PDCD1 and CTLA4 polymorphisms affect the susceptibility to, and clinical features of, chronic immune thrombocytopenia
Corresponding Author
Tetsuhiro Kasamatsu
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan
These authors contributed equally to this work.Correspondence: Tetsuhiro Kasamatsu, Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, 3-39-22 Showa-machi, Maebashi, Gunma 371-8514, Japan.
E-mail: [email protected]
Search for more papers by this authorRumi Ino
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan
These authors contributed equally to this work.Search for more papers by this authorNoriyuki Takahashi
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan
Search for more papers by this authorNanami Gotoh
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan
Search for more papers by this authorYusuke Minato
Department of Anatomy and Cell Biology, Hyogo College of Medicine, Maebashi, Japan
Search for more papers by this authorMakiko Takizawa
Department of Haematology, Gunma University Graduate School of Medicine, Maebashi, Japan
Search for more papers by this authorAkihiko Yokohama
Blood Transfusion Service, Gunma University Hospital, Maebashi, Japan
Search for more papers by this authorHiroshi Handa
Department of Haematology, Gunma University Graduate School of Medicine, Maebashi, Japan
Search for more papers by this authorTakayuki Saitoh
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan
Search for more papers by this authorNorifumi Tsukamoto
Oncology Centre, Gunma University Hospital, Maebashi, Japan
Search for more papers by this authorHirokazu Murakami
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan
Search for more papers by this authorCorresponding Author
Tetsuhiro Kasamatsu
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan
These authors contributed equally to this work.Correspondence: Tetsuhiro Kasamatsu, Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, 3-39-22 Showa-machi, Maebashi, Gunma 371-8514, Japan.
E-mail: [email protected]
Search for more papers by this authorRumi Ino
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan
These authors contributed equally to this work.Search for more papers by this authorNoriyuki Takahashi
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan
Search for more papers by this authorNanami Gotoh
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan
Search for more papers by this authorYusuke Minato
Department of Anatomy and Cell Biology, Hyogo College of Medicine, Maebashi, Japan
Search for more papers by this authorMakiko Takizawa
Department of Haematology, Gunma University Graduate School of Medicine, Maebashi, Japan
Search for more papers by this authorAkihiko Yokohama
Blood Transfusion Service, Gunma University Hospital, Maebashi, Japan
Search for more papers by this authorHiroshi Handa
Department of Haematology, Gunma University Graduate School of Medicine, Maebashi, Japan
Search for more papers by this authorTakayuki Saitoh
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan
Search for more papers by this authorNorifumi Tsukamoto
Oncology Centre, Gunma University Hospital, Maebashi, Japan
Search for more papers by this authorHirokazu Murakami
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan
Search for more papers by this authorSummary
Programmed death-1 (PD-1, PDCD1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CTLA4) play central roles in immune checkpoint pathways. Single nucleotide polymorphisms (SNPs) of PDCD1 and CTLA4 have been reported to be associated with susceptibility to some autoimmune diseases. However, the potential association between SNPs in these immune checkpoint genes and risk of chronic immune thrombocytopenia (cITP) remain controversial and obscure. The aims of this study were to clarify the influence of PDCD1 and CTLA4 SNPs on the risk of developing cITP and its clinical features. We obtained genomic DNA from 119 patients with cITP and 223 healthy controls; their genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Patients with cITP had a significantly higher frequency of the PDCD1 +7209 TT genotype compared with healthy controls. The CTLA4 −1577 GG genotype and CT60 GG genotype showed higher frequencies of platelet count <5 × 109/l at diagnosis, minimum platelet count <5 × 109/l, and bleeding symptoms. Moreover, the PDCD1 −606 AA genotype and +63379 TT genotype were significantly associated with a lower number of patients who achieved a complete response to prednisolone treatment. Our results suggest that the immune checkpoint polymorphisms may affect the susceptibility to the clinical features of cITP, and treatment response of the affected patients.
References
- Aktürk, F., Hançer, V.S. & Küçükkaya, R. (2010) Cytotoxic T lymphocyte antigen-4 (CTLA-4) A49G polymorphism and autoimmune blood diseases. Turkish Journal of Hematology, 27, 78–81.
- Anjos, S., Nguyen, A., Ounissi-Benkalha, H., Tessier, M.C. & Polychronakos, C. (2002) A common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. Journal of Biological Chemistry, 277, 46478–46486.
- Atesoglu, E.B., Tarkun, P., Demirsoy, E.T., Geduk, A., Mehtap, O., Batman, A., Kaya, F., Cekmen, M.B., Gulbas, Z. & Hacıhanefioglu, A. (2016) Soluble programmed death 1 (PD-1) is decreased in patients with immune thrombocytopenia (ITP): potential involvement of PD-1 pathway in ITP immunopathogenesis. Clinical and Applied Thrombosis/Hemostasis, 22, 248–251.
- Bao, W., Bussel, J.B., Heck, S., He, W., Karpoff, M., Boulad, N. & Yazdanbakhsh, K. (2010) Improved regulatory Tcell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agents. Blood, 116, 4639–4645.
- Barreto, M., Santos, E., Ferreira, R., Fesel, C., Fontes, M.F., Pereira, C., Martins, B., Andreia, R., Viana, J.F., Crespo, F., Vasconcelos, C., Ferreira, C. & Vicente, A.M. (2004) Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus. European Journal of Human Genetics, 12, 620–626.
- Chang, M., Nakagawa, P.A., Williams, S.A., Schwartz, M.R., Imfeld, K.L., Buzby, J.S. & Nugent, D.J. (2003) Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood, 102, 887–895.
- Chun, J.K., Kang, D.W., Yoo, B.W., Shin, J.S. & Kim, D.S. (2010) Programmed death-1 (PD-1) gene polymorphisms lodged in the genetic predispositions of Kawasaki disease. European Journal of Pediatrics, 169, 181–185.
- Collins, A.V., Brodie, D.W., Gilbert, R.J., Iaboni, A., Manso-Sancho, R., Walse, B., Stuart, D.I., van der Merwe, P.A. & Davis, S.J. (2002) The interaction properties of costimulatory molecules revisited. Immunity, 17, 201–210.
- Dong, H., Zhu, G., Tamada, K. & Chen, L. (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Medicine, 5, 1365–1369.
- Freeman, G.J., Long, A.J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitz, L.J., Malenkovich, N., Okazaki, T., Byrne, M.C., Horton, H.F., Fouser, L., Carter, L., Ling, V., Bowman, M.R., Carreno, B.M., Collins, M., Wood, C.R. & Honjo, T. (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. Journal of Experimental Medicine, 192, 1027–1034.
- Gilson, C.R., Patel, S.R. & Zimring, J.C. (2012) CTLA4-Ig prevents alloantibody production and BMT rejection in response to platelet transfusions in mice. Transfusion, 52, 2209–2219.
- Guo, X., Yasen, H., Zhao, F., Wang, L., Sun, M., Pang, N., Wang, X., Zhang, Y., Ding, J. & Ma, X. (2016) The effect of single course high dose dexamethasone on CD28/CTLA-4 balance in the treatment of patients with newly diagnosed primary immune thrombocytopenia. Human Vaccines & Immunotherapeutics, 12, 97–103.
10.1080/21645515.2015.1059975 Google Scholar
- Ishizaki, Y., Yukaya, N., Kusuhara, K., Kira, R., Torisu, H., Ihara, K., Sakai, Y., Sanefuji, M., Pipo-Deveza, J.R., Silao, C.L., Sanchez, B.C., Lukban, M.B., Salonga, A.M. & Hara, T. (2010) PD1 as a common candidate susceptibility gene of subacute sclerosing panencephalitis. Human Genetics, 127, 411–419.
- Kanameishi, S., Otsuka, A., Nonomura, Y., Fujisawa, A., Endo, Y. & Kabashima, K. (2016) Idiopathic thrombocytopenic purpura induced by nivolumab in a metastatic melanoma patient with elevated PD-1 expression on B cells. Annals of Oncology, 27, 546–547.
- Krummel, M.F. & Allison, J.P. (1995) CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. Journal of Experimental Medicine, 182, 459–465.
- Mostowska, M., Wudarski, M., Chwalińska-Sadowska, H. & Jagodziński, P.P. (2008) The programmed cell death 1 gene 7209 C>T polymorphism is associated with the risk of systemic lupus erythematosus in the Polish population. Clinical and Experimental Rheumatology, 26, 457–460.
- Ni, R., Ihara, K., Miyako, K., Kuromaru, R., Inuo, M., Kohno, H. & Hara, T. (2007) PD-1 gene haplotype is associated with the development of type 1 diabetes mellitus in Japanese children. Human Genetics, 121, 223–232.
- Nielsen, C., Ohm-Laursen, L., Barington, T., Husby, S. & Lillevang, S.T. (2005) Alternative splice variants of the human PD-1 gene. Cellular Immunology, 235, 109–116.
- Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity, 11, 141–151.
- Ogawara, H., Handa, H., Morita, K., Hayakawa, M., Kojima, J., Amagai, H., Tsumita, Y., Kaneko, Y., Tsukamoto, N., Nojima, Y. & Murakami, H. (2003) High Th1/Th2 ratio in patients with chronic idiopathic thrombocytopenic purpura. European Journal of Haematology, 71, 283–288.
- Pérez-García, A., Osca, G., Bosch-Vizcaya, A., Kelleher, N., Santos, N.Y., Rodríguez, R., González, Y., Roncero, J.M., Coll, R., Serrando, M., Lloveras, N., Tuset, E. & Gallardo, D. (2013) Kinetics of the CTLA-4 isoforms expression after T-lymphocyte activation and role of the promoter polymorphisms on CTLA-4 gene transcription. Human Immunology, 74, 1219–1224.
- Rodeghiero, F., Stasi, R., Gernsheimer, T., Michel, M., Provan, D., Arnold, D.M., Bussel, J.B., Cines, D.B., Chong, B.H., Cooper, N., Godeau, B., Lechner, K., Mazzucconi, M.G., McMillan, R., Sanz, M.A., Imbach, P., Blanchette, V., Kühne, T., Ruggeri, M. & George, J.N. (2009) Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood, 113, 2386–2393.
- Semple, J.W., Milev, Y., Cosgrave, D., Mody, M., Hornstein, A., Blanchette, V. & Freedman, J. (1996) Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity. Blood, 87, 4245–4254.
- Shiuan, E., Beckermann, K.E., Ozgun, A., Kelly, C., McKean, M., McQuade, J., Thompson, M.A., Puzanov, I., Greer, J.P., Rapisuwon, S., Postow, M., Davies, M.A., Eroglu, Z. & Johnson, D. (2017) Thrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy. Journal for Immunotherapy of Cancer, 5, 8. https://doi.org/10.1186/s40425-017-0210-0
- Stasi, R., Del Poeta, G., Stipa, E., Evangelista, M.L., Trawinska, M.M., Cooper, N. & Amadori, S. (2007) Response to B-cell depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura. Blood, 110, 2924–2930.
- Stasi, R., Cooper, N., Del Poeta, G., Stipa, E., Laura Evangelista, M., Abruzzese, E. & Amadori, S. (2008) Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood, 112, 1147–1150.
- Takahashi, Y., Mogami, Y., Mine, J., Imai, K., Koide, Y., Matsuda, K., Akasaka, N., Konishi, T., Imamura, A. & Inoue, Y. (2013) Genetic variations of immunoregulatory genes associated with Rasmussen syndrome. Epilepsy Research, 107, 238–243.
10.1016/j.eplepsyres.2013.09.004 Google Scholar
- Tang, M.J. & Zhou, Z.B. (2013) Association of the CTLA-4 +49A/G polymorphism with rheumatoid arthritis in Chinese Han population. Molecular Biology Reports, 40, 2627–2631.
10.1007/s11033-012-2349-6 Google Scholar
- Tivol, E.A., Borriello, F., Schweitzer, A.N., Lynch, W.P., Bluestone, J.A. & Sharpe, A.H. (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity, 3, 541–547.
- Zheng, L., Li, D., Wang, F., Wu, H., Li, X., Fu, J., Chen, X., Wang, L., Liu, Y. & Wang, S. (2010) Association between hepatitis B viral burden in chronic infection and a functional single nucleotide polymorphism of the PDCD1 gene. Journal of Clinical Immunology, 30, 855–860.
- Zhong, J., Chen, S., Xu, L., Lai, J., Liao, Z., Zhang, T., Yu, Z., Lu, Y., Yang, L., Wu, X., Li, B. & Li, Y. (2016) Lower expression of PD-1 and PD-L1 in peripheral blood from patients with chronic ITP. Hematology, 21, 552–557.
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