992. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356: 314-317.  https://doi.org/10.1038/356314a0
  57. Jacobson, B. A., D. J. Panka, K. A. Nguyen, J. Erikson, A. K. Abbas, and A. Marshak-Rothstein. 1995. Anatomy of autoantibody production: dominant localization of antibody-producing cells to T cell zones in Fas-deficient mice. Immunity 3: 509-519.  https://doi.org/10.1016/1074-7613(95)90179-5
  58. Odegard, J. M., B. R. Marks, L. D. DiPlacido, A. C. Poholek, D. H. Kono, C. Dong, R. A. Flavell, and J. Craft. 2008. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J. Exp. Med. 205: 2873-2886.  https://doi.org/10.1084/jem.20080840
  59. Poholek, A. C., K. Hansen, S. G. Hernandez, D. Eto, A. Chandele, J. S. Weinstein, X. Dong, J. M. Odegard, S. M. Kaech, A. L. Dent, S. Crotty, and J. Craft. 2010. In vivo regulation of Bcl6 and T follicular helper cell development. J. Immunol. 185: 313-326.  https://doi.org/10.4049/jimmunol.0904023
  60. Helyer, B. J., and J. B. Howie. 1963. Renal disease associated with positive lupus erythematosus tests in a cross-bred strain of mice. Nature 197: 197. 
  61. Jacob, C. O., P. H. van der Meide, and H. O. McDevitt. 1987. In vivo treatment of (NZB X NZW)F1 lupus-like nephritis with monoclonal antibody to gamma interferon. J. Exp. Med. 166: 798-803.  https://doi.org/10.1084/jem.166.3.798
  62. Nicoletti, F., P. Meroni, M. R. Di, W. Barcellini, M. O. Borghi, M. Gariglio, A. Mattina, S. Grasso, and S. Landolfo. 1992. In vivo treatment with a monoclonal antibody to interferon-gamma neither affects the survival nor the incidence of lupusnephritis in the MRL/lpr-lpr mouse. Immunopharmacology 24: 11-16.  https://doi.org/10.1016/0162-3109(92)90064-J
  63. Mountz, J. D., P. Yang, Q. Wu, J. Zhou, A. Tousson, A. Fitzgerald, J. Allen, X. Wang, S. Cartner, W. E. Grizzle, N. Yi, L. Lu, R. W. Williams, and H. C. Hsu. 2005. Genetic segregation of spontaneous erosive arthritis and generalized autoimmune disease in the BXD2 recombinant inbred strain of mice. Scand. J. Immunol. 61: 128-138.  https://doi.org/10.1111/j.0300-9475.2005.01548.x
  64. Kim, Y. U., H. Lim, H. E. Jung, R. A. Wetsel, and Y. Chung. 2015. Regulation of autoimmune germinal center reactions in lupus-prone BXD2 mice by follicular helper T cells. PLoS One 10: e0120294. 
  65. Ding, Y., J. Li, P. Yang, B. Luo, Q. Wu, A. J. Zajac, O. Wildner, H. C. Hsu, and J. D. Mountz. 2014. Interleukin-21 promotes germinal center reaction by skewing the follicular regulatory T cell to follicular helper T cell balance in autoimmune BXD2 mice. Arthritis Rheumatol. 66: 2601-2612.  https://doi.org/10.1002/art.38735
  66. Scott, D. L., F. Wolfe, and T. W. Huizinga. 2010. Rheumatoid arthritis. Lancet 376: 1094-1108.  https://doi.org/10.1016/S0140-6736(10)60826-4
  67. Weyand, C. M., K. C. Hicok, D. L. Conn, and J. J. Goronzy. 1992. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann. Intern. Med. 117: 801-806.  https://doi.org/10.7326/0003-4819-117-10-801
  68. Liu, R., Q. Wu, D. Su, N. Che, H. Chen, L. Geng, J. Chen, W. Chen, X. Li, and L. Sun. 2012. A regulatory effect of IL21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis Res. Ther. 14: R255. 
  69. Monach, P. A., D. Mathis, and C. Benoist. 2008. The K/BxN arthritis model. Curr. Protoc. Immunol. Chapter 15: Unit 15.22. 
  70. Korganow, A. S., H. Ji, S. Mangialaio, V. Duchatelle, R. Pelanda, T. Martin, C. Degott, H. Kikutani, K. Rajewsky, J. L. Pasquali, C. Benoist, and D. Mathis. 1999. From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity 10: 451-461.  https://doi.org/10.1016/S1074-7613(00)80045-X
  71. Block, K. E., and H. Huang. 2013. The cellular source and target of IL-21 in K/BxN autoimmune arthritis. J. Immunol. 191: 2948-2955.  https://doi.org/10.4049/jimmunol.1301173
  72. Chaiamnuay, S., and S. L. Bridges, Jr. 2005. The role of B cells and autoantibodies in rheumatoid arthritis. Pathophysiology 12: 203-216.  https://doi.org/10.1016/j.pathophys.2005.07.007
  73. Kyburz, D., D. A. Carson, and M. Corr. 2000. The role of CD40 ligand and tumor necrosis factor alpha signaling in the transgenic K/BxN mouse model of rheumatoid arthritis. Arthritis Rheum. 43: 2571-2577.  https://doi.org/10.1002/1529-0131(200011)43:11<2571::AID-ANR26>3.0.CO;2-4
  74. Eisenstein, E. M., and C. B. Williams. 2009. The T(reg)/Th17 cell balance: a new paradigm for autoimmunity. Pediatr. Res. 65: 26R-31R.  https://doi.org/10.1203/PDR.0b013e31819e76c7
  75. Leipe, J., M. Grunke, C. Dechant, C. Reindl, U. Kerzendorf, H. Schulze-Koops, and A. Skapenko. 2010. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum. 62: 2876-2885.  https://doi.org/10.1002/art.27622
  76. Jacobs, J. P., H. J. Wu, C. Benoist, and D. Mathis. 2009. IL-17-producing T cells can augment autoantibody-induced arthritis. Proc. Natl. Acad. Sci. U. S. A. 106: 21789-21794.  https://doi.org/10.1073/pnas.0912152106
  77. Maccioni, M., G. Zeder-Lutz, H. Huang, C. Ebel, P. Gerber, J. Hergueux, P. Marchal, V. Duchatelle, C. Degott, R. M. van, C. Benoist, and D. Mathis. 2002. Arthritogenic monoclonal antibodies from K/BxN mice. J. Exp. Med. 195: 1071-1077.  https://doi.org/10.1084/jem.20011941
  78. Sakaguchi, N., T. Takahashi, H. Hata, T. Nomura, T. Tagami, S. Yamazaki, T. Sakihama, T. Matsutani, I. Negishi, S. Nakatsuru, and S. Sakaguchi. 2003. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426: 454-460.  https://doi.org/10.1038/nature02119
  79. Brand, D. D., K. A. Latham, and E. F. Rosloniec. 2007. Collagen-induced arthritis. Nat. Protoc. 2: 1269-1275.  https://doi.org/10.1038/nprot.2007.173
  80. Hu, Y. L., D. P. Metz, J. Chung, G. Siu, and M. Zhang. 2009. B7RP-1 blockade ameliorates autoimmunity through regulation of follicular helper T cells. J. Immunol. 182: 1421-1428.  https://doi.org/10.4049/jimmunol.182.3.1421
  81. Frohman, E. M., M. K. Racke, and C. S. Raine. 2006. Multiple sclerosis--the plaque and its pathogenesis. N. Engl. J. Med. 354: 942-955.  https://doi.org/10.1056/NEJMra052130
  82. Ramagopalan, S. V., J. C. Knight, and G. C. Ebers. 2009. Multiple sclerosis and the major histocompatibility complex. Curr. Opin. Neurol. 22: 219-225.  https://doi.org/10.1097/WCO.0b013e32832b5417
  83. Damsker, J. M., A. M. Hansen, and R. R. Caspi. 2010. Th1 and Th17 cells: adversaries and collaborators. Ann. N. Y. Acad. Sci. 1183: 211-221.  https://doi.org/10.1111/j.1749-6632.2009.05133.x
  84. Weber, M. S., B. Hemmer, and S. Cepok. 2011. The role of antibodies in multiple sclerosis. Biochim. Biophys. Acta 1812: 239-245.  https://doi.org/10.1016/j.bbadis.2010.06.009
  85. Zhou, D., R. Srivastava, S. Nessler, V. Grummel, N. Sommer, W. Bruck, H. P. Hartung, C. Stadelmann, and B. Hemmer. 2006. Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis. Proc. Natl. Acad. Sci. U. S. A. 103: 19057-19062.  https://doi.org/10.1073/pnas.0607242103
  86. Tzartos, J. S., M. J. Craner, M. A. Friese, K. B. Jakobsen, J. Newcombe, M. M. Esiri, and L. Fugger. 2011. IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. Am. J. Pathol. 178: 794-802.  https://doi.org/10.1016/j.ajpath.2010.10.043
  87. Domingues, H. S., M. Mues, H. Lassmann, H. Wekerle, and G. Krishnamoorthy. 2010. Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. PLoS One 5: e15531. 
  88. Miller, S. D., W. J. Karpus, and T. S. Davidson. 2010. Experimental autoimmune encephalomyelitis in the mouse. Curr. Protoc. Immunol. Chapter 15: Unit 15.1. 
  89. Magliozzi, R., O. Howell, A. Vora, B. Serafini, R. Nicholas, M. Puopolo, R. Reynolds, and F. Aloisi. 2007. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130: 1089-1104. 
  90. Peters, A., L. A. Pitcher, J. M. Sullivan, M. Mitsdoerffer, S. E. Acton, B. Franz, K. Wucherpfennig, S. Turley, M. C. Carroll, R. A. Sobel, E. Bettelli, and V. K. Kuchroo. 2011. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35: 986-996.  https://doi.org/10.1016/j.immuni.2011.10.015
  91. Mahad, D. H., B. D. Trapp, and H. Lassmann. 2015. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 14: 183-193.  https://doi.org/10.1016/S1474-4422(14)70256-X
  92. Sadatipour, B. T., J. M. Greer, and M. P. Pender. 1998. Increased circulating antiganglioside antibodies in primary and secondary progressive multiple sclerosis. Ann. Neurol. 44: 980-983.  https://doi.org/10.1002/ana.410440621
  93. Hauser, S. L., and J. R. Oksenberg. 2006. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52: 61-76.  https://doi.org/10.1016/j.neuron.2006.09.011
  94. Kaushansky, N., D. M. Altmann, S. Ascough, C. S. David, H. Lassmann, and A. Ben-Nun. 2009. HLA-DQB1*0602 determines disease susceptibility in a new "humanized" multiple sclerosis model in HLA-DR15 (DRB1*1501;DQB1*0602) (DRB1*1501;DQB1*0602)  (DRB1*1501;DQB1*0602) transgenic mice. J. Immunol. 183: 3531-3541.  https://doi.org/10.4049/jimmunol.0900784
  95. Kaushansky, N., D. M. Altmann, C. S. David, H. Lassmann, and A. Ben-Nun. 2012. DQB1*0602 rather than DRB1*1501 DRB1*1501  DRB1*1501 confers susceptibility to multiple sclerosis-like disease induced by proteolipid protein (PLP). J. Neuroinflammation. 9: 29. 
  96. Conti-Fine, B. M., M. Milani, and H. J. Kaminski. 2006. Myasthenia gravis: past, present, and future. J. Clin. Invest 116: 2843-2854.  https://doi.org/10.1172/JCI29894
  97. Nichols, P., R. Croxen, A. Vincent, R. Rutter, M. Hutchinson, J. Newsom-Davis, and D. Beeson. 1999. Mutation of the acetylcholine receptor epsilon-subunit promoter in congenital myasthenic syndrome. Ann. Neurol. 45: 439-443.  https://doi.org/10.1002/1531-8249(199904)45:4<439::AID-ANA4>3.0.CO;2-W
  98. Luo, C., Y. Li, W. Liu, H. Feng, H. Wang, X. Huang, L. Qiu, and J. Ouyang. 2013. Expansion of circulating counterparts of follicular helper T cells in patients with myasthenia gravis. J. Neuroimmunol. 256: 55-61.  https://doi.org/10.1016/j.jneuroim.2012.12.001
  99. Fuchs, S., R. Aricha, D. Reuveni, and M. C. Souroujon. 2014. Experimental Autoimmune Myasthenia Gravis (EAMG): from immunochemical characterization to therapeutic approaches. J. Autoimmun. 54: 51-59.  https://doi.org/10.1016/j.jaut.2014.06.003
  100. Wu, B., E. Goluszko, R. Huda, E. Tuzun, and P. Christadoss. 2013. Experimental autoimmune myasthenia gravis in the mouse. Curr. Protoc. Immunol. Chapter 15: Unit 15.8. 
  101. Xin, N., L. Fu, Z. Shao, M. Guo, X. Zhang, Y. Zhang, C. Dou, S. Zheng, X. Shen, Y. Yao, J. Wang, J. Wang, G. Cui, Y. Liu, D. Geng, C. Xiao, Z. Zhang, and R. Dong. 2014. RNA interference targeting Bcl-6 ameliorates experimental autoimmune myasthenia gravis in mice. Mol. Cell. Neurosci. 58: 85-94.  https://doi.org/10.1016/j.mcn.2013.12.006
  102. Borchers, A. T., S. M. Naguwa, C. L. Keen, and M. E. Gershwin. 2003. Immunopathogenesis of Sjogren's syndrome. Clin. Rev. Allergy Immunol. 25: 89-104.  https://doi.org/10.1385/CRIAI:25:1:89
  103. Chaigne, B., G. Lasfargues, I. Marie, B. Huttenberger, C. Lavigne, S. Marchand-Adam, F. Maillot, and E. Diot. 2015. Primary Sjogren's syndrome and occupational risk factors: A case-control study. J. Autoimmun. 60: 80-85.  https://doi.org/10.1016/j.jaut.2015.04.004
  104. Priori, R., E. Medda, F. Conti, E. A. Cassara, M. G. Sabbadini, C. M. Antonioli, R. Gerli, M. G. Danieli, R. Giacomelli, M. Pietrogrande, G. Valesini, and M. A. Stazi. 2007. Risk factors for Sjogren's syndrome: a case-control study. Clin. Exp. Rheumatol. 25: 378-384. 
  105. Aggarwal, R., J. M. Anaya, K. A. Koelsch, B. T. Kurien, and R. H. Scofield. 2015. Association between secondary and primary Sjogren's syndrome in a large collection of lupus families. Autoimmune Dis. 2015: 298506. 
  106. Ben-Chetrit, E., R. Fischel, and A. Rubinow. 1993. Anti-SSA/Ro and anti-SSB/La antibodies in serum and saliva of patients with Sjogren's syndrome. Clin. Rheumatol. 12: 471-474.  https://doi.org/10.1007/BF02231773
  107. Jin, L., D. Yu, X. Li, N. Yu, X. Li, Y. Wang, and Y. Wang. 2014. CD4+CXCR5+ follicular helper T cells in salivary gland promote B cells maturation in patients with primary Sjogren's syndrome. Int. J. Clin. Exp. Pathol. 7: 1988-1996. 
  108. Li, X. Y., Z. B. Wu, J. Ding, Z. H. Zheng, X. Y. Li, L. N. Chen, and P. Zhu. 2012. Role of the frequency of blood CD4(+) CXCR5(+) CCR6(+) T cells in autoimmunity in patients with Sjogren's syndrome. Biochem. Biophys. Res. Commun. 422: 238-244.  https://doi.org/10.1016/j.bbrc.2012.04.133
  109. Park, Y. S., A. E. Gauna, and S. Cha. 2015. Mouse Models of Primary Sjogren's Syndrome. Curr. Pharm. Des 21: 2350-2364.  https://doi.org/10.2174/1381612821666150316120024
  110. Manning, D. D., N. D. Reed, and C. F. Shaffer. 1973. Maintenance of skin xenografts of widely divergent phylogenetic origin of congenitally athymic (nude) mice. J. Exp. Med. 138: 488-494.  https://doi.org/10.1084/jem.138.2.488
  111. Larsen, C. P., S. J. Knechtle, A. Adams, T. Pearson, and A. D. Kirk. 2006. A new look at blockade of T-cell costimulation: a therapeutic strategy for long-term maintenance immunosuppression. Am. J. Transplant. 6: 876-883.  https://doi.org/10.1111/j.1600-6143.2006.01259.x
  112. Ziolkowski, J., L. Paczek, M. Niewczas, G. Senatorski, U. Oldakowska-Jedynak, J. Wyzgal, B. Foroncewicz, K. Mucha, J. Zegarska, P. Nyckowski, K. Zieniewicz, W. Patkowski, M. Krawczyk, B. Ziarkiewicz-Wroblewska, and B. Gornicka. 2003. Effect of immunosuppressive regimen on acute rejection and liver graft function. Transplant. Proc. 35: 2281-2283.  https://doi.org/10.1016/S0041-1345(03)00794-2
  113. Colvin, R. B., and R. N. Smith. 2005. Antibody-mediated organ-allograft rejection. Nat. Rev. Immunol. 5: 807-817.  https://doi.org/10.1038/nri1702
  114. Jindra, P. T., A. Hsueh, L. Hong, D. Gjertson, X. D. Shen, F. Gao, J. Dang, P. S. Mischel, W. M. Baldwin, III, M. C. Fishbein, J. W. Kupiec-Weglinski, and E. F. Reed. 2008. Anti-MHC class I antibody activation of proliferation and survival signaling in murine cardiac allografts. J. Immunol. 180: 2214-2224.  https://doi.org/10.4049/jimmunol.180.4.2214
  115. Clatworthy, M. R. 2011. Targeting B cells and antibody in transplantation. Am. J. Transplant. 11: 1359-1367.  https://doi.org/10.1111/j.1600-6143.2011.03554.x
  116. Gorbacheva, V., K. Ayasoufi, R. Fan, W. M. Baldwin, III, and A. Valujskikh. 2015. B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) mediate CD40-independent help by memory CD4 T cells. Am. J. Transplant. 15: 346-357.  https://doi.org/10.1111/ajt.12984
  117. Gorbacheva, V., R. Fan, X. Wang, W. M. Baldwin, III, R. L. Fairchild, and A. Valujskikh. 2015. IFN-gamma production by memory helper T cells is required for CD40-independent alloantibody responses. J. Immunol. 194: 1347-1356. 
  118. Lynch, R. J., I. A. Silva, B. J. Chen, J. D. Punch, M. Cascalho, and J. L. Platt. 2013. Cryptic B cell response to renal transplantation. Am. J. Transplant. 13: 1713-1723.  https://doi.org/10.1111/ajt.12308
  119. de Graav, G. N., M. Dieterich, D. A. Hesselink, K. Boer, M. C. Clahsen-van Groningen, R. Kraaijeveld, N. H. Litjens, R. Bouamar, J. Vanderlocht, M. Tilanus, I. Houba, A. Boonstra, D. L. Roelen, F. H. Claas, M. G. Betjes, W. Weimar, and C. C. Baan. 2015. Follicular T helper cells and humoral reactivity in kidney transplant patients. Clin. Exp. Immunol. 180: 329-340.  https://doi.org/10.1111/cei.12576
  120. Flynn, R., J. Du, R. G. Veenstra, D. K. Reichenbach, A. Panoskaltsis-Mortari, P. A. Taylor, G. J. Freeman, J. S. Serody, W. J. Murphy, D. H. Munn, S. Sarantopoulos, L. Luznik, I. Maillard, J. Koreth, C. Cutler, R. J. Soiffer, J. H. Antin, J. Ritz, J. A. Dubovsky, J. C. Byrd, K. P. MacDonald, G. R. Hill, and B. R. Blazar. 2014. Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood 123: 3988-3998. https://doi.org/10.1182/blood-2014-03-562231