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T-Cell Abnormalities

  • Takashi SatohEmail author
  • Masataka Kuwana
Chapter

Abstract

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction and reduced platelet production caused primarily by IgG antiplatelet autoantibodies, which mainly target platelet membrane glycoproteins (GPs), including GPIIb/IIIa and GPIb/IX. GPIIb/IIIa-reactive CD4+ T cells play a central role in the pathogenic process by triggering and maintaining antiplatelet autoantibodies. The mechanism for ongoing antiplatelet antibody production is explained by a “pathogenic loop” model consisting of macrophages in the reticuloendothelial system, GPIIb/IIIa-reactive CD4+ T cells, and B cells producing antiplatelet antibodies. Among T helper (Th) cell subsets, Th1 and Th17 cells as well as newly identified T follicular helper (Tfh) cells, which support B cell maturation and differentiation within the germinal center, are actively involved in antiplatelet antibody production. Finally, platelet-reactive CD8+ cytotoxic T cells directly induce lysis and apoptosis of circulating platelets as well as megakaryocytes. On the other hand, CD4+ regulatory T cells (Tregs), which contribute to maintenance of peripheral immune tolerance, are defective in patients with ITP, through decreased numbers and impaired function of Tregs. In fact, mice lacking Foxp3 Tregs spontaneously develop chronic thrombocytopenia mediated through the production of IgG antiplatelet autoantibodies. Further studies evaluating mechanisms for T-cell dysregulation are useful in elucidating the pathogenesis of ITP and in developing novel treatment strategies.

Keywords

Germinal Center Platelet Production Severe Combine Immunodeficiency Mouse Platelet Membrane Glycoprotein Platelet Apoptosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We dedicate this chapter to the late Tetsuya Nishimoto, who had contributed to elucidation of autoimmune mechanisms of ITP.

References

  1. 1.
    Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995–1008.CrossRefPubMedGoogle Scholar
  2. 2.
    McMillan R. Autoantibodies and autoantigens in chronic immune thrombocytopenic purpura. Semin Hematol. 2000;37:239–48.CrossRefPubMedGoogle Scholar
  3. 3.
    Semple JW, Provan D. The immunopathogenesis of immune thrombocytopenia: T cells still take center-stage. Curr Opin Hematol. 2012;19:357–62.CrossRefPubMedGoogle Scholar
  4. 4.
    Audia S, Rossato M, Santegoets K, et al. Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia. Blood. 2014;124:2858–66.CrossRefPubMedGoogle Scholar
  5. 5.
    Kuwana M, Kaburaki J, Ikeda Y. Autoreactive T cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura. Role in production of anti-platelet autoantibody. J Clin Invest. 1998;102:1393–402.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Olsson B, Andersson PO, Jernas M, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med. 2003;9:1123–4.CrossRefPubMedGoogle Scholar
  7. 7.
    Ma L, Simpson E, Li J, et al. CD8+ T cells are predominantly protective and required for effective steroid therapy in murine models of immune thrombocytopenia. Blood. 2015;126:247–56.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Nishimoto T, Kuwana M. CD4+CD25+Foxp3+ regulatory T cells in the pathophysiology of immune thrombocytopenia. Semin Hematol. 2013;1:S43–9.CrossRefGoogle Scholar
  9. 9.
    Kuwana M, Kawakami Y, Ikeda Y. Suppression of autoreactive T-cell response to glycoprotein IIb/IIIa by blockade of CD40/CD154 interaction: implications for treatment of immune thrombocytopenic purpura. Blood. 2003;101:621–3.CrossRefPubMedGoogle Scholar
  10. 10.
    Meabed MH, Taha GM, Mohamed SO, et al. Autoimmune thrombocytopenia: flow cytometric determination of platelet-associated CD154/CD40L and CD40 on peripheral blood T and B lymphocytes. Hematology. 2007;12:301–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Kuwana M, Okazaki Y, Ikeda Y. Splenic macrophages maintain the anti-platelet autoimmune response via uptake of opsonized platelets in patients with immune thrombocytopenic purpura. J Thromb Haemost. 2009;7:322–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Kuwana M, Okazaki Y, Kaburaki J, et al. Spleen is a primary site for activation of platelet-reactive T and B cells in patients with immune thrombocytopenic purpura. J Immunol. 2002;168:3675–82.CrossRefPubMedGoogle Scholar
  13. 13.
    Daridon C, Loddenkemper C, Spieckermann S, et al. Splenic proliferative lymphoid nodules distinct from germinal centers are sites of autoantigen stimulation in immune thrombocytopenia. Blood. 2012;120:5021–31.CrossRefPubMedGoogle Scholar
  14. 14.
    Mahévas M, Patin P, Huetz F, et al. B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cell. J Clin Invest. 2013;123:432–42.CrossRefPubMedGoogle Scholar
  15. 15.
    Asahi A, Nishimoto T, Okazaki Y, et al. Helicobacter pylori eradication shifts monocytes Fcγ receptor balance toward inhibitory FcγRIIB in immune thrombocytopenic purpura patients. J Clin Invest. 2008;118:2939–49.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Lui XG, Liu S, Feng Q, et al. Thrombopoietin receptor agonists shift the balance of Fcγ receptors toward inhibitory receptor IIb on monocytes in ITP. Blood. 2016;128:852–61.CrossRefGoogle Scholar
  17. 17.
    Sakaguchi S, Miyara M, Costantino CM, et al. Foxp3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10:490–500.CrossRefPubMedGoogle Scholar
  18. 18.
    Buckner JH. Mechanisms of impaired regulation by CD4+CD25+Foxp3+ regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010;10:849–59.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Audia S, Samson M, Guy J, et al. Immunologic effects of rituximab on the human spleen in immune thrombocytopenia. Blood. 2011;118:4394–400.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Olsson B, Ridell B, Carlsson L, et al. Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1. Blood. 2008;112:1078–84.CrossRefPubMedGoogle Scholar
  21. 21.
    Song Y, Wang YT, Huang XJ, et al. Abnormalities of the bone marrow immune microenvironment in patients with immune thrombocytopenia. Ann Hematol. 2016;95:959–65.CrossRefPubMedGoogle Scholar
  22. 22.
    Bao W, Bussel JB, Heck S, et al. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010;116:4639–45.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Liu B, Zhao H, Poon MC, et al. Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura. Eur J Haematol. 2007;78:139–43.PubMedGoogle Scholar
  24. 24.
    Stasi R, Cooper N, Del Poeta G, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood. 2008;112:1147–50.CrossRefPubMedGoogle Scholar
  25. 25.
    Yu J, Heck S, Patel V, et al. Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura. Blood. 2008;112:1325–8.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ling Y, Cao X, Yu Z, et al. Circulating dendritic cells subsets and CD4+Foxp3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasome. Eur J Haematol. 2007;79:310–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Nishimoto T, Satoh T, Takeuchi T, et al. Critical role of CD4(+)CD25(+) regulatory T cells in preventing murine autoantibody-mediated thrombocytopenia. Exp Hematol. 2012;40:279–89.CrossRefPubMedGoogle Scholar
  28. 28.
    Nishimoto T, Satoh T, Simpson EK, et al. Predominant autoantibody response to GPIb/IX in a regulatory T-cell-deficient mouse model for immune thrombocytopenia. J Thromb Haemost. 2013;11:369–72.CrossRefPubMedGoogle Scholar
  29. 29.
    Nishimoto T, Numajiri M, Nakazaki H, et al. Induction of immune tolerance to platelet antigen by short-term thrombopoietin treatment in a mouse model of immune thrombocytopenia. Int J Hematol. 2014;100:341–4.CrossRefPubMedGoogle Scholar
  30. 30.
    González-López TJ, Pascual C, Álvarez-Román MT, et al. Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia. Am J Hematol. 2015;90:E40–3.CrossRefPubMedGoogle Scholar
  31. 31.
    Chow L, Aslam R, Speck ER, et al. A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy. Blood. 2010;115:1247–53.CrossRefPubMedGoogle Scholar
  32. 32.
    Aslam R, Hu Y, Gebremeskel S, et al. Thymic retention of CD4+CD25+Foxp3+ T regulatory cells is associated with their peripheral deficiency and thrombocytopenia in a murine model of immune thrombocytopenia. Blood. 2012;120:2127–32.CrossRefPubMedGoogle Scholar
  33. 33.
    Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014;41:529–42.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Craft JE. Follicular helper T cells in immunity and systemic autoimmunity. Nat Rev Rheumatol. 2012;8:337–47.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ma CS, Deenick EK. Human T follicular helper (Tfh) cells and disease. Immunol Cell Biol. 2014;92:64–71.CrossRefPubMedGoogle Scholar
  36. 36.
    Xie J, Cui D, Liu Y, et al. Changes in follicular helper T cells in idiopathic thrombocytopenic purpura patients. Int J Biol Sci. 2015;11:220–9.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Yao X, Li C, Yang J, et al. Differences in frequency and regulation of T follicular helper cells between newly diagnosed and chronic pediatric immune thrombocytopenia. Blood Cells Mol Dis. 2016;61:26–36.CrossRefPubMedGoogle Scholar
  38. 38.
    Jernas M, Nookaew I, Wadenvik H, et al. MicroRNA regulate immunological pathways in T-cells in immune thrombocytopenia (ITP). Blood. 2013;121:2095–8.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Li JQ, Hu SY, Wang ZY, et al. MicroRNA-125-5p targeted CXCL13: a potential biomarker associated with immune thrombocytopenia. Am J Transl Res. 2015b;15:772–80.CrossRefGoogle Scholar
  40. 40.
    Li S, Wang L, Zhao C, et al. CD8+ T cells suppress autologous megakaryocyte apoptosis in idiopathic thrombocytopenic purpura. Br J Haematol. 2007;139:605–11.CrossRefPubMedGoogle Scholar
  41. 41.
    Guo L, Kapur R, Aslam R, et al. CD20+ B-cell depletion therapy suppresses murine CD8+ T-cell-mediated immune thrombocytopenia. Blood. 2016;127:735–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Li J, van der Wal DE, Zhu G, et al. Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia. Nat Commun. 2015a;6:7737.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Qiu J, Liu X, Li X, et al. CD8(+) T cells induce platelet clearance in the liver via platelet desialylation in immune thrombocytopenia. Sci Rep. 2016;6:27445.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Zhou H, Qiu JH, Wang T, et al. Interleukin 27 inhibits cytotoxic T-lymphocyte-mediated platelet destruction in primary immune thrombocytopenia. Blood. 2014;124:3316–9.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Lu L, Cantor H. Generation and regulation of CD8(+) regulatory T cells. Cell Mol Immunol. 2008;5:401–6.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Tsai YG, Yang KD, Niu DM, et al. TLR2 agonists enhance CD8+Foxp3 regulatory T cells and suppress Th2 immune responses during allergen immunotherapy. J Immunol. 2010;184:7229–37.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Division of HematologyKitasato University School of Allied Health SciencesSagamiharaJapan
  2. 2.Division of Molecular HematologyKitasato University Graduate School of Medical SciencesSagamiharaJapan
  3. 3.Department of Allergy and RheumatologyNippon Medical School Graduate School of MedicineTokyoJapan

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