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DOI: 10.1160/TH13-11-0949
B cells facilitate platelet production mediated by cytokines in patients with essential thrombocythaemia
Financial support: This work was supported by Mackay Memorial Hospital grants.Publikationsverlauf
Received:
18. November 2013
Accepted after major revision:
22. März 2014
Publikationsdatum:
20. November 2017 (online)
Summary
We investigated the role of activated B cells in thrombopoiesis through the production of interleukin (IL)-1beta and IL-6 in patients with essential thrombocythaemia. The number of B cells did not differ between essential thrombocythaemia patients, irrespective of the presence of Janus activated kinase-2 V617F mutation or wild type, and age-matched healthy adults. However, the number of IL-1beta/IL- 6-producing B cells was significantly higher in essential thrombocythaemia patients than that in healthy controls. The relatively high level of IL-1beta/IL-6 production by B cells was associated with serum B cell-activating factor and expression of Toll-like receptor 4 on B cells. A high level of B cell-activating factor was present in essential thrombocythaemia patients with both Janus activated kinase-2 genotypes. Incubation with B cell-activating factor enhanced the expression of Toll-like receptor 4 on B cells. IL-1beta and IL-6 production was not stimulated by B cell-activating factor alone; Toll-like receptor 4 was activated by lipopolysaccharide or patients’ sera to produce IL-1beta and IL-6 in B cells. Moreover, essential thrombocythaemia patient B cells facilitated megakaryocyte differentiation when co-cultured with CD34+ haematopoietic stem cells. Antibody neutralisation of IL-1beta and IL-6 attenuated megakaryocyte differentiation. These data suggest that B cells play a crucial role in thrombopoiesis in essential thrombocythaemia patients.
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References
- 1 Vardiman JW, Thiele J, Arber DA. et al. The 2008 revision of the World Health Organisation (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114: 937-951.
- 2 Quintas-Cardama A, Kantarjian H, Cortes J. et al. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov 2011; 10: 127-140.
- 3 James C, Ugo V, Le Couedic JP. et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144-1148.
- 4 Kralovics R, Passamonti F, Buser AS. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779-1790.
- 5 Lu X, Levine R, Tong W. et al. Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. Proc Natl Acad Sci USA 2005; 102: 18962-18967.
- 6 Levine RL, Wadleigh M, Cools J. et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 07: 387-397.
- 7 Li S, Kralovics R, De Libero G. et al. Clonal heterogeneity in polycythemia vera patients with JAK2 exon12 and JAK2-V617F mutations. Blood 2008; 111: 3863-3866.
- 8 Beer PA, Jones AV, Bench AJ. et al. Clonal diversity in the myeloproliferative neoplasms: independent origins of genetically distinct clones. Br J Haematol 2009; 144: 904-908.
- 9 Tefferi A, Pardanani A. JAK inhibitors in myeloproliferative neoplasms: rationale, current data and perspective. Blood Rev 2011; 25: 229-237.
- 10 Pardanani AD, Levine RL, Lasho T. et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006; 108: 3472-3476.
- 11 Nangalia J, Massie CE, Baxter EJ. et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013; 369: 2391-2405.
- 12 Klampfl T, Gisslinger H, Harutyunyan AS. et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013; 369: 2379-2390.
- 13 Panteli KE, Hatzimichael EC, Bouranta PK. et al. Serum interleukin (IL)-1, IL-2, sIL-2Ra, IL-6 and thrombopoietin levels in patients with chronic myeloproliferative diseases. Br J Haematol 2005; 130: 709-715.
- 14 Hasselbalch HC. Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer?. Blood 2012; 119: 3219-3225.
- 15 Siitonen T, Savolainen ER, Koistinen P. Flt-3 ligand does not induce the growth of peripheral blood granulocyte-macrophage colony-forming cells in myeloproliferative disorders. Eur J Haematol 1999; 62: 103-108.
- 16 Eaton DL, de Sauvage FJ. Thrombopoietin: the primary regulator of megakaryocytopoiesis and thrombopoiesis. Exp Hematol 1997; 25: 1-7.
- 17 Araneda M, Krishnan V, Hall K. et al. Reactive and clonal thrombocytosis: proinflammatory and hematopoietic cytokines and acute phase proteins. South Med J 2001; 94: 417-420.
- 18 Zheng C, Yang R, Han Z. et al. TPO-independent megakaryocytopoiesis. Crit Rev Oncol Hematol 2008; 65: 212-222.
- 19 Pistoia V. Production of cytokines by human B cells in health and disease. Immunol Today 1997; 18: 343-350.
- 20 Mackay F, Figgett WA, Saulep D. et al. B-cell stage and context-dependent requirements for survival signals from BAFF and the B-cell receptor. Immunol Rev 2010; 237: 205-225.
- 21 Ng LG, Ng CH, Woehl B. et al. BAFF costimulation of Toll-like receptor-activated B-1 cells. Eur J Immunol 2006; 36: 1837-1846.
- 22 Elzey BD, Tian J, Jensen RJ. et al. Platelet-mediated modulation of adaptive immunity. A communication link between innate and adaptive immune compartments. Immunity 2003; 19: 9-19.
- 23 Solanilla A, Pasquet JM, Viallard JF. et al. Platelet-associated CD154 in immune thrombocytopenic purpura. Blood 2005; 105: 215-218.
- 24 Sims GP, Ettinger R, Shirota Y. et al. Identification and characterisation of circulating human transitional B cells. Blood 2005; 105: 4390-4398.
- 25 Palanichamy A, Barnard J, Zheng B. et al. Novel human transitional B cell populations revealed by B cell depletion therapy. J Immunol 2009; 182: 5982-5993.
- 26 Landolt-Marticorena C, Wither R, Reich H. et al. Increased expression of B cell activation factor supports the abnormal expansion of transitional B cells in systemic lupus erythematosus. J Rheumatol 2011; 38: 642-651.
- 27 Daridon C, Pers JO, Devauchelle V. et al. Identification of transitional type II B cells in the salivary glands of patients with Sjogren’s syndrome. Arthritis Rheum 2006; 54: 2280-2288.
- 28 Moore PA, Belvedere O, Orr A. et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 1999; 285: 260-263.
- 29 Scapini P, Nardelli B, Nadali G. et al. G-CSF-stimulated neutrophils are a prominent source of functional BLyS. J Exp Med 2003; 197: 297-302.
- 30 McMillan R, Wang L, Tomer A. et al. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 2004; 103: 1364-1369.
- 31 Scapini P, Carletto A, Nardelli B. et al. Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases. Blood 2005; 105: 830-837.
- 32 Wardemann H, Yurasov S, Schaefer A. et al. Predominant autoantibody production by early human B cell precursors. Science 2003; 301: 1374-1377.
- 33 Anderson LA, Pfeiffer RM, Landgren O. et al. Risks of myeloid malignancies in patients with autoimmune conditions. Br J Cancer 2009; 100: 822-828.
- 34 Kristinsson SY, Landgren O, Samuelsson J. et al. Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica 2010; 95: 1216-1220.
- 35 Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340: 115-126.
- 36 Maugeri N, Baldini M, Ramirez GA. et al. Platelet-leukocyte deregulated interactions foster sterile inflammation and tissue damage in immune-mediated vessel diseases. Thromb Res 2012; 129: 267-273.
- 37 Michiels JJ, Berneman Z, Van Bockstaele D. et al. Clinical and laboratory features, pathobiology of platelet-mediated thrombosis and bleeding complications, and the molecular etiology of essential thrombocythemia and polycythemia vera: therapeutic implications. Semin Thromb Hemost 2006; 32: 174-207.
- 38 Kristinsson SY, Bjorkholm M, Hultcrantz M. et al. Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or myelodysplastic syndromes. J Clin Oncol 2011; 29: 2897-2903.
- 39 Avery DT, Kalled SL, Ellyard JI. et al. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J Clin Invest 2003; 112: 286-297.
- 40 Stohl W, Hiepe F, Latinis KM. et al. Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus. Arthritis Rheum 2012; 64: 2328-2337.
- 41 Kjaer L, Westman M, Hasselbalch Riley C. et al. A highly sensitive quantitative real-time PCR assay for determination of mutant JAK2 exon 12 allele burden. PloS one 2012; 07: e33100.
- 42 Kremer M, Horn T, Koch I. et al. Quantitation of the JAK2V617F mutation in microdissected bone marrow trephines: equal mutational load in myeloid lineages and rare involvement of lymphoid cells. Am J Surg Pathol 2008; 32: 928-935.
- 43 Hagihara M, Higuchi A, Tamura N. et al. Platelets, after exposure to a high shear stress, induce IL-10-producing, mature dendritic cells in vitro. J Immunol 2004; 172: 5297-5303.
- 44 Treml LS, Carlesso G, Hoek KL. et al. TLR stimulation modifies BLyS receptor expression in follicular and marginal zone B cells. J Immunol 2007; 178: 7531-7539.
- 45 Groom JR, Fletcher CA, Walters SN. et al. BAFF and MyD88 signals promote a lupuslike disease independent of T cells. J Exp Med 2007; 204: 1959-1971.
- 46 Erridge C. Endogenous ligands of TLR2 and TLR4: agonists or assistants?. J Leukoc Biol 2010; 87: 989-999.
- 47 Sohn SJ, Rajpal A, Winoto A. Apoptosis during lymphoid development. Curr Opin Immunol 2003; 15: 209-216.
- 48 Bekeredjian-Ding I, Jego G. Toll-like receptors--sentries in the B-cell response. Immunology 2009; 128: 311-323.
- 49 Jagannathan M, McDonnell M, Liang Y. et al. Toll-like receptors regulate B cell cytokine production in patients with diabetes. Diabetologia 2010; 53: 1461-1471.
- 50 Machida K, Cheng KT, Sung VM. et al. Hepatitis C virus induces toll-like receptor 4 expression, leading to enhanced production of beta interferon and interleukin-6. J Virol 2006; 80: 866-874.
- 51 McDonnell M, Liang Y, Noronha A. et al. Systemic Toll-like receptor ligands modify B-cell responses in human inflammatory bowel disease. Inflamm Bowel Dis 2011; 17: 298-307.
- 52 Yan ZQ. Regulation of TLR4 expression is a tale about tail. Arterioscler Thromb Vasc Biol 2006; 26: 2582-2584.
- 53 Kim HA, Seo GY, Kim PH. Macrophage-derived BAFF induces AID expression through the p38MAPK/CREB and JNK/AP-1 pathways. J Leukoc Biol 2011; 89: 393-398.
- 54 Hasselbalch HC. A role of NF-E2 in chronic inflammation and clonal evolution in essential thrombocythemia, polycythemia vera and myelofibrosis?. Leuk Res 2014; 38: 263-266.
- 55 Kovacs CJ, Powell DS, Evans MJ. et al. Enhanced platelet recovery in myelosup-pressed mice treated with interleukin-1 and macrophage colony-stimulating factor: potential interactions with cytokines having megakaryocyte colony-stimulating activity. J Interferon Cytokine Res 1996; 16: 187-194.
- 56 Chuen CK, Li K, Yang M. et al. Interleukin-1beta up-regulates the expression of thrombopoietin and transcription factors c-Jun, c-Fos, GATA-1, and NF-E2 in megakaryocytic cells. J Lab Clin Med 2004; 143: 75-88.
- 57 Kaufmann KB, Grunder A, Hadlich T. et al. A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2. J Exp Med 2012; 209: 35-50.
- 58 Kaser A, Brandacher G, Steurer W. et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood 2001; 98: 2720-2725.
- 59 Alexandrakis MG, Passam FH, Moschandrea IA. et al. Levels of serum cytokines and acute phase proteins in patients with essential and cancer-related thrombocytosis. Am J Clin Oncol 2003; 26: 135-140.
- 60 Cattaneo C, Spedini P, Casari S. et al. Delayed-onset peripheral blood cytopenia after rituximab: frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk Lymphoma 2006; 47: 1013-1017.
- 61 Giezen TJ, Mantel-Teeuwisse AK, ten Berg MJ. et al. Rituximab-induced thrombocytopenia: a cohort study. Eur J Haematol 2012; 89: 256-266.