Subscribe to RSS
DOI: 10.1160/TH04-06-0385
Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura
Financial support: The study was supported by grants from the Swedish Medical Research Council (project no.: 14945, 11285, 13141), FoU Västra Götaland, Tore Nilsson’s Foundation for Medical Research, Åke Wiberg’s Foundation, Inga Britt and Arne Lundberg Research Foundation and the National Board for Health and Welfare.Publication History
Received
21 June 2004
Accepted after resubmission
16 September 2004
Publication Date:
14 December 2017 (online)
Summary
Idiopathic thrombocytopenic purpura (ITP) is an organ specific autoimmune disorder in whichT-lymphocyte abnormalities have pathogenetic importance.In a DNA microarray screen of CD3+ T-lymphocytes from ITP patients and healthy controls we found an altered expression of genes associated with apoptosis, e.g. A20, caspase-8 and Bax.This together with our previous findings of increased gene expression of Fas,interferon-g and IL-2 receptor beta (IL2RB) indicated an altered activation induced cell death (AICD) of T-cells in ITP. Using a proliferation assay we found that CD3+ lymphocytes from ITP patients were significantly more resistant to dexamethasone induced suppression compared to normal lymphocytes.We also found that cultured CD3+ lymphocytes from ITP patients in remission were more susceptible to apoptosis both in the presence and absence of dexamethasone compared to cells from patient with active ITP and healthy controls, as indicated by increased staining of AnnexinV binding. Our findings suggest that apoptotic resistance of activated T-lymphocytes in patients with active ITP may lead to defective clearance of autoreactive T-lymphocytes through AICD, which might cause a continued immune destruction of platelets. Conversely, a loss of resistance to AICD in ITP patients in remission might be an important mechanism for the achievement of remission.
-
References
- 1 Hed J. Role of complement in immune or idiopathic thrombocytopenic purpura. Acta Paediatr Suppl 1998; 424: 37-40.
- 2 McMillan R. The pathogenesis of chronic immune (idiopathic) thrombocytopenic purpura. Semin Hematol 2000; 37: 5-9.
- 3 Olsson B, Andersson PO, Jernas M. et al T-cellmediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med 2003; 9: 1123-4.
- 4 Erduran E, Aslan Y, Aliyazicioglu Y. et al Plasma soluble interleukin-2 receptor levels in patients with idiopathic thrombocytopenic purpura. Am J Hematol 1998; 57: 119-23.
- 5 Semple JW, Freedman J. Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia. Blood 1991; 78: 2619-25.
- 6 Yong K, Salooja N, Donahue RE. et al Human macrophage colony-stimulating factor levels are elevated in pregnancy and in immune thrombocytopenia. Blood 1992; 80: 2897-902.
- 7 Haznedaroglu IC, Sayinalp NM, Ozcebe I O. et al Megakaryocytopoietic cytokines in autoimmune thrombocytopenic purpura. Am J Hematol 1995; 49: 265.
- 8 Nomura S, Yanabu M, Kido H. et al Significance of cytokines and CD68-positive microparticles in immune thrombocytopenic purpura. Eur J Haematol 1995; 55: 49-56.
- 9 Andersson PO, Stockelberg D, Jacobsson S. et al A transforming growth factor-beta1-mediated bystander immune suppression could be associated with remission of chronic idiopathic thrombocytopenic purpura. Ann Hematol 2000; 79: 507-13.
- 10 Crossley AR, Dickinson AM, Proctor SJ. et al Effects of interferon-alpha therapy on immune parameters in immune thrombocytopenic purpura. Autoimmunity 1996; 24: 81-100.
- 11 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.
- 12 Kuwana M, Kaburaki J, Kitasato H. et al Immunodominant epitopes on glycoprotein IIb-IIIa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura. Blood 2001; 98: 130-9.
- 13 Shi YF, Sahai BM, Green DR. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature 1989; 339: 625-6.
- 14 Filion MC, Bradley AJ, Devine DV. et al Autoreactive T cells in healthy individuals show tolerance in vitro with characteristics similar to but distinct from clonal anergy. Eur J Immunol 1995; 25: 3123-7.
- 15 Coopamah MD, Garvey MB, Freedman J. et al Cellular immune mechanisms in autoimmune thrombocytopenic purpura: An update. Transfus Med Rev 2003; 17: 69-80.
- 16 Kawabe Y, Ochi A. Programmed cell death and extrathymic reduction of Vbeta8+ CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B. Nature 1991; 349: 245-8.
- 17 Brunner T, Mogil RJ, LaFace D. et al Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation- induced apoptosis in T-cell hybridomas. Nature 1995; 373: 441-4.
- 18 Wang J, Stohlman SA, Dennert G. TCR cross-linking induces CTL death via internal action of TNF. J Immunol 1994; 152: 3824-32.
- 19 Refaeli Y, Van Parijs L, Alexander I S. et al Interferon gamma is required for activation-induced death of T lymphocytes. J Exp Med 2002; 196: 999-1005.
- 20 Willerford DM, Chen J, Ferry JA. et al Interleukin- 2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 1995; 3: 521-30.
- 21 Lamhamedi-Cherradi SE, Zheng SJ, Maguschak KA. et al Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL-/- mice. Nat Immunol 2003; 4: 255-60.
- 22 Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thio-cyanate-phenol- chloroform extraction. Anal Biochem 1987; 162: 156-9.
- 23 Vermes I, Haanen C, Steffens-Nakken H. et al A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods 1995; 184: 39-51.
- 24 Koopman G, Reutelingsperger CP, Kuijten GA. et al Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 1994; 84: 1415-20.
- 25 Hockenbery D, Nunez G, Milliman C. et al Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990; 348: 334-6.
- 26 Ngan BY, Chen-Levy Z, Weiss LM. et al Expression in non-Hodgkin’s lymphoma of the bcl-2 protein associated with the t(14;18) chromosomal translocation. N Engl J Med 1988; 318: 1638-44.
- 27 Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74: 609-19.
- 28 Longo CR, Arvelo MB, Patel I V. et al A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis. Circulation 2003; 108: 1113-8.
- 29 Malewicz M, Zeller N, Yilmaz ZB. et al NF kappa B controls the balance between Fas and tumor necrosis factor cell death pathways during T cell receptor-induced apoptosis via the expression of its target gene A20. J Biol Chem 2003; 278: 32825-33.
- 30 Jaattela M, Mouritzen H, Elling F. et al A20 zinc finger protein inhibits TNF and IL-1 signaling. J Immunol 1996; 156: 1166-73.
- 31 Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 1995; 81: 495-504.
- 32 Ruland J, Mak TW. Transducing signals from antigen receptors to nuclear factor kappaB. Immunol Rev 2003; 193: 93-100.
- 33 Rothe M, Xiong J, Shu HB. et al I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction. Proc Natl Acad Sci U S A 1996; 93: 8241-6.
- 34 Altznauer F, Conus S, Cavalli A. et al Calpain-1 regulates Bax and subsequent Smac-dependent caspase- 3 activation in neutrophil apoptosis. J Biol Chem 2004; 279: 5947-57.
- 35 Muzio M, Chinnaiyan AM, Kischkel FC. et al FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death—inducing signaling complex. Cell 1996; 85: 817-27.
- 36 Muzio M, Salvesen GS, Dixit VM. FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens. J Biol Chem 1997; 272: 2952-6.
- 37 Chun HJ, Zheng L, Ahmad M. et al Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 2002; 419: 395-9.
- 38 Lenardo MJ. Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature 1991; 353: 858-61.
- 39 Kneitz B, Herrmann T, Yonehara S. et al Normal clonal expansion but impaired Fas-mediated cell death and anergy induction in interleukin-2-deficient mice. Eur J Immunol 1995; 25: 2572-7.
- 40 Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 1980; 284: 555-6.
- 41 Yoshimura C, Nomura S, Nagahama M. et al Plasma- soluble Fas (APO-1, CD95) and soluble Fas ligand in immune thrombocytopenic purpura. Eur J Haematol 2000; 64: 219-24.
- 42 Shenoy S, Mohanakumar T, Chatila T. et al Defective apoptosis in lymphocytes and the role of IL-2 in autoimmune hematologic cytopenias. Clin Immunol 2001; 99: 266-75.
- 43 Sharief MK, Semra YK. Upregulation of the inhibitor of apoptosis proteins in activated T lymphocytes from patients with multiple sclerosis. J Neuroimmunol 2001; 119: 350-7.
- 44 Xu L, Zhang L, Yi Y. et al Human lupus T cells resist inactivation and escape death by upregulating COX-2. Nat Med 2004; 10: 411-5.
- 45 Schirmer M, Vallejo AN, Weyand CM. et al Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4+CD28– T cells from rheumatoid arthritis patients. J Immunol 1998; 161: 1018-25.
- 46 Lev N, Barhum Y, Melamed E. et al Bax-ablation attenuates experimental autoimmune encephalomyelitis in mice. Neurosci Lett 2004; 359: 139-42.