Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

Anne Zufferey, Rick Kapur, John W Semple, Anne Zufferey, Rick Kapur, John W Semple

Abstract

Immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by low platelet counts. The pathogenesis of ITP remains unclear although both antibody-mediated and/or T cell-mediated platelet destruction are key processes. In addition, impairment of T cells, cytokine imbalances, and the contribution of the bone marrow niche have now been recognized to be important. Treatment strategies are aimed at the restoration of platelet counts compatible with adequate hemostasis rather than achieving physiological platelet counts. The first line treatments focus on the inhibition of autoantibody production and platelet degradation, whereas second-line treatments include immunosuppressive drugs, such as Rituximab, and splenectomy. Finally, thirdline treatments aim to stimulate platelet production by megakaryocytes. This review discusses the pathophysiology of ITP and how the different treatment modalities affect the pathogenic mechanisms.

Keywords: immune thrombocytopenia (ITP); B cells; T cells; autoimmunity; platelets.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cellular pathogenic mechanisms in immune thrombocytopenia (ITP). Multiple cells are involved in the pathogenesis of ITP. B cells and plasma cells are abnormally regulated and produce autoantibodies, which bind platelets and megakaryocytes (MKs), inducing their impairment and/or degradation in the spleen and liver. The cellular immune response is also affected, leading to a decrease of Tregs and Bregs, which contributes to autoreactive plasma cell survival (supporting autoantibody production) and unbalanced Th CD4+ T cell subsets. Moreover, cytotoxic CD8+ T cells are also activated, inducing platelet and MK apoptosis as well as the dysregulation of BM niche homeostasis. Therefore, ITP pathogenesis does not only results in platelet destruction, but also in a megakayopoiesis and thrombopoiesis defect.
Figure 2
Figure 2
Therapeutic mechanisms of current ITP treatments. Several drugs are used to treat chronic ITP. The first line of treatment consists of corticosteroids alone or in combination with intravenous immunoglobulin (IVIg) or anti-D, which aim to decrease platelet destruction and platelet antigen presentation by antigen presenting cells (APC) to restore a normal immune response. They also act on B cells and plasma cells, thus decreasing autoantibody production, and rescue impaired Treg function. Second-line therapies include immunosupressive drugs such as Rituximab, which directly targets B cells, and splenectomy. Both treatments also modulate the T cell compartment, notably increasing Tregs. Thrombopoietin (TPO)-receptor agonists (Romiplostim and Eltrombopag), which stimulate platelet production by MKs, are third-line treatments and are used for patients who do not respond to other therapies. Here again, TPO-agonists present indirect immunomodulatory effects on Bregs and Tregs. Combining multiple therapeutic approaches is often required to ensure the restoration of a physiological platelet count.

References

    1. Rodeghiero F., Stasi R., Gernsheimer T., Michel M., Provan D., Arnold D.M., Bussel J.B., Cines D.B., Chong B.H., Cooper N., 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;113:2386–2393. doi: 10.1182/blood-2008-07-162503.
    1. Harrington W.J., Minnich V., Hollingsworth J.W., Moore C.V. Demonstration of a thrombocytopenic factor in the blood of patients with thrombocytopenic purpura. J. Lab. Clin. Med. 1951;38:1–10.
    1. Shulman N.R., Marder V.J., Weinrach R.S. Similarities between known antiplatelet antibodies and the factor responsible for thrombocytopenia in idiopathic purpura. Physiologic, serologic and isotopic studies. Ann. N. Y. Acad. Sci. 1965;124:499–542. doi: 10.1111/j.1749-6632.1965.tb18984.x.
    1. Olsson B., Andersson P.O., Jernas M., Jacobsson S., Carlsson B., Carlsson L.M., Wadenvik H. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat. Med. 2003;9:1123–1124. doi: 10.1038/nm921.
    1. Khodadi E., Asnafi A.A., Shahrabi S., Shahjahani M., Saki N. Bone marrow niche in immune thrombocytopenia: A focus on megakaryopoiesis. Ann. Hematol. 2016;95:1765–1776. doi: 10.1007/s00277-016-2703-1.
    1. Dameshek W., Miller E.B. The megakaryocytes in idiopathic thrombocytopenic purpura, a form of hypersplenism. Blood. 1946;1:27–50.
    1. Pisciotta A.V., Stefanini M., Dameshek W. Studies on platelets. X. Morphologic characteristics of megakaryocytes by phase contrast microscopy in normals and in patients with idiopathic thrombocytopenic purpura. Blood. 1953;8:703–723.
    1. Neylon A.J., Saunders P.W., Howard M.R., Proctor S.J., Taylor P.R., Northern Region Haematology Group Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: A prospective study of a population-based cohort of 245 patients. Br. J. Haematol. 2003;122:966–974. doi: 10.1046/j.1365-2141.2003.04547.x.
    1. Perera M., Garrido T. Advances in the pathophysiology of primary immune thrombocytopenia. Hematology. 2016;22:41–53. doi: 10.1080/10245332.2016.1219497.
    1. Schulze H., Gaedicke G. Immune thrombocytopenia in children and adults: What’s the same, what’s different? Haematologica. 2011;96:1739–1741. doi: 10.3324/haematol.2011.055830.
    1. Provan D., Newland A.C. Current Management of Primary Immune Thrombocytopenia. Adv. Ther. 2015;32:875–887. doi: 10.1007/s12325-015-0251-z.
    1. Zhang W., Nardi M.A., Borkowsky W., Li Z., Karpatkin S. Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia. Blood. 2009;113:4086–4093. doi: 10.1182/blood-2008-09-181073.
    1. Wright J.F., Blanchette V.S., Wang H., Arya N., Petric M., Semple J.W., Chia W.K., Freedman J. Characterization of platelet-reactive antibodies in children with varicella-associated acute immune thrombocytopenic purpura (ITP) Br. J. Haematol. 1996;95:145–152. doi: 10.1046/j.1365-2141.1996.d01-1872.x.
    1. Takahashi T., Yujiri T., Shinohara K., Inoue Y., Sato Y., Fujii Y., Okubo M., Zaitsu Y., Ariyoshi K., Nakamura Y., et al. Molecular mimicry by Helicobacter pylori CagA protein may be involved in the pathogenesis of H. pylori-associated chronic idiopathic thrombocytopenic purpura. Br. J. Haematol. 2004;124:91–96. doi: 10.1046/j.1365-2141.2003.04735.x.
    1. Li Z., Nardi M.A., Karpatkin S. Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia. Blood. 2005;106:572–576. doi: 10.1182/blood-2005-01-0243.
    1. Cines D.B., Bussel J.B., Liebman H.A., Luning Prak E.T. The ITP syndrome: Pathogenic and clinical diversity. Blood. 2009;113:6511–6521. doi: 10.1182/blood-2009-01-129155.
    1. Terrell D.R., Beebe L.A., Vesely S.K., Neas B.R., Segal J.B., George J.N. The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports. Am. J. Hematol. 2010;85:174–180. doi: 10.1002/ajh.21616.
    1. Frederiksen H., Schmidt K. The incidence of idiopathic thrombocytopenic purpura in adults increases with age. Blood. 1999;94:909–913.
    1. Fogarty P.F., Segal J.B. The epidemiology of immune thrombocytopenic purpura. Curr. Opin. Hematol. 2007;14:515–519. doi: 10.1097/MOH.0b013e3282ab98c7.
    1. Semple J.W., Italiano J.E., Jr., Freedman J. Platelets and the immune continuum. Nat. Rev. Immunol. 2011;11:264–274. doi: 10.1038/nri2956.
    1. Lazarus A.H., Semple J.W., Cines D.B. Innate and adaptive immunity in immune thrombocytopenia. Semin. Hematol. 2013;50:S68–S70. doi: 10.1053/j.seminhematol.2013.03.012.
    1. Heitink-Polle K.M., Haverman L., Annink K.V., Schep S.J., de Haas M., Bruin M.C. Health-related quality of life in children with newly diagnosed immune thrombocytopenia. Haematologica. 2014;99:1525–1531. doi: 10.3324/haematol.2014.106963.
    1. George J.N., Mathias S.D., Go R.S., Guo M., Henry D.H., Lyons R., Redner R.L., Rice L., Schipperus M.R. Improved quality of life for romiplostim-treated patients with chronic immune thrombocytopenic purpura: Results from two randomized, placebo-controlled trials. Br. J. Haematol. 2009;144:409–415. doi: 10.1111/j.1365-2141.2008.07464.x.
    1. Efficace F., Mandelli F., Fazi P., Santoro C., Gaidano G., Cottone F., Borchiellini A., Carpenedo M., Simula M.P., Di Giacomo V., et al. Health-related quality of life and burden of fatigue in patients with primary immune thrombocytopenia by phase of disease. Am. J. Hematol. 2016;91:995–1001. doi: 10.1002/ajh.24463.
    1. Hill Q.A., Newland A.C. Fatigue in immune thrombocytopenia. Br. J. Haematol. 2015;170:141–149. doi: 10.1111/bjh.13385.
    1. Newton J.L., Reese J.A., Watson S.I., Vesely S.K., Bolton-Maggs P.H., George J.N., Terrell D.R. Fatigue in adult patients with primary immune thrombocytopenia. Eur. J. Haematol. 2011;86:420–429. doi: 10.1111/j.1600-0609.2011.01587.x.
    1. Neunert C., Lim W., Crowther M., Cohen A., Solberg L., Jr., Crowther M.A., American Society of Hematology The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117:4190–4207. doi: 10.1182/blood-2010-08-302984.
    1. Karpatkin S., Siskind G.W. In vitro detection of platelet antibody in patients with idiopathic thrombocytopenic purpura and systemic lupus erythematosus. Blood. 1969;33:795–812.
    1. Karpatkin S., Strick N., Karpatkin M.B., Siskind G.W. Cumulative experience in the detection of antiplatelet antibody in 234 patients with idiopathic thrombocytopenic purpura, systemic lupus erythematosus and other clinical disorders. Am. J. Med. 1972;52:776–785. doi: 10.1016/0002-9343(72)90084-8.
    1. Lightsey A.L., Jr., McMillan R., Koenig H.M., Schanberger J.E., Lang J.E. In vitro production of platelet-binding IgG in childhood idiopathic thrombocytopenic purpura. J. Pediatr. 1976;88:415–418. doi: 10.1016/S0022-3476(76)80255-7.
    1. He R., Reid D.M., Jones C.E., Shulman N.R. Spectrum of Ig classes, specificities, and titers of serum antiglycoproteins in chronic idiopathic thrombocytopenic purpura. Blood. 1994;83:1024–1032.
    1. Boylan B., Chen H., Rathore V., Paddock C., Salacz M., Friedman K.D., Curtis B.R., Stapleton M., Newman D.K., Kahn M.L., et al. Anti-GPVI-associated ITP: An acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FcRgamma-chain complex from the human platelet surface. Blood. 2004;104:1350–1355. doi: 10.1182/blood-2004-03-0896.
    1. Saleh M.N., Moore D.L., Lee J.Y., LoBuglio A.F. Monocyte-platelet interaction in immune and nonimmune thrombocytopenia. Blood. 1989;74:1328–1331.
    1. Chow L., Aslam R., Speck E.R., Kim M., Cridland N., Webster M.L., Chen P., Sahib K., Ni H., Lazarus A.H., 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;115:1247–1253. doi: 10.1182/blood-2009-09-244772.
    1. Chang M., Nakagawa P.A., Williams S.A., Schwartz M.R., Imfeld K.L., Buzby J.S., Nugent D.J. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood. 2003;102:887–895. doi: 10.1182/blood-2002-05-1475.
    1. McMillan R., Wang L., Tomer A., Nichol J., Pistillo J. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood. 2004;103:1364–1369. doi: 10.1182/blood-2003-08-2672.
    1. Aledort L.M., Hayward C.P., Chen M.G., Nichol J.L., Bussel J., Group I.T.P.S. Prospective screening of 205 patients with ITP, including diagnosis, serological markers, and the relationship between platelet counts, endogenous thrombopoietin, and circulating antithrombopoietin antibodies. Am. J. Hematol. 2004;76:205–213. doi: 10.1002/ajh.20104.
    1. Kaushansky K. The molecular mechanisms that control thrombopoiesis. J. Clin. Investig. 2005;115:3339–3347. doi: 10.1172/JCI26674.
    1. Ballem P.J., Segal G.M., Stratton J.R., Gernsheimer T., Adamson J.W., Slichter S.J. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J. Clin. Investig. 1987;80:33–40. doi: 10.1172/JCI113060.
    1. Emmons R.V., Reid D.M., Cohen R.L., Meng G., Young N.S., Dunbar C.E., Shulman N.R. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood. 1996;87:4068–4071.
    1. Semple J.W., Freedman J. Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia. Blood. 1991;78:2619–2625.
    1. Stasi R. Immune thrombocytopenia: Pathophysiologic and clinical update. Semin. Thromb. Hemost. 2012;38:454–462. doi: 10.1055/s-0032-1305780.
    1. Olsson B., Ridell B., Carlsson L., Jacobsson S., Wadenvik H. Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1. Blood. 2008;112:1078–1084. doi: 10.1182/blood-2008-02-139402.
    1. Houwerzijl E.J., Blom N.R., van der Want J.J., Esselink M.T., Koornstra J.J., Smit J.W., Louwes H., Vellenga E., de Wolf J.T. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood. 2004;103:500–506. doi: 10.1182/blood-2003-01-0275.
    1. Houwerzijl E.J., Blom N.R., van der Want J.J., Vellenga E., de Wolf J.T. Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death. Leukemia. 2006;20:1937–1942. doi: 10.1038/sj.leu.2404385.
    1. Semple J.W., Milev Y., Cosgrave D., Mody M., Hornstein A., Blanchette V., Freedman J. Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: Relationship to platelet phenotype and antiplatelet T-cell reactivity. Blood. 1996;87:4245–4254.
    1. Feng X., Scheinberg P., Samsel L., Rios O., Chen J., McCoy J.P., Jr., Ghanima W., Bussel J.B., Young N.S. Decreased plasma cytokines are associated with low platelet counts in aplastic anemia and immune thrombocytopenic purpura. J. Thromb. Haemost. 2012;10:1616–1623. doi: 10.1111/j.1538-7836.2012.04757.x.
    1. Talaat R.M., Elmaghraby A.M., Barakat S.S., El-Shahat M. Alterations in immune cell subsets and their cytokine secretion profile in childhood idiopathic thrombocytopenic purpura (ITP) Clin. Exp. Immunol. 2014;176:291–300. doi: 10.1111/cei.12279.
    1. Cuker A., Prak E.T., Cines D.B. Can immune thrombocytopenia be cured with medical therapy? Semin. Thromb. Hemost. 2015;41:395–404.
    1. Nomura S. Advances in Diagnosis and Treatments for Immune Thrombocytopenia. Clin. Med. Insights Blood Disord. 2016;9:15–22. doi: 10.4137/CMBD.S39643.
    1. Nielsen O.H., Tuckuviene R., Nielsen K.R., Rosthoj S. Flow cytometric measurement of platelet-associated immunoglobulin in children with newly diagnosed Immune Thrombocytopenia. Eur. J. Haematol. 2016;96:397–403. doi: 10.1111/ejh.12605.
    1. Arnason J.E., Campigotto F., Neuberg D., Bussel J.B. Abnormalities in IgA and IgM are associated with treatment-resistant ITP. Blood. 2012;119:5016–5020. doi: 10.1182/blood-2011-09-381020.
    1. Cines D.B., Cuker A., Semple J.W. Pathogenesis of immune thrombocytopenia. Presse Med. 2014;43:e49–e59. doi: 10.1016/j.lpm.2014.01.010.
    1. Zhang H.Y., Hou M., Zhang X.H., Guan X.H., Sun G.Z. The diagnostic value of platelet glycoprotein-specific autoantibody detection in idiopathic thrombocytopenic purpura. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2004;12:204–206.
    1. Fujisawa K., O’Toole T.E., Tani P., Loftus J.C., Plow E.F., Ginsberg M.H., McMillan R. Autoantibodies to the presumptive cytoplasmic domain of platelet glycoprotein IIIa in patients with chronic immune thrombocytopenic purpura. Blood. 1991;77:2207–2213.
    1. 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. Investig. 1998;102:1393–1402. doi: 10.1172/JCI4238.
    1. Jin C.Q., Dong H.X., Cheng P.P., Zhou J.W., Zheng B.Y., Liu F. Antioxidant status and oxidative stress in patients with chronic ITP. Scand. J. Immunol. 2013;77:482–487. doi: 10.1111/sji.12048.
    1. Nieswandt B., Bergmeier W., Rackebrandt K., Gessner J.E., Zirngibl H. Identification of critical antigen-specific mechanisms in the development of immune thrombocytopenic purpura in mice. Blood. 2000;96:2520–2527.
    1. Webster M.L., Sayeh E., Crow M., Chen P., Nieswandt B., Freedman J., Ni H. Relative efficacy of intravenous immunoglobulin G in ameliorating thrombocytopenia induced by antiplatelet GPIIbIIIa versus GPIbalpha antibodies. Blood. 2006;108:943–946. doi: 10.1182/blood-2005-06-009761.
    1. Mason K.D., Carpinelli M.R., Fletcher J.I., Collinge J.E., Hilton A.A., Ellis S., Kelly P.N., Ekert P.G., Metcalf D., Roberts A.W., et al. Programmed anuclear cell death delimits platelet life span. Cell. 2007;128:1173–1186. doi: 10.1016/j.cell.2007.01.037.
    1. Leytin V., Mykhaylov S., Starkey A.F., Allen D.J., Lau H., Ni H., Semple J.W., Lazarus A.H., Freedman J. Intravenous immunoglobulin inhibits anti-glycoprotein IIb-induced platelet apoptosis in a murine model of immune thrombocytopenia. Br. J. Haematol. 2006;133:78–82. doi: 10.1111/j.1365-2141.2006.05981.x.
    1. Deng G., Yu S., Li Q., He Y., Liang W., Yu L., Xu D. Investigation of platelet apoptosis in adult patients with chronic immune thrombocytopenia. Hematology. 2016:1–7. doi: 10.1080/10245332.2016.1237004.
    1. Urbanus R.T., van der Wal D.E., Koekman C.A., Huisman A., van den Heuvel D.J., Gerritsen H.C., Deckmyn H., Akkerman J.N., Schutgens R.E.G., Gitz E. Patient autoantibodies induce platelet destruction signals via raft-associated glycoprotein Ibalpha and Fc RIIa in immune thrombocytopenia. Haematologica. 2013;98:e70–e72. doi: 10.3324/haematol.2013.087874.
    1. Kapur R., Heitink-Polle K.M., Porcelijn L., Bentlage A.E., Bruin M.C., Visser R., Roos D., Schasfoort R.B., de Haas M., van der Schoot C.E., et al. C-reactive protein enhances IgG-mediated phagocyte responses and thrombocytopenia. Blood. 2015;125:1793–1802. doi: 10.1182/blood-2014-05-579110.
    1. Weiss H.J., Rosove M.H., Lages B.A., Kaplan K.L. Acquired storage pool deficiency with increased platelet-associated IgG. Report of five cases. Am. J. Med. 1980;69:711–717. doi: 10.1016/0002-9343(80)90436-2.
    1. Sarpatwari A., Bennett D., Logie J.W., Shukla A., Beach K.J., Newland A.C., Sanderson S., Proven D. Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database. Haematologica. 2010;95:1167–1175. doi: 10.3324/haematol.2009.018390.
    1. Severinsen M.T., Engebjerg M.C., Farkas D.K., Jensen A.O., Norgaard M., Zhao S., Sorensen H.T. Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: A Danish population-based cohort study. Br. J. Haematol. 2011;152:360–362. doi: 10.1111/j.1365-2141.2010.08418.x.
    1. Norgaard M., Severinsen M.T., Lund Maegbaek M., Jensen A.O., Cha S., Sorensen H.T. Risk of arterial thrombosis in patients with primary chronic immune thrombocytopenia: A Danish population-based cohort study. Br. J. Haematol. 2012;159:109–111. doi: 10.1111/j.1365-2141.2012.09231.x.
    1. Jy W., Horstman L.L., Arce M., Ahn Y.S. Clinical significance of platelet microparticles in autoimmune thrombocytopenias. J. Lab. Clin. Med. 1992;119:334–345.
    1. Alvarez-Roman M.T., Fernandez-Bello I., Jimenez-Yuste V., Martin-Salces M., Arias-Salgado E.G., Rivas Pollmar M.I., Justo Sanz R., Butta N.V. Procoagulant profile in patients with immune thrombocytopenia. Br. J. Haematol. 2016;175:925–934. doi: 10.1111/bjh.14412.
    1. Yanabu M., Nomura S., Fukuroi T., Suzuki M., Kawakatsu T., Kido H., Yamaguchi K. Platelet activation induced by an antiplatelet autoantibody against CD9 antigen and its inhibition by another autoantibody in immune thrombocytopenic purpura. Br. J. Haematol. 1993;84:694–701. doi: 10.1111/j.1365-2141.1993.tb03148.x.
    1. Chen J.F., Yang L.H., Chang L.X., Feng J.J., Liu J.Q. The clinical significance of circulating B cells secreting anti-glycoprotein IIb/IIIa antibody and platelet glycoprotein IIb/IIIa in patients with primary immune thrombocytopenia. Hematology. 2012;17:283–290. doi: 10.1179/1607845412Y.0000000014.
    1. Emmerich F., Bal G., Barakat A., Milz J., Muhle C., Martinez-Gamboa L., Dorner T., Salama A. High-level serum B-cell activating factor and promoter polymorphisms in patients with idiopathic thrombocytopenic purpura. Br. J. Haematol. 2007;136:309–314. doi: 10.1111/j.1365-2141.2006.06431.x.
    1. Zhou Z.H., Zhuang L., Li X.Y., Li J., Luo S.K. The role of B cell-activating factor secreted by peripheral blood monocyte-derived dendritic cell in chronic idiopathic thrombocytopenic purpura. Zhonghua Xue Ye Xue Za Zhi. 2010;31:599–602.
    1. Yang Q., Xu S., Li X., Wang B., Wang X., Ma D., Yang L., Peng J., Hou M. Pathway of Toll-like receptor 7/B cell activating factor/B cell activating factor receptor plays a role in immune thrombocytopenia in vivo. PLoS ONE. 2011;6:e22708. doi: 10.1371/journal.pone.0022708.
    1. Yu H., Liu Y., Han J., Yang Z., Sheng W., Dai H., Wang Y., Xia T., Hou M. TLR7 regulates dendritic cell-dependent B-cell responses through BlyS in immune thrombocytopenic purpura. Eur. J. Haematol. 2011;86:67–74. doi: 10.1111/j.1600-0609.2010.01534.x.
    1. Olsson B., Ridell B., Jernas M., Wadenvik H. Increased number of B-cells in the red pulp of the spleen in ITP. Ann. Hematol. 2012;91:271–277. doi: 10.1007/s00277-011-1292-2.
    1. Daridon C., Loddenkemper C., Spieckermann S., Kuhl A.A., Salama A., Burmester G.R., Lipsky P.E., Dörner T. Splenic proliferative lymphoid nodules distinct from germinal centers are sites of autoantigen stimulation in immune thrombocytopenia. Blood. 2012;120:5021–5031. doi: 10.1182/blood-2012-04-424648.
    1. Li X., Zhong H., Bao W., Boulad N., Evangelista J., Haider M.A., Bussel J., Yazdanbakhsh K. Defective regulatory B-cell compartment in patients with immune thrombocytopenia. Blood. 2012;120:3318–3325. doi: 10.1182/blood-2012-05-432575.
    1. Semple J.W. Bregging rights in ITP. Blood. 2012;120:3169. doi: 10.1182/blood-2012-08-448522.
    1. Nishimoto T., Kuwana M. CD4+CD25+Foxp3+ regulatory T cells in the pathophysiology of immune thrombocytopenia. Semin. Hematol. 2013;50:S43–S49. doi: 10.1053/j.seminhematol.2013.03.018.
    1. Mauri C., Bosma A. Immune regulatory function of B cells. Annu. Rev. Immunol. 2012;30:221–241. doi: 10.1146/annurev-immunol-020711-074934.
    1. Aslam R., Segel G.B., Burack R., Spence S.A., Speck E.R., Guo L., Semple J.W. Splenic lymphocyte subtypes in immune thrombocytopenia: Increased presence of a subtype of B-regulatory cells. Br. J. Haematol. 2016;173:159–160. doi: 10.1111/bjh.13567.
    1. Jansen P.H., Renier W.O., de Vaan G., Reekers P., Vingerhoets D.M., Gabreels F.J. Effect of thymectomy on myasthenia gravis and autoimmune thrombocytopenic purpura in a 13-year-old girl. Eur. J. Pediatr. 1987;146:587–589. doi: 10.1007/BF02467359.
    1. Stuart M.J., Tomar R.H., Miller M.L., Davey F.R. Chronic idiopathic thrombocytopenic purpura. A familial immunodeficiency syndrome? JAMA. 1978;239:939–942. doi: 10.1001/jama.1978.03280370035020.
    1. Waters A.H. Autoimmune thrombocytopenia: Clinical aspects. Semin. Hematol. 1992;29:18–25.
    1. Qiu J., Liu X., Li X., Zhang X., Han P., Zhou H., Shao L., Hou Y., Min Y., Kong Z., et al. CD8(+) T cells induce platelet clearance in the liver via platelet desialylation in immune thrombocytopenia. Sci. Rep. 2016;6:27445. doi: 10.1038/srep27445.
    1. Zhang F., Chu X., Wang L., Zhu Y., Li L., Ma D., Peng J., Hou M. Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura. Eur. J. Haematol. 2006;76:427–431. doi: 10.1111/j.1600-0609.2005.00622.x.
    1. Zhao C., Li X., Zhang F., Wang L., Peng J., Hou M. Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies. Haematologica. 2008;93:1428–1430. doi: 10.3324/haematol.12889.
    1. Stasi R., Cooper N., Del Poeta G., Stipa E., Laura Evangelista M., Abruzzese E., Amadori S. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood. 2008;112:1147–1150. doi: 10.1182/blood-2007-12-129262.
    1. Bao W., Bussel J.B., Heck S., He W., Karpoff M., Boulad N., Yazdanbakhsh K. Improved regulatory T-cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010;116:4639–4645. doi: 10.1182/blood-2010-04-281717.
    1. Audia S., Samson M., Guy J., Janikashvili N., Fraszczak J., Trad M., Ciudad M., Leguy V., Berthier S., Petrella T., et al. Immunologic effects of rituximab on the human spleen in immune thrombocytopenia. Blood. 2011;118:4394–4400. doi: 10.1182/blood-2011-03-344051.
    1. Li Z., Mou W., Lu G., Cao J., He X., Pan X., Xu K. Low-dose rituximab combined with short-term glucocorticoids up-regulates Treg cell levels in patients with immune thrombocytopenia. Int. J. Hematol. 2011;93:91–98. doi: 10.1007/s12185-010-0753-z.
    1. Li H., Ge J., Zhao H., Du W., Xu J., Sui T., Ma L., Zhou Z., Qi A., Yang R. Association of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with idiopathic thrombocytopenic purpura in a Chinese population. Platelets. 2011;22:39–44. doi: 10.3109/09537104.2010.521601.
    1. Fahim N.M., Monir E. Functional role of CD4+CD25+ regulatory T cells and transforming growth factor-beta1 in childhood immune thrombocytopenic purpura. Egypt. J. Immunol. 2006;13:173–187.
    1. Ling Y., Cao X., Yu Z., Ruan C. 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;79:310–316. doi: 10.1111/j.1600-0609.2007.00917.x.
    1. Ling Y., Cao X.S., Yu Z.Q., Luo G.H., Bai X., Su J., Dai L., Ruan C.G. Alterations of CD4+ CD25+ regulatory T cells in patients with idiopathic thrombocytopenic purpura. Zhonghua Xue Ye Xue Za Zhi. 2007;28:184–188.
    1. Sakakura M., Wada H., Tawara I., Nobori T., Sugiyama T., Sagawa N., Shiku H. Reduced Cd4+Cd25+ T cells in patients with idiopathic thrombocytopenic purpura. Thromb. Res. 2007;120:187–193. doi: 10.1016/j.thromres.2006.09.008.
    1. Zhang J., Ma D., Zhu X., Qu X., Ji C., Hou M. Elevated profile of Th17, Th1 and Tc1 cells in patients with immune thrombocytopenic purpura. Haematologica. 2009;94:1326–1329. doi: 10.3324/haematol.2009.007823.
    1. Zhang X.L., Peng J., Sun J.Z., Liu J.J., Guo C.S., Wang Z.G., Yu Y., Shi Y., Qin P., Li S.G., et al. De novo induction of platelet-specific CD4(+)CD25(+) regulatory T cells from CD4(+)CD25(−) cells in patients with idiopathic thrombocytopenic purpura. Blood. 2009;113:2568–2577. doi: 10.1182/blood-2008-03-148288.
    1. Abudureheman A., Yasen H., Zhao F., Zhang X., Ding J., Ma X., Guo X. Expression of CD4+ CD25+ regulatory T cells and TGF-ss1 in patient with idiopathic thrombocytopenic purpura. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2010;26:895–897.
    1. Chang D.Y., Ouyang J., Zhou R.F., Xu J.Y., Chen B., Yang Y.G., Zhang Q.G., Shao X.Y., Guan C.Y., Xu Y. Profiles of different subsets of CD(4)(+) T cells in chronic idiopathic thrombocytopenic purpura. Zhonghua Nei Ke Za Zhi. 2010;49:213–216.
    1. Aboul-Fotoh Lel M., Abdel Raheem M.M., El-Deen M.A., Osman A.M. Role of CD4+CD25+ T cells in children with idiopathic thrombocytopenic purpura. J. Pediatr. Hematol. Oncol. 2011;33:81–85. doi: 10.1097/MPH.0b013e3181f46b82.
    1. Wang X.P., Qiu Y.S., Hao G.P., Zhu L. Levels of regulatory T cells in peripheral blood of children with idiopathic thrombocytopenic purpura. Zhongguo Dang Dai Er Ke Za Zhi. 2011;13:282–284.
    1. Park S.H., Kim J.Y., Kim S.K., Choe J.Y., Kim S.G., Ryoo H.M. Regulatory T-cells in systemic lupus erythematosus-associated thrombocytopenia: A comparison with idiopathic thrombocytopenic purpura. Lupus. 2010;19:888–889. doi: 10.1177/0961203309357062.
    1. Ji L., Zhan Y., Hua F., Li F., Zou S., Wang W., Song D. The ratio of Treg/Th17 cells correlates with the disease activity of primary immune thrombocytopenia. PLoS ONE. 2012;7:e50909. doi: 10.1371/journal.pone.0050909.
    1. Olsson B., Andersson P.O., Jacobsson S., Carlsson L., Wadenvik H. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb. Haemost. 2005;93:139–144. doi: 10.1160/TH04-06-0385.
    1. Gratz I.K., Rosenblum M.D., Abbas A.K. The life of regulatory T cells. Ann. N. Y. Acad. Sci. 2013;1283:8–12. doi: 10.1111/nyas.12011.
    1. Sakaguchi S., Miyara M., Costantino C.M., Hafler D.A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 2010;10:490–500. doi: 10.1038/nri2785.
    1. Semple J.W., Provan D., Garvey M.B., Freedman J. Recent progress in understanding the pathogenesis of immune thrombocytopenia. Curr. Opin. Hematol. 2010;17:590–595. doi: 10.1097/MOH.0b013e32833eaef3.
    1. Kuwana M., Ikeda Y. The role of autoreactive T-cells in the pathogenesis of idiopathic thrombocytopenic purpura. Int. J. Hematol. 2005;81:106–112. doi: 10.1532/IJH97.04176.
    1. Andre S., Tough D.F., Lacroix-Desmazes S., Kaveri S.V., Bayry J. Surveillance of antigen-presenting cells by CD4+ CD25+ regulatory T cells in autoimmunity: Immunopathogenesis and therapeutic implications. Am. J. Pathol. 2009;174:1575–1587. doi: 10.2353/ajpath.2009.080987.
    1. Liu B., Zhao H., Poon M.C., Han Z., Gu D., Xu M., Jia H., Yang R., Han Z.C. Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura. Eur. J. Haematol. 2007;78:139–143. doi: 10.1111/j.1600-0609.2006.00780.x.
    1. Yu J., Heck S., Patel V., Levan J., Yu Y., Bussel J.B., Yazdanbakhsh K. Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura. Blood. 2008;112:1325–1328. doi: 10.1182/blood-2008-01-135335.
    1. Aslam R., Hu Y., Gebremeskel S., Segel G.B., Speck E.R., Guo L., Kim M. 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;120:2127–2132. doi: 10.1182/blood-2012-02-413526.
    1. Catani L., Sollazzo D., Trabanelli S., Curti A., Evangelisti C., Polverelli N., Palandri F. Decreased expression of indoleamine 2,3-dioxygenase 1 in dendritic cells contributes to impaired regulatory T cell development in immune thrombocytopenia. Ann. Hematol. 2013;92:67–78. doi: 10.1007/s00277-012-1556-5.
    1. Yang Y., Zhang X., Zhang D., Li H., Ma L., Xuan M., Wang H., Yang R. Abnormal Distribution and Function of Monocyte Subsets in Patients With Primary Immune Thrombocytopenia. Clin. Appl. Thromb. Hemost. 2016 doi: 10.1177/1076029616652726.
    1. Zhong H., Bao W., Li X., Miller A., Seery C., Haq N., Bussel J., Yazdanbakhsh K. CD16+ monocytes control T-cell subset development in immune thrombocytopenia. Blood. 2012;120:3326–3335. doi: 10.1182/blood-2012-06-434605.
    1. Ware R.E., Howard T.A. Phenotypic and clonal analysis of T lymphocytes in childhood immune thrombocytopenic purpura. Blood. 1993;82:2137–2142.
    1. Filion M.C., Bradley A.J., Devine D.V., Decary F., Chartrand P. Autoreactive T cells in healthy individuals show tolerance in vitro with characteristics similar to but distinct from clonal anergy. Eur. J. Immunol. 1995;25:3123–3127. doi: 10.1002/eji.1830251120.
    1. Coopamah M.D., Garvey M.B., Freedman J., Semple J.W. Cellular immune mechanisms in autoimmune thrombocytopenic purpura: An update. Transfus. Med. Rev. 2003;17:69–80. doi: 10.1053/tmrv.2003.50004.
    1. Eyerich S., Eyerich K., Pennino D., Carbone T., Nasorri F., Pallotta S., Cianfarani F., Odorisio T., Traidl-Hoffmann C., Behrendt H. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J. Clin. Investig. 2009;119:3573–3585. doi: 10.1172/JCI40202.
    1. Cao J., Chen C., Li L., Zeng L., Li Z., Yan Z., Chen W., Cheng H., Sang W., Xu K. Effects of high-dose dexamethasone on regulating interleukin-22 production and correcting Th1 and Th22 polarization in immune thrombocytopenia. J. Clin. Immunol. 2012;32:523–529. doi: 10.1007/s10875-012-9649-4.
    1. Cao J., Chen C., Zeng L., Li L., Li X., Li Z., Xu K. Elevated plasma IL-22 levels correlated with Th1 and Th22 cells in patients with immune thrombocytopenia. Clin. Immunol. 2011;141:121–123. doi: 10.1016/j.clim.2011.05.003.
    1. Hu Y., Li H., Zhang L., Shan B., Xu X., Li H., Liu X., Xu S., Yu S., Ma D., et al. Elevated profiles of Th22 cells and correlations with Th17 cells in patients with immune thrombocytopenia. Hum. Immunol. 2012;73:629–635. doi: 10.1016/j.humimm.2012.04.015.
    1. Liu L.M., Zhang X.X., Zhao G.S., Si Y.J., Lin G.Q., Zhang Y.M., He G.S., Wu D.P. Change of Th22 cells in peripheral blood of patients with primary immune thrombocytopenia and clinical implication. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2012;28:1314–1316.
    1. Guo N.H., Shi Q.Z., Hua J.Y., Li Z.J., Li J., He W.F., Wu Q. Expression of regulatory T cells and Th17 cells in idiopathic thrombocytopenic purpura and its significance. Zhonghua Xue Ye Xue Za Zhi. 2010;31:610–612.
    1. Hu Y., Ma D.X., Shan N.N., Zhu Y.Y., Liu X.G., Zhang L., Yu S. Increased number of Tc17 and correlation with Th17 cells in patients with immune thrombocytopenia. PLoS ONE. 2011;6:e26522. doi: 10.1371/journal.pone.0026522.
    1. Rocha A.M., Souza C., Rocha G.A., de Melo F.F., Clementino N.C., Marino M.C., Bozzi A., Silva M.L., Martins Filho O.A., Queiroz D.M. The levels of IL-17A and of the cytokines involved in Th17 cell commitment are increased in patients with chronic immune thrombocytopenia. Haematologica. 2011;96:1560–1564. doi: 10.3324/haematol.2011.046417.
    1. Duan X.J., Yang L.H., Zhang L., Ren F.G., Zhang R.J., Chen J.F., Qin X.Y., Liang H.Z. Expressions of Th17 cells and interleukin 17 in patients with primary immune thrombocytopenia and their clinical significance. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2012;20:1154–1157.
    1. Yoh K., Morito N., Ojima M., Shibuya K., Yamashita Y., Morishima Y., Ishii Y., Kusakabe M., Nishikii H., Fujita A., et al. Overexpression of RORgammat under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice. Eur. J. Immunol. 2012;42:1999–2009. doi: 10.1002/eji.201142250.
    1. Baeten D.L., Kuchroo V.K. How Cytokine networks fuel inflammation: Interleukin-17 and a tale of two autoimmune diseases. Nat. Med. 2013;19:824–825. doi: 10.1038/nm.3268.
    1. Guo Z.X., Chen Z.P., Zheng C.L., Jia H.R., Ge J., Gu D.S., Du W.T., Wang X.Y., Zhao H.F., Yang R.C. The role of Th17 cells in adult patients with chronic idiopathic thrombocytopenic purpura. Eur. J. Haematol. 2009;82:488–489. doi: 10.1111/j.1600-0609.2009.01229.x.
    1. Ma D., Zhu X., Zhao P., Zhao C., Li X., Zhu Y., Li L. Profile of Th17 cytokines (IL-17, TGF-beta, IL-6) and Th1 cytokine (IFN-gamma) in patients with immune thrombocytopenic purpura. Ann. Hematol. 2008;87:899–904. doi: 10.1007/s00277-008-0535-3.
    1. Sollazzo D., Trabanelli S., Curti A., Vianelli N., Lemoli R.M., Catani L. Circulating CD4+CD161+CD196+ Th17 cells are not increased in immune thrombocytopenia. Haematologica. 2011;96:632–634. doi: 10.3324/haematol.2010.038638.
    1. Rock K.L., Benacerraf B., Abbas A.K. Antigen presentation by hapten-specific B lymphocytes. I. Role of surface immunoglobulin receptors. J. Exp. Med. 1984;160:1102–1113. doi: 10.1084/jem.160.4.1102.
    1. Unanue E.R. Antigen-presenting function of the macrophage. Annu. Rev. Immunol. 1984;2:395–428. doi: 10.1146/annurev.iy.02.040184.002143.
    1. Amodio G., Gregori S. Dendritic cells a double-edge sword in autoimmune responses. Front. Immunol. 2012;3:233. doi: 10.3389/fimmu.2012.00233.
    1. Watts C. Capture and processing of exogenous antigens for presentation on MHC molecules. Annu. Rev. Immunol. 1997;15:821–850. doi: 10.1146/annurev.immunol.15.1.821.
    1. Banchereau J., Briere F., Caux C., Davoust J., Lebecque S., Liu Y.J., Pulendran B. Immunobiology of dendritic cells. Annu. Rev. Immunol. 2000;18:767–811. doi: 10.1146/annurev.immunol.18.1.767.
    1. Chaplin D.D. Overview of the immune response. J. Allergy Clin. Immunol. 2010;125:S3–23. doi: 10.1016/j.jaci.2009.12.980.
    1. Hughes C.E., Benson R.A., Bedaj M., Maffia P. Antigen-Presenting Cells and Antigen Presentation in Tertiary Lymphoid Organs. Front. Immunol. 2016;7:481. doi: 10.3389/fimmu.2016.00481.
    1. Coutant F., Miossec P. Altered dendritic cell functions in autoimmune diseases: Distinct and overlapping profiles. Nat. Rev. Rheumatol. 2016;12:703–715. doi: 10.1038/nrrheum.2016.147.
    1. Catani L., Fagioli M.E., Tazzari P.L., Ricci F., Curti A., Rovito M., Preda P. Dendritic cells of immune thrombocytopenic purpura (ITP) show increased capacity to present apoptotic platelets to T lymphocytes. Exp. Hematol. 2006;34:879–887. doi: 10.1016/j.exphem.2006.03.009.
    1. Saito A., Yokohama A., Osaki Y., Ogawa Y., Nakahashi H., Toyama K., Mitsui T., Hashimoto Y., Koiso H., Uchiumi H., et al. Circulating plasmacytoid dendritic cells in patients with primary and Helicobacter pylori-associated immune thrombocytopenia. Eur. J. Haematol. 2012;88:340–349. doi: 10.1111/j.1600-0609.2011.01745.x.
    1. Swiecki M., Colonna M. The multifaceted biology of plasmacytoid dendritic cells. Nat. Rev. Immunol. 2015;15:471–485. doi: 10.1038/nri3865.
    1. Panda S.K., Kolbeck R., Sanjuan M.A. Plasmacytoid dendritic cells in autoimmunity. Curr. Opin. Immunol. 2016;44:20–25. doi: 10.1016/j.coi.2016.10.006.
    1. Andonegui G., Kerfoot S.M., McNagny K., Ebbert K.V., Patel K.D., Kubes P. Platelets express functional Toll-like receptor-4. Blood. 2005;106:2417–2423. doi: 10.1182/blood-2005-03-0916.
    1. Aslam R., Speck E.R., Kim M., Crow A.R., Bang K.W., Nestel F.P., Ni H., Lazarus A.H., Freedman J., Semple J.W. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood. 2006;107:637–641. doi: 10.1182/blood-2005-06-2202.
    1. Semple J.W., Aslam R., Kim M., Speck E.R., Freedman J. Platelet-bound lipopolysaccharide enhances Fc receptor-mediated phagocytosis of IgG-opsonized platelets. Blood. 2007;109:4803–4805. doi: 10.1182/blood-2006-12-062695.
    1. Machlus K.R., Thon J.N., Italiano J.E., Jr. Interpreting the developmental dance of the megakaryocyte: A review of the cellular and molecular processes mediating platelet formation. Br. J. Haematol. 2014;165:227–236. doi: 10.1111/bjh.12758.
    1. Stahl C.P., Zucker-Franklin D., McDonald T.P. Incomplete antigenic cross-reactivity between platelets and megakaryocytes: Relevance to ITP. Blood. 1986;67:421–428.
    1. Nugent D., McMillan R., Nichol J.L., Slichter S.J. Pathogenesis of chronic immune thrombocytopenia: Increased platelet destruction and/or decreased platelet production. Br. J. Haematol. 2009;146:585–596. doi: 10.1111/j.1365-2141.2009.07717.x.
    1. Norol F., Vitrat N., Cramer E., Guichard J., Burstein S.A., Vainchenker W., Debili N. Effects of cytokines on platelet production from blood and marrow CD34+ cells. Blood. 1998;91:830–843.
    1. Hou M., Andersson P.O., Stockelberg D., Mellqvist U.H., Ridell B., Wadenvik H. Plasma thrombopoietin levels in thrombocytopenic states: Implication for a regulatory role of bone marrow megakaryocytes. Br. J. Haematol. 1998;101:420–424. doi: 10.1046/j.1365-2141.1998.00747.x.
    1. Iraqi M., Perdomo J., Yan F., Choi P.Y., Chong B.H. Immune thrombocytopenia: Antiplatelet autoantibodies inhibit proplatelet formation by megakaryocytes and impair platelet production in vitro. Haematologica. 2015;100:623–632. doi: 10.3324/haematol.2014.115634.
    1. Zhang D., Li H., Ma L., Zhang X., Xue F., Zhou Z., Chi Y. The defective bone marrow-derived mesenchymal stem cells in patients with chronic immune thrombocytopenia. Autoimmunity. 2014;47:519–529. doi: 10.3109/08916934.2014.938320.
    1. Bruns I., Lucas D., Pinho S., Ahmed J., Lambert M.P., Kunisaki Y., Scheiermann C., Schiff L., Poncz M., Bergman A., et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat. Med. 2014;20:1315–1320. doi: 10.1038/nm.3707.
    1. Nakamura-Ishizu A., Takubo K., Kobayashi H., Suzuki-Inoue K., Suda T. CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow. J. Exp. Med. 2015;212:2133–2146. doi: 10.1084/jem.20150057.
    1. Malara A., Abbonante V., Di Buduo C.A., Tozzi L., Currao M., Balduini A. The secret life of a megakaryocyte: Emerging roles in bone marrow homeostasis control. Cell. Mol. Life Sci. 2015;72:1517–1536. doi: 10.1007/s00018-014-1813-y.
    1. Winter O., Moser K., Mohr E., Zotos D., Kaminski H., Szyska M., Roth K., Wong D.M., Dame C., Tarlinton D.M., et al. Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood. 2010;116:1867–1875. doi: 10.1182/blood-2009-12-259457.
    1. Uccelli A., Moretta L., Pistoia V. Immunoregulatory function of mesenchymal stem cells. Eur. J. Immunol. 2006;36:2566–2573. doi: 10.1002/eji.200636416.
    1. Kong Y., Hu Y., Zhang X.H., Wang Y.Z., Mo X.D., Zhang Y.Y., Wang Y., Han W., Xu L.P., Chang Y.J., et al. Association between an impaired bone marrow vascular microenvironment and prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 2014;20:1190–1197. doi: 10.1016/j.bbmt.2014.04.015.
    1. Kojouri K., Vesely S.K., Terrell D.R., George J.N. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: A systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood. 2004;104:2623–2634. doi: 10.1182/blood-2004-03-1168.
    1. Rodeghiero F., Ruggeri M. Short- and long-term risks of splenectomy for benign haematological disorders: Should we revisit the indications? Br. J. Haematol. 2012;158:16–29. doi: 10.1111/j.1365-2141.2012.09146.x.
    1. Lazarus A.H. Monoclonal versus polyclonal anti-D in the treatment of ITP. Expert Opin. Biol. Ther. 2013;13:1353–1356. doi: 10.1517/14712598.2013.825243.
    1. Crow A.R., Lazarus A.H. Mechanistic properties of intravenous immunoglobulin in murine immune thrombocytopenia: Support for FcgammaRIIB falls by the wayside. Semin. Hematol. 2016;53:S20–S22. doi: 10.1053/j.seminhematol.2016.04.007.
    1. Provan D., Stasi R., Newland A.C., Blanchette V.S., Bolton-Maggs P., Bussel J.B., Chong B.H. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168–186. doi: 10.1182/blood-2009-06-225565.
    1. Bussel J.B., Lee C.S., Seery C., Imahiyerobo A.A., Thompson M.V., Catellier D., Turenne I.G. Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration. Haematologica. 2014;99:1264–1271. doi: 10.3324/haematol.2013.103291.
    1. Zaja F., Baccarani M., Mazza P., Bocchia M., Gugliotta L., Zaccaria A., Vianelli N., Defina M., Tieghi A., Amadori S., et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia. Blood. 2010;115:2755–2762. doi: 10.1182/blood-2009-07-229815.
    1. McHeyzer-Williams L.J., McHeyzer-Williams M.G. Antigen-specific memory B cell development. Annu. Rev. Immunol. 2005;23:487–513. doi: 10.1146/annurev.immunol.23.021704.115732.
    1. Grimaldi D., Canoui-Poitrine F., Croisille L., Lee K., Roudot-Thoraval F., Languille L., Khellaf M. Antiplatelet antibodies detected by the MAIPA assay in newly diagnosed immune thrombocytopenia are associated with chronic outcome and higher risk of bleeding. Ann. Hematol. 2014;93:309–315. doi: 10.1007/s00277-013-1855-5.
    1. Cole T.J. Glucocorticoid action and the development of selective glucocorticoid receptor ligands. Biotechnol. Annu. Rev. 2006;12:269–300.
    1. Li J., Wang Z., Dai L., Cao L., Su J., Zhu M., Yu Z., Bai X., Ruan C. Effects of rapamycin combined with low dose prednisone in patients with chronic immune thrombocytopenia. Clin. Dev. Immunol. 2013;2013:548085. doi: 10.1155/2013/548085.
    1. Li J., Wang Z., Hu S., Zhao X., Cao L. Correction of abnormal T cell subsets by high-dose dexamethasone in patients with chronic idiopathic thrombocytopenic purpura. Immunol. Lett. 2013;154:42–48. doi: 10.1016/j.imlet.2013.08.006.
    1. Guo X.H., Zhao F., Shi W., Ma X.M., Xu Q., Patiguli A.B., Halida Y.S. Detection and clinical significance of Th1/Th2 cytokines in patients with idiopathic thrombocytopenic purpura. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2012;28:1185–1187.
    1. Clynes R. Immune complexes as therapy for autoimmunity. J. Clin. Investig. 2005;115:25–27. doi: 10.1172/JCI23994.
    1. Nagelkerke S.Q., Kuijpers T.W. Immunomodulation by IVIg and the Role of Fc-Gamma Receptors: Classic Mechanisms of Action after all? Front. Immunol. 2014;5:674. doi: 10.3389/fimmu.2014.00674.
    1. Gilardin L., Bayry J., Kaveri S.V. Intravenous immunoglobulin as clinical immune-modulating therapy. CMAJ. 2015;187:257–264. doi: 10.1503/cmaj.130375.
    1. Park-Min K.H., Serbina N.V., Yang W., Ma X., Krystal G., Neel B.G., Nutt S.L., Hu X., Ivashkiv L.B. FcgammaRIII-dependent inhibition of interferon-gamma responses mediates suppressive effects of intravenous immune globulin. Immunity. 2007;26:67–78. doi: 10.1016/j.immuni.2006.11.010.
    1. Pang S.J., Lazarus A.H. Mechanisms of platelet recovery in ITP associated with therapy. Ann. Hematol. 2010;89:31–35. doi: 10.1007/s00277-010-0916-2.
    1. Crow A.R., Lazarus A.H. The mechanisms of action of intravenous immunoglobulin and polyclonal anti-d immunoglobulin in the amelioration of immune thrombocytopenic purpura: What do we really know? Transfus. Med. Rev. 2008;22:103–116. doi: 10.1016/j.tmrv.2007.12.001.
    1. Fehr J., Hofmann V., Kappeler U. Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin. N. Engl. J. Med. 1982;306:1254–1258. doi: 10.1056/NEJM198205273062102.
    1. Berchtold P., Dale G.L., Tani P., McMillan R. Inhibition of autoantibody binding to platelet glycoprotein IIb/IIIa by anti-idiotypic antibodies in intravenous gammaglobulin. Blood. 1989;74:2414–2417.
    1. Hansen R.J., Balthasar J.P. Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor. Thromb. Haemost. 2002;88:898–899.
    1. Bayry J., Lacroix-Desmazes S., Carbonneil C., Misra N., Donkova V., Pashov A., Chevailler A., Mouthon L., Weill B., Bruneval P., et al. Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood. 2003;101:758–765. doi: 10.1182/blood-2002-05-1447.
    1. Siragam V., Crow A.R., Brinc D., Song S., Freedman J., Lazarus A.H. Intravenous immunoglobulin ameliorates ITP via activating Fc gamma receptors on dendritic cells. Nat. Med. 2006;12:688–692. doi: 10.1038/nm1416.
    1. Anthony R.M., Wermeling F., Karlsson M.C., Ravetch J.V. Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc. Natl. Acad. Sci. USA. 2008;105:19571–19578. doi: 10.1073/pnas.0810163105.
    1. Salama A., Kiefel V., Amberg R., Mueller-Eckhardt C. Treatment of autoimmune thrombocytopenic purpura with rhesus antibodies (anti-Rho(D)) Blut. 1984;49:29–35. doi: 10.1007/BF00320381.
    1. Song S., Crow A.R., Siragam V., Freedman J., Lazarus A.H. Monoclonal antibodies that mimic the action of anti-D in the amelioration of murine ITP act by a mechanism distinct from that of IVIg. Blood. 2005;105:1546–1548. doi: 10.1182/blood-2004-05-1886.
    1. Ambriz-Fernandez R., Martinez-Murillo C., Quintana-Gonzalez S., Collazo-Jaloma J., Bautista-Juarez J. Fc receptor blockade in patients with refractory chronic immune thrombocytopenic purpura with anti-D IgG. Arch. Med. Res. 2002;33:536–540. doi: 10.1016/S0188-4409(02)00412-5.
    1. Boughton B.J., Cooke R.M., Smith N.A., Simpson A.W. Autoimmune thrombocytopenia: Anti-glycoprotein IIb/IIIa auto antibodies are reduced after human anti-D immunoglobulin treatment. Autoimmunity. 1994;18:141–144. doi: 10.3109/08916939409007987.
    1. Kuwana M., Okazaki Y., Kaburaki J., Kawakami Y., Ikeda Y. Spleen is a primary site for activation of platelet-reactive T and B cells in patients with immune thrombocytopenic purpura. J. Immunol. 2002;168:3675–3682. doi: 10.4049/jimmunol.168.7.3675.
    1. Knobl P. Inherited and acquired thrombotic thrombocytopenic purpura (TTP) in adults. Semin. Thromb. Hemost. 2014;40:493–502. doi: 10.1055/s-0034-1376883.
    1. Guan Y., Wang S., Xue F., Liu X., Zhang L., Li H., Yang R. Long-term results of splenectomy in adult chronic immune thrombocytopenia. Eur. J. Haematol. 2016 doi: 10.1111/ejh.12821.
    1. Golay J., Manganini M., Facchinetti V., Gramigna R., Broady R., Borleri G., Rambaldi A., Introna M. Rituximab-mediated antibody-dependent cellular cytotoxicity against neoplastic B cells is stimulated strongly by interleukin-2. Haematologica. 2003;88:1002–1012.
    1. Guo L., Kapur R., Aslam R., Speck E.R., Zufferey A., Zhao Y., Kim M., Lazarus A.H., Ni H., Semple J.W. CD20+ B-cell depletion therapy suppresses murine CD8+ T-cell-mediated immune thrombocytopenia. Blood. 2016;127:735–738. doi: 10.1182/blood-2015-06-655126.
    1. Rudnicka D., Oszmiana A., Finch D.K., Strickland I., Schofield D.J., Lowe D.C., Sleeman M.A. Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell-mediated antibody-dependent cellular cytotoxicity. Blood. 2013;121:4694–4702. doi: 10.1182/blood-2013-02-482570.
    1. Stasi R., Del Poeta G., Stipa E., Evangelista M.L., Trawinska M.M., Cooper N., Amadori S. Response to B-cell depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura. Blood. 2007;110:2924–2930. doi: 10.1182/blood-2007-02-068999.
    1. Eisenbeis C.F., Grainger A., Fischer B., Baiocchi R.A., Carrodeguas L., Roychowdhury S., Chen L. Combination immunotherapy of B-cell non-Hodgkin’s lymphoma with rituximab and interleukin-2: A preclinical and phase I study. Clin. Cancer Res. 2004;10:6101–6110. doi: 10.1158/1078-0432.CCR-04-0525.
    1. Gluck W.L., Hurst D., Yuen A., Levine A.M., Dayton M.A., Gockerman J.P., Lucas J. Phase I studies of interleukin (IL)-2 and rituximab in B-cell non-hodgkin’s lymphoma: IL-2 mediated natural killer cell expansion correlations with clinical response. Clin. Cancer Res. 2004;10:2253–2264. doi: 10.1158/1078-0432.CCR-1087-3.
    1. Stasi R., Pagano A., Stipa E., Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood. 2001;98:952–957. doi: 10.1182/blood.V98.4.952.
    1. Chapin J., Lee C.S., Zhang H., Zehnder J.L., Bussel J.B. Gender and duration of disease differentiate responses to rituximab-dexamethasone therapy in adults with immune thrombocytopenia. Am. J. Hematol. 2016;91:907–911. doi: 10.1002/ajh.24434.
    1. Marangon M., Vianelli N., Palandri F., Mazzucconi M.G., Santoro C., Barcellini W., Fattizzo B., Volpetti S., Lucchini E., Polverelli N., et al. Rituximab in immune thrombocytopenia: Gender, age and response as predictors of long-term response. Eur. J. Haematol. 2016 doi: 10.1111/ejh.12839.
    1. Reboursiere E., Fouques H., Maigne G., Johnson H., Chantepie S., Gac A.C., Reman O., Macro M., Benabed K., Troussard X., et al. Rituximab salvage therapy in adults with immune thrombocytopenia: Retrospective study on efficacy and safety profiles. Int. J. Hematol. 2016;104:85–91. doi: 10.1007/s12185-016-1992-4.
    1. Patel V.L., Mahevas M., Lee S.Y., Stasi R., Cunningham-Rundles S., Godeau B., Kanter J. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood. 2012;119:5989–5995. doi: 10.1182/blood-2011-11-393975.
    1. Ghanima W., Khelif A., Waage A., Michel M., Tjonnfjord G.E., Romdhan N.B., Kahrs J. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:1653–1661. doi: 10.1016/S0140-6736(14)61495-1.
    1. Erickson-Miller C.L., DeLorme E., Tian S.S., Hopson C.B., Stark K., Giampa L., Valoret E.I., Duffy K.J., Luengo J.L., Rosen J., et al. Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist. Exp. Hematol. 2005;33:85–93. doi: 10.1016/j.exphem.2004.09.006.
    1. Cohn C.S., Bussel J.B. Romiplostim: A second-generation thrombopoietin agonist. Drugs Today. 2009;45:175–188. doi: 10.1358/dot.2009.45.3.1343793.
    1. Newland A., Godeau B., Priego V., Viallard J.F., Lopez Fernandez M.F., Orejudos A., Eisen M. Remission and platelet responses with romiplostim in primary immune thrombocytopenia: Final results from a phase 2 study. Br. J. Haematol. 2016;172:262–273. doi: 10.1111/bjh.13827.
    1. McKenzie C.G., Guo L., Freedman J., Semple J.W. Cellular immune dysfunction in immune thrombocytopenia (ITP) Br. J. Haematol. 2013;163:10–23. doi: 10.1111/bjh.12480.
    1. Klinger M.H., Jelkmann W. Subcellular localization of thrombopoietin in human blood platelets and its release upon thrombin stimulation. Br. J. Haematol. 2001;115:421–427. doi: 10.1046/j.1365-2141.2001.03104.x.
    1. Stasi R., Bosworth J., Rhodes E., Shannon M.S., Willis F., Gordon-Smith E.C. Thrombopoietic agents. Blood Rev. 2010;24:179–190. doi: 10.1016/j.blre.2010.04.002.
    1. Kapur R., Zufferey A., Boilard E., Semple J.W. Nouvelle Cuisine: Platelets Served with Inflammation. J. Immunol. 2015;194:5579–5587. doi: 10.4049/jimmunol.1500259.
    1. Kapur R., Semple J.W. The nonhemostatic immune functions of platelets. Semin. Hematol. 2016;53:S2–S6. doi: 10.1053/j.seminhematol.2016.04.002.
    1. Kapur R., Semple J.W. Platelets as immune-sensing cells. Blood Adv. 2016;1:10–14. doi: 10.1182/bloodadvances.2016000067.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi