Abstract
Immune thrombocytopenia (ITP) is an autoimmune disease mediated by anti-platelet autoantibodies. We recently established a mouse ITP model exhibiting regulatory T-cell (Treg) deficiency, although only one-third of the Treg-deficient mice developed ITP. To clarify mechanisms involved in the emergence of platelet-specific autoimmunity in this model, we examined the T helper (Th)-cell balance and macrophage Fcγ receptor (FcγR) expression profiles in Treg-deficient mice with and without ITP. Splenocytes from both populations of Treg-deficient mice and control BALB/c mice were subjected to flow cytometry-based analyses to evaluate Th cell subset proportions and the expression of activating and inhibitory FcγRs on macrophages. In addition, IgG subclass distribution of anti-platelet autoantibodies in splenocyte culture supernatants was determined by flow cytometry using IgG subclass-specific antibodies. Treg-deficient ITP mice exhibited a significantly higher proportion of Th1 cells than either Treg-deficient non-ITP or control mice. The predominant anti-platelet autoantibody subclasses in the ITP mice were Th1-associated IgG2a and IgG2b. Furthermore, the FcγRI/FcγRIIB expression ratio in splenic macrophages was higher in the Treg-deficient ITP than in the Treg-deficient non-ITP and control mice. In summary, Th1 polarization and macrophages’ activating FcγR expression profile are associated with the development of ITP in Treg-deficient mice.
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References
Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995–1008.
McMillan R. The pathogenesis of chronic immune (idiopathic) thrombocytopenic purpura. Semin Hematol. 2000;37:5–9.
McMillan R. The pathogenesis of chronic immune thrombocytopenic purpura. Semin Hematol. 2007;44:S3–11.
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.
Kuwana M, Okazaki Y, Ikeda Y. Splenic macrophages maintain the anti-platelet autoimmune response via uptake of opsonized platelets in patients with immune thrombocytopenic purpura. J Thromb Haemost. 2009;7:322–9.
Nishimoto T, Satoh T, Takeuchi T, Ikeda Y, Kuwana M. Critical role of CD4(+)CD25(+) regulatory T cells in preventing murine autoantibody-mediated thrombocytopenia. Exp Hematol. 2012;40:279–89.
Nishimoto T, Satoh T, Simpson EK, Ni H, Kuwana M. Predominant autoantibody response to GPIb/IX in a regulatory T-cell-deficient mouse model for immune thrombocytopenia. J Thromb Haemost. 2012;11:369–72.
Nishimoto T, Numajiri M, Nakazaki H, Okazaki Y, Kuwana M. Induction of immune tolerance to platelet antigen by short-term thrombopoietin treatment in a mouse model of immune thrombocytopenia. Int J Hematol. 2014;100:341–4.
Le Campion A, Gagnerault MC, Auffray C, Becourt C, Poitrasson-Riviere M, Lallemand E, et al. Lymphopenia-induced spontaneous T-cell proliferation as a cofactor for autoimmune disease development. Blood. 2009;114:1784–93.
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.
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.
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.
Gu D, Chen Z, Zhao H, Du W, Xue F, Ge J, et al. Th1 (CXCL10) and Th2 (CCL2) chemokine expression in patients with immune thrombocytopenia. Hum Immunol. 2010;71:586–91.
Clarkson SB, Bussel JB, Kimberly RP, Valinsky JE, Nachman RL, Unkeless JC. Treatment of refractory immune thrombocytopenic purpura with an anti-Fc gamma-receptor antibody. N Engl J Med. 1986;314:1236–9.
Asahi A, Nishimoto T, Okazaki Y, Suzuki H, Masaoka T, Kawakami Y, et al. Helicobacter pylori eradication shifts monocyte Fcgamma receptor balance toward inhibitory FcgammaRIIB in immune thrombocytopenic purpura patients. J Clin Invest. 2008;118:2939–49.
Estes DM, Brown WC. Type 1 and type 2 responses in regulation of Ig isotype expression in cattle. Vet Immunol Immunopathol. 2002;90:1–10.
Kaplan C, Valdez JC, Chandrasekaran R, Eibel H, Mikecz K, Glant TT, et al. Th1 and Th2 cytokines regulate proteoglycan-specific autoantibody isotypes and arthritis. Arthritis Res. 2002;4:54–8.
Baudino L, Azeredo da Silveira S, Nakata M, Izui S. Molecular and cellular basis for pathogenicity of autoantibodies: lessons from murine monoclonal autoantibodies. Springer Semin Immunopathol. 2006;28:175–84.
Hashino S, Mori A, Suzuki S, Izumiyama K, Kahata K, Yonezumi M, et al. Platelet recovery in patients with idiopathic thrombocytopenic purpura after eradication of Helicobacter pylori. Int J Hematol. 2003;77:188–91.
Takahashi T, Yujiri T, Tanizawa Y. Helicobacter pylori and chronic ITP: the discrepancy in the clinical responses to eradication therapy might be due to differences in the bacterial strains (letter). Blood. 2004;104:594.
Rocha AM, Souza C, Melo FF, Clementino NC, Marino MC, Rocha GA, et al. Cytokine profile of patients with chronic immune thrombocytopenia affects platelet count recovery after Helicobacter pylori eradication. Br J Haematol. 2015;168:421–8.
Chan H, Moore JC, Finch CN, Warkentin TE, Kelton JG. The IgG subclasses of platelet-associated autoantibodies directed against platelet glycoproteins IIb/IIIa in patients with idiopathic thrombocytopenic purpura. Br J Haematol. 2003;122:818–24.
Tijhuis GJ, Klaassen RJ, Modderman PW, Ouwehand WH, von dem Borne AE. Quantification of platelet-bound immunoglobulins of different class and subclass using radiolabelled monoclonal antibodies: assay conditions and clinical application. Br J Haematol. 1991;77:93–101.
Rosse WF, Adams JP, Yount WJ. Subclasses of IgG antibodies in immune thrombocytopenic purpura (ITP). Br J Haematol. 1980;46:109–14.
Yamamoto M, Vancott JL, Okahashi N, Marinaro M, Kiyono H, Fujihashi K, et al. The role of Th1 and Th2 cells for mucosal IgA responses. Ann NY Acad Sci. 1996;778:64–71.
Liu XG, Ma SH, Sun JZ, Ren J, Shi Y, Sun L, et al. High-dose dexamethasone shifts the balance of stimulatory and inhibitory Fcgamma receptors on monocytes in patients with primary immune thrombocytopenia. Blood. 2011;117:2061–9.
Nishimoto T, Kuwana M. CD4 + CD25 + Foxp3 + regulatory T cells in the pathophysiology of immune thrombocytopenia. Semin Hematol. 2013;50:S43–9.
Acknowledgements
We are grateful to Fumiaki Kumagai and Masayoshi Monno (Keio University School of Medicine) for assistance in performing the experiments. This work was supported by a research grant on intractable diseases from the Japanese Ministry of Health, Labor, and Welfare.
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T. Nishimoto: Deceased.
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Nishimoto, T., Okazaki, Y., Numajiri, M. et al. Mouse immune thrombocytopenia is associated with Th1 bias and expression of activating Fcγ receptors. Int J Hematol 105, 598–605 (2017). https://doi.org/10.1007/s12185-016-2172-2
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DOI: https://doi.org/10.1007/s12185-016-2172-2