Skip to main content

Advertisement

SpringerLink
Log in

Effects of CD70 and CD11a in Immune Thrombocytopenia Patients

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Introduction

CD70 and CD11a are co-stimulatory molecules that are important for the immune functions of T, B lymphocytes. Over-expressions of CD70 or CD11a cause T cell to be autoreactive.

Objectives

The purpose of this study was to explore the effect of CD70 and CD11a in immune thrombocytopenia (ITP).

Methods

CD70 and CD11a mRNAs and protein expressions in CD4+ T cells from ITP patients were measured respectively by real-time quantitative-PCR (RT-PCR) and flow cytometry. The apoptosis of T cells, B cells, and platelets in the PBMCs were analyzed by flow cytometry, and secretion of IL-4, IFN-γ, as well as IgG in the reaction supernatant were detected by ELISA. In order to investigate the effects of CD70 and CD11a over-expression on pathogenesis of ITP, anti-CD70, and anti-CD11a mAbs were used to block the signaling pathways.

Results

CD70 and CD11a mRNAs and protein expressions in CD4+ T cells from ITP patients were significantly higher than healthy controls. In vitro co-culturing of PBMCs with anti-CD70 or anti-CD11a, the apoptosis of T, B lymphocytes were significantly increased but apoptosis of platelets were reduced. Anti-CD11a and anti-CD70 both significantly suppressed the secretion of IFN-γ, while anti-CD11a significantly promoted the secretion of IL-4. There was no significant difference in the healthy group.

Conclusions

CD70 and CD11a facilitate the survival of T, B lymphocytes and indirectly enhance the destruction of platelets in ITP. Blockade of CD70 or CD11a are promising therapeutic approaches for ITP.

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. McMillan R. The pathogenesis of chronic immune (idiopathic) thrombocytopenic purpura. Semin Hematol. 2000;37:5–9.

    Article  PubMed  CAS  Google Scholar 

  2. Semple JW, Milev Y, Cosgrave D, Mody M, Hornstein A, Blanchette V, et al. Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity. Blood. 1996;87:4245–54.

    PubMed  CAS  Google Scholar 

  3. Wang T, Zhao H, Ren H, Guo J, Xu M, Yang R, et al. Type 1 and type 2 T-cell profiles in idiopathic thrombocytopenic purpura. Haematologica. 2005;90:914–23.

    PubMed  CAS  Google Scholar 

  4. Panitsas FP, Theodoropoulou M, Kouraklis A, Karakantza M, Theodorou GL, Zoumbos NC, et al. Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response. Blood. 2004;103:2645–7.

    Article  PubMed  CAS  Google Scholar 

  5. Olsson B, Andersson PO, Jernas M, Jacobsson S, Carlsson B, Carlsson LM, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med. 2003;9:1123–4.

    Article  PubMed  CAS  Google Scholar 

  6. Zhang F, Chu X, Wang L, Zhu Y, Li L, Ma D, et al. Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura. Eur J Haematol. 2006;76:427–31.

    Article  PubMed  CAS  Google Scholar 

  7. Liu B, Zhao H, Poon MC, Han Z, Gu D, Xu M, et al. Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura. Eur J Haematol. 2007;78:139–43.

    PubMed  CAS  Google Scholar 

  8. Borst J, Hendriks J, Xiao Y. CD27 and CD70 in T cell and B cell activation. Curr Opin Immunol. 2005;17:275–81.

    Article  PubMed  CAS  Google Scholar 

  9. Hintzen RQ, Lens SM, Koopman G, Pals ST, Spits H, van Lier RA. CD70 represents the human ligand for CD27. Int Immunol. 1994;6:477–80.

    Article  PubMed  CAS  Google Scholar 

  10. Goodwin RG, Alderson MR, Smith CA, Armitage RJ, VandenBos T, Jerzy R, et al. Molecular and biological characterization of a ligand for CD27 defines a new family of cytokines with homology to tumor necrosis factor. Cell. 1993;73:447–56.

    Article  PubMed  CAS  Google Scholar 

  11. van Lier RA, Borst J, Vroom TM, Klein H, Van Mourik P, Zeijlemaker WP, et al. Tissue distribution and biochemical and functional properties of Tp55 (CD27), a novel T cell differentiation antigen. J Immunol. 1987;139:1589–96.

    PubMed  Google Scholar 

  12. Maurer D, Holter W, Majdic O, Fischer GF, Knapp W. CD27 expression by a distinct subpopulation of human B lymphocytes. Eur J Immunol. 1990;20:2679–84.

    Article  PubMed  CAS  Google Scholar 

  13. Croft M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol. 2003;3:609–20.

    Article  PubMed  CAS  Google Scholar 

  14. Lens SM, Tesselaar K, van Oers MH, van Lier RA. Control of lymphocyte function through CD27–CD70 interactions. Semin Immunol. 1998;10:491–9.

    Article  PubMed  CAS  Google Scholar 

  15. Lee WW, Yang ZZ, Li G, Weyand CM, Goronzy JJ. Unchecked CD70 expression on T cells lowers threshold for T cell activation in rheumatoid arthritis. J Immunol. 2007;179:2609–15.

    PubMed  CAS  Google Scholar 

  16. Brugnoni D, Airo P, Marino R, Notarangelo LD, van Lier RA, Cattaneo R. CD70 expression on T-cell subpopulations: study of normal individuals and patients with chronic immune activation. Immunol Lett. 1997;55:99–104.

    Article  PubMed  CAS  Google Scholar 

  17. Oflazoglu E, Boursalian TE, Zeng W, Edwards AC, Duniho S, McEarchern JA, et al. Blocking of CD27–CD70 pathway by anti-CD70 antibody ameliorates joint disease in murine collagen-induced arthritis. J Immunol. 2009;183:3770–7.

    Article  PubMed  CAS  Google Scholar 

  18. Oelke K, Lu Q, Richardson D, Wu A, Deng C, Hanash S, et al. Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors. Arthritis Rheum. 2004;50:1850–60.

    Article  PubMed  CAS  Google Scholar 

  19. Van Seventer GA, Shimizu Y, Horgan KJ, Shaw S. The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. J Immunol. 1990;144:4579–86.

    PubMed  Google Scholar 

  20. Kaplan MJ, Beretta L, Yung RL, Richardson BC. LFA-1 overexpression and T cell autoreactivity: mechanisms. Immunol Invest. 2000;29:427–42.

    PubMed  CAS  Google Scholar 

  21. Richardson B, Powers D, Hooper F, Yung RL, O'Rourke K. Lymphocyte function-associated antigen 1 overexpression and T cell autoreactivity. Arthritis Rheum. 1994;37:1363–72.

    Article  PubMed  CAS  Google Scholar 

  22. Suzuki J, Yamasaki S, Wu J, Koretzky GA, Saito T. The actin cloud induced by LFA-1-mediated outside-in signals lowers the threshold for T-cell activation. Blood. 2007;109:168–75.

    Article  PubMed  CAS  Google Scholar 

  23. Wang Y, Shibuya K, Yamashita Y, Shirakawa J, Shibata K, Kai H, et al. LFA-1 decreases the antigen dose for T cell activation in vivo. Int Immunol. 2008;20:1119–27.

    Article  PubMed  CAS  Google Scholar 

  24. Yung R, Powers D, Johnson K, Amento E, Carr D, Laing T, et al. Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice. J Clin Invest. 1996;97:2866–71.

    Article  PubMed  CAS  Google Scholar 

  25. Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2009;115:168–86.

    Article  PubMed  Google Scholar 

  26. Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113:2386–93.

    Article  PubMed  CAS  Google Scholar 

  27. Koopman G, Reutelingsperger CP, Kuijten GA, Keehnen RM, Pals ST, van Oers MH. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood. 1994;84:1415–20.

    PubMed  CAS  Google Scholar 

  28. Zhu XJ, Shi Y, Peng J, Guo CS, Shan NN, Qin P, et al. The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia. Blood. 2009;114:5362–7.

    Article  PubMed  CAS  Google Scholar 

  29. Boursalian TE, McEarchern JA, Law CL, Grewal IS. Targeting CD70 for human therapeutic use. Adv Exp Med Biol. 2009;647:108–19.

    Article  PubMed  Google Scholar 

  30. Perez OD, Mitchell D, Jager GC, South S, Murriel C, McBride J, et al. Leukocyte functional antigen 1 lowers T cell activation thresholds and signaling through cytohesin-1 and Jun-activating binding protein 1. Nat Immunol. 2003;4:1083–92.

    Article  PubMed  CAS  Google Scholar 

  31. Dolfi DV, Boesteanu AC, Petrovas C, Xia D, Butz EA, Katsikis PD. Late signals from CD27 prevent Fas-dependent apoptosis of primary CD8+ T cells. J Immunol. 2008;180:2912–21.

    PubMed  CAS  Google Scholar 

  32. Yamada A, Salama AD, Sho M, Najafian N, Ito T, Forman JP, et al. CD70 signaling is critical for CD28-independent CD8+ T cell-mediated alloimmune responses in vivo. J Immunol. 2005;174:1357–64.

    PubMed  CAS  Google Scholar 

  33. Arens R, Schepers K, Nolte MA, van Oosterwijk MF, van Lier RA, Schumacher TN, et al. Tumor rejection induced by CD70-mediated quantitative and qualitative effects on effector CD8+ T cell formation. J Exp Med. 2004;199:1595–605.

    Article  PubMed  CAS  Google Scholar 

  34. Koopman G, Keehnen RM, Lindhout E, Newman W, Shimizu Y, van Seventer GA, et al. Adhesion through the LFA-1 (CD11a/CD18)-ICAM-1 (CD54) and the VLA-4 (CD49d)-VCAM-1 (CD106) pathways prevents apoptosis of germinal center B cells. J Immunol. 1994;152:3760–7.

    PubMed  CAS  Google Scholar 

  35. Ogawara H, Handa H, Morita K, Hayakawa M, Kojima J, Amagai H, et al. High Th1/Th2 ratio in patients with chronic idiopathic thrombocytopenic purpura. Eur J Haematol. 2003;71:283–8.

    Article  PubMed  CAS  Google Scholar 

  36. van Oosterwijk MF, Juwana H, Arens R, Tesselaar K, van Oers MH, Eldering E, et al. CD27–CD70 interactions sensitise naive CD4+ T cells for IL-12-induced Th1 cell development. Int Immunol. 2007;19:713–8.

    Article  PubMed  Google Scholar 

  37. Rowley TF, Al-Shamkhani A. Stimulation by soluble CD70 promotes strong primary and secondary CD8+ cytotoxic T cell responses in vivo. J Immunol. 2004;172:6039–46.

    PubMed  CAS  Google Scholar 

  38. Onder TT, Ho IC, Pai SY. GATA3 and the T -cell lineage: essential functions before and after T -helper-2-cell differentiation. Nat Rev Immunol. 2009;9(2):125–35.

    Article  Google Scholar 

  39. Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LH. Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science. 2002;295:338–42.

    Article  PubMed  CAS  Google Scholar 

  40. Stasi R, Cooper N, Del Poeta G, Stipa E, Laura Evangelista M, Abruzzese E, 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.

    Article  PubMed  CAS  Google Scholar 

  41. Xiao Y, Peperzak V, Keller AM, Borst J. CD27 instructs CD4+ T cells to provide help for the memory CD8+ T cell response after protein immunization. J Immunol. 2008;181:1071–82.

    PubMed  CAS  Google Scholar 

  42. Ochsenbein AF, Riddell SR, Brown M, Corey L, Baerlocher GM, Lansdorp PM, et al. CD27 expression promotes long-term survival of functional effector-memory CD8+ cytotoxic T lymphocytes in HIV-infected patients. J Exp Med. 2004;200:1407–17.

    Article  PubMed  CAS  Google Scholar 

  43. Tohma S, Hirohata S, Lipsky PE. The role of CD11a/CD18–CD54 interactions in human T cell-dependent B cell activation. J Immunol. 1991;146:492–9.

    PubMed  CAS  Google Scholar 

  44. Tohma S, Ramberg JE, Lipsky PE. Expression and distribution of CD11a/CD18 and CD54 during human T cell–B cell interactions. J Leukoc Biol. 1992;52:97–103.

    PubMed  CAS  Google Scholar 

  45. Olsson B, Andersson PO, Jacobsson S, Carlsson L, Wadenvik H. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost. 2005;93:139–44.

    PubMed  CAS  Google Scholar 

  46. Nolte MA, van Olffen RW, van Gisbergen KP, van Lier RA. Timing and tuning of CD27–CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology. Immunol Rev. 2009;229:216–31.

    Article  PubMed  CAS  Google Scholar 

  47. Aruffo A, Hollenbaugh D. Therapeutic intervention with inhibitors of co-stimulatory pathways in autoimmune disease. Curr Opin Immunol. 2001;13:683–6.

    Article  PubMed  CAS  Google Scholar 

  48. Xingyuan M, Wenyun Z, Tianwen W. Leukocyte function-associated antigen-1: structure, function and application prospects. Protein Pept Lett. 2006;13:397–400.

    Article  PubMed  Google Scholar 

  49. Calcagno AM, Yusuf-Makagiansar H, Yakovleva TV, Murray JS, Siahaan TJ. Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune diseases. Med Res Rev. 2002;22(2):146–67.

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported in part by grants of National Natural Science Foundation of China (30670900, 81070397), Ministry of Health of China (No. 200802031), and Tianjin Municipal Science and Technology Commission (09JCYBJC10900, 10JCZDJC19700). The authors would like to thank Prof. Man-Chiu Poon (University of Calgary, Canada) for critical review of the manuscript.

Author information

Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People’s Republic of China

    Li Ma, Zeping Zhou, Hairong Jia, Hu Zhou, Aiping Qi, Huiyuan Li, Hongmei Wang, Lei Zhang & Renchi Yang

Authors
  1. Li Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zeping Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hairong Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hu Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aiping Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Huiyuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hongmei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Renchi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Renchi Yang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ma, L., Zhou, Z., Jia, H. et al. Effects of CD70 and CD11a in Immune Thrombocytopenia Patients. J Clin Immunol 31, 632–642 (2011). https://doi.org/10.1007/s10875-011-9539-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-011-9539-1

Keywords

Search

Navigation