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Liu FQ, Qu QY, Lei Y, Chen Q, Chen YX, Li ML, Sun XY, Wu YJ, Huang QS, Fu HX, Kong Y, Li YY, Wang QF, Huang XJ, Zhang XH. High dimensional proteomic mapping of bone marrow immune characteristics in immune thrombocytopenia. SCIENCE CHINA. LIFE SCIENCES 2024; 67:1635-1647. [PMID: 38644444 DOI: 10.1007/s11427-023-2520-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 01/09/2024] [Indexed: 04/23/2024]
Abstract
To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia (ITP), this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight (CyTOF). Thirty-six patients with ITP and nine healthy volunteers were enrolled in the study. As soluble immunomodulatory molecules, more sCD25 and sGalectin-9 were detected in ITP patients. On the cell surface, co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T cells. In contrast, co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell subsets. Taking a platelet count of 30×109 L-1 as the cutoff value, ITP patients with high and low platelet counts showed different T cell immune profiles. Antigen-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions, respectively, and participate in the pathogenesis of ITP. In conclusion, the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of ITP. They may offer novel targets to develop personalized immunotherapies.
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Affiliation(s)
- Feng-Qi Liu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Collaborative Innovation Centre of Hematology, Peking University, Beijing, 100044, China
| | - Qing-Yuan Qu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Collaborative Innovation Centre of Hematology, Peking University, Beijing, 100044, China
| | - Ying Lei
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qi Chen
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Collaborative Innovation Centre of Hematology, Peking University, Beijing, 100044, China
| | - Yu-Xiu Chen
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Collaborative Innovation Centre of Hematology, Peking University, Beijing, 100044, China
| | - Meng-Lin Li
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Collaborative Innovation Centre of Hematology, Peking University, Beijing, 100044, China
| | - Xue-Yan Sun
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Collaborative Innovation Centre of Hematology, Peking University, Beijing, 100044, China
| | - Ye-Jun Wu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Collaborative Innovation Centre of Hematology, Peking University, Beijing, 100044, China
| | - Qiu-Sha Huang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Collaborative Innovation Centre of Hematology, Peking University, Beijing, 100044, China
| | - Hai-Xia Fu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Collaborative Innovation Centre of Hematology, Peking University, Beijing, 100044, China
| | - Yuan Kong
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Collaborative Innovation Centre of Hematology, Peking University, Beijing, 100044, China
| | - Yue-Ying Li
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qian-Fei Wang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China
- Collaborative Innovation Centre of Hematology, Peking University, Beijing, 100044, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100074, China
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, 100044, China.
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China.
- National Clinical Research Center for Hematologic Disease, Beijing, 100044, China.
- Collaborative Innovation Centre of Hematology, Peking University, Beijing, 100044, China.
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Matsuura Y, Tomita T, Kondo M, Mukai M, Kataoka H. Severe Thrombocytopenia Secondary to Systemic Lupus Erythematosus With Antiphospholipid Antibodies in a Middle-Aged Woman. Cureus 2024; 16:e62804. [PMID: 39040719 PMCID: PMC11260694 DOI: 10.7759/cureus.62804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2024] [Indexed: 07/24/2024] Open
Abstract
Thrombocytopenia is a common hematological complication of systemic lupus erythematosus (SLE). However, severe thrombocytopenia is a relatively rare presentation, accounting for only 3-10% of cases. A 52-year-old woman was being treated with 4 mg/day of prednisolone for 12 years for SLE-induced autoimmune hemolytic anemia. She presented to her family physician with nasal bleeding and purpura, which required more than two hours to control. She had bruises on her legs and mild multiple arthralgia. The platelet count was 19,000/µL. She was suspected to have developed immune thrombocytopenia as an exacerbation of SLE. Thus, she was referred to our hospital. Laboratory examination revealed thrombocytopenia, hypocomplementemia, and a positive result for anti-cardiolipin (CL) and anti-β2-glycoprotein (GP) I IgG antibodies. The patient was diagnosed with thrombocytopenic purpura, complicated by SLE. Methylprednisolone pulse therapy, followed by 60 mg/day of prednisolone and 200/400 mg of hydroxychloroquine on alternate days, was initiated. The platelet count increased from 5,000/µl to 50,000/µl, and the immature platelet fraction (IPF) decreased from 14.9% to 6.3%. Anti-CL and anti-β2-GPI IgG antibodies were considered to be associated with thrombocytopenia and a risk of thrombotic events after normalization of her platelet counts. Therefore, aspirin therapy was initiated to prevent thrombosis. As an episode of acute thrombocytopenia occurred without other clinical findings indicating active SLE, it was important to determine the exact cause of thrombocytopenia in this situation. Immediate recovery of thrombocytopenia with high-dose prednisolone reduced the risk of bleeding that could have otherwise been fatal.
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Affiliation(s)
- Yuki Matsuura
- Rheumatology and Clinical Immunology, Sapporo City General Hospital, Sapporo, JPN
| | - Tomoko Tomita
- Rheumatology and Clinical Immunology, Sapporo City General Hospital, Sapporo, JPN
| | - Makoto Kondo
- Rheumatology and Clinical Immunology, Sapporo City General Hospital, Sapporo, JPN
| | - Masaya Mukai
- Rheumatology and Clinical Immunology, Sapporo City General Hospital, Sapporo, JPN
| | - Hiroshi Kataoka
- Rheumatology and Clinical Immunology, Sapporo City General Hospital, Sapporo, JPN
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Delshad M, Davoodi-Moghaddam Z, Pourbagheri-Sigaroodi A, Faranoush M, Abolghasemi H, Bashash D. Translating mechanisms into therapeutic strategies for immune thrombocytopenia (ITP): Lessons from clinical trials. Thromb Res 2024; 235:125-147. [PMID: 38335568 DOI: 10.1016/j.thromres.2024.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 02/12/2024]
Abstract
Immune thrombocytopenia (ITP) is an autoimmune disorder that causes a significant reduction in peripheral blood platelet count. Fortunately, due to an increased understanding of ITP, there have been significant improvements in the diagnosis and treatment of these patients. Over the past decade, there have been a variety of proven therapeutic options available for ITP patients, including intravenous immunoglobulins (IVIG), Rituximab, corticosteroids, and thrombopoietin receptor agonists (TPO-RAs). Although the effectiveness of current therapies in treating more than two-thirds of patients, still some patients do not respond well to conventional therapies or fail to achieve long-term remission. Recently, a significant advancement has been made in identifying various mechanisms involved in the pathogenesis of ITP, leading to the development of novel treatments targeting these pathways. It seems that new agents that target plasma cells, Bruton tyrosine kinase, FcRn, platelet desialylation, splenic tyrosine kinase, and classical complement pathways are opening new ways to treat ITP. In this study, we reviewed the pathophysiology of ITP and summarized updates in this population's management and treatment options. We also took a closer look at the 315 ongoing trials to investigate their progress status and compare the effectiveness of interventions. May our comprehensive view of ongoing clinical trials serve as a guiding beacon, illuminating the path towards future trials of different drugs in the treatment of ITP patients.
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Affiliation(s)
- Mahda Delshad
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Laboratory Sciences, School of Allied Medical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Zeinab Davoodi-Moghaddam
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Faranoush
- Pediatric Growth and Development Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hassan Abolghasemi
- Pediatric Congenital Hematologic Disorders Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Thakre R, Gharde P, Raghuwanshi M. Idiopathic Thrombocytopenic Purpura: Current Limitations and Management. Cureus 2023; 15:e49313. [PMID: 38143653 PMCID: PMC10748795 DOI: 10.7759/cureus.49313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 11/23/2023] [Indexed: 12/26/2023] Open
Abstract
Idiopathic thrombocytopenic purpura (ITP), also known as immune thrombocytopenia, is a blood disorder characterized by a reduction in the number of platelets. A reduction in the number of platelets beyond the normal levels leads to several consequences. A severe reduction in blood platelet levels leads to a rash of purple spots on the skin, joints, etc. due to leakage in the small blood vessels, easy bruising, bleeding gums, intestinal bleeding, and hemorrhage. Suppose a case of ITP resolves in fewer than six months. In that case, it is an acute case of ITP. Still, if a case settles in more than six months, it is a case of ITP. The cause of a reduced platelet count can be increased peripheral destruction or impaired production; this is termed an autoimmune condition in which the body's immune system attacks platelets thinking it to be a foreign antigen. ITP in children occurs commonly following a previous viral attack. Even though evaluating patients' reports is useful for understanding and guiding the treatment, these estimates might not be regularly evaluated in clinical settings. First-line drugs in the treatment of ITP are corticosteroids, and long-term use of these drugs has several side effects, such as excessive increase in weight, mental health disturbances, and sleep disturbances; additional therapies to treat hemorrhage are usually momentary. As a result, it is essential to recognize the flaws in current procedures and adopt innovative measures for the management and minimization of difficulties.
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Affiliation(s)
- Rakshanda Thakre
- Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Pankaj Gharde
- Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Mohit Raghuwanshi
- Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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Cines DB. Pathogenesis of refractory ITP: Overview. Br J Haematol 2023; 203:10-16. [PMID: 37735546 PMCID: PMC10539016 DOI: 10.1111/bjh.19083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 06/09/2023] [Accepted: 07/31/2023] [Indexed: 09/23/2023]
Abstract
A subset of individuals with 'primary' or 'idiopathic' immune thrombocytopenia (ITP) who fail to respond to conventional first- and second-line agents or who lose responsiveness are considered to have 'refractory' disease (rITP), placing them at increased risk of bleeding and complications of intensive treatment. However, the criteria used to define the refractory state vary among studies, which complicates research and clinical investigation. Moreover, it is unclear whether rITP is simply 'more severe' ITP, or if there are specific pathogenic pathways that are more likely to result in refractory disease, and whether the presence or development of rITP can be established or anticipated based on these differences. This paper reviews potential biological features that may be associated with rITP, including genetic and epigenetic risk factors, dysregulation of T cells and cytokine networks, antibody affinity and specificity, activation of complement, impaired platelet production and alterations in platelet viability and clearance. These findings indicate the need for longitudinal studies using novel clinically available methodologies to identify and monitor pathogenic T cells, platelet antibodies and other clues to the development of refractory disease.
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Affiliation(s)
- Douglas B Cines
- Department of Pathology and Laboratory Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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Posa DK, Kamoga GR, Walton R. The Reactivation of Immune Thrombocytopenic Purpura After SARS-CoV-2 Infection. Cureus 2023; 15:e44873. [PMID: 37692177 PMCID: PMC10484802 DOI: 10.7759/cureus.44873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2023] [Indexed: 09/12/2023] Open
Abstract
Immune thrombocytopenic purpura (ITP) is an autoimmune disease associated with bleeding symptoms and thrombocytopenia. It is diagnosed in patients with low platelet count after all the other causes of thrombocytopenia are ruled out. It can be presented as a primary condition, or it can be associated with other diseases. We report a case of ITP in a 65-year-old female with a one-day history of spontaneous bleeding gums, bruising, and petechiae all over her body. In further review of her history, it was noted that she had a history of ITP in remission and was recovering from a recent SARS-CoV-2 infection. We have excluded all the other causes of her thrombocytopenia, and we suspected that her viral illness would likely trigger this episode. Here, we report a case of ITP reactivation after SARS-CoV-2 infection.
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Affiliation(s)
| | | | - Robert Walton
- Internal Medicine, White River Health System, Batesville, USA
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Xie D, Feng Z, Yang W, Wang Y, Li R, Zhang S, Zhou Z. A mAb to SIRPα downregulates the priming of naive CD4 + T cell in Primary immune thrombocytopenia. Cell Immunol 2023; 391-392:104757. [PMID: 37660478 DOI: 10.1016/j.cellimm.2023.104757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 08/17/2023] [Indexed: 09/05/2023]
Abstract
SIRPα is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is abundantly expressed on monocytes, dendritic cells, and macrophages. Studies recently showed that SIRPα is essential for priming of CD4 + T cells by DCs and for development of Th17 cell-mediated autoimmune diseases. We have now further evaluated the importance of SIRPα and that of its ligand CD47 in primary immune thrombocytopenia (ITP). In this study, we show that there was a low expression state of SIRPα on the surface of monocytes. Treatment of cells culture from ITP patients with a mAb to SIRPα that blocks the binding of SIRPα to CD47 downregulated the ITP response. The abilities of monocytes from ITP patients to stimulate an allogenic MLR were reduced. The proliferation of, and production of IL-2, by CD4 + T cells from ITP patients were inhibited, the Treg cell numbers and the production of IL-10 pairs were upregulated, and the production of TGF-β not was inhibited, by a mAb to SIRPα. Moreover, a mAb to SIRPα, the expression of HLA-DR and CD86 were markedly inhibited and the expression of CD80 was slightly upregulated, on the surface of CD14 + monocytes from ITP patients as compared with healthy subjects. However, blockade of SIRPα increased the secretion of TLR-dependent cytokines TNF-α, IL-6 and IL-1β by PBMCs, which may be considered as a reserve in response to danger signals. These results suggest that SIRPα on monocytes is essential for the priming of naive T cells and the development of ITP. Therefore, SIRPα is a potential therapeutic target for ITP and other autoimmune diseases.
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Affiliation(s)
- Dongmei Xie
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Zhihui Feng
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Wen Yang
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Yacan Wang
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Renxia Li
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Shiqi Zhang
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Zeping Zhou
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China.
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Yin DM, Yuan D, Sun RJ, Xu HZ, Hun SY, Sui XH, Shan NN. Identification of ORM1, vWF, SPARC, and PPBP as immune-related proteins involved in immune thrombocytopenia by quantitative LC-MS/MS. Clin Proteomics 2023; 20:24. [PMID: 37355563 DOI: 10.1186/s12014-023-09413-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 06/03/2023] [Indexed: 06/26/2023] Open
Abstract
BACKGROUND Immune thrombocytopenia (ITP) is a common autoimmune disease characterized by loss of immune tolerance to platelet autoantigens leading to excessive destruction and insufficient production of platelets. METHOD Quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed to detect the differentially expressed proteins in bone marrow samples from active ITP patients and normal controls. RESULT Our bioinformatic analysis identified two upregulated proteins (ORM1 and vWF) and two downregulated proteins (PPBP and SPARC) related to immune function. The four proteins were all found to be related to the tumor necrosis factor (TNF) -α signalling pathway and involved in the pathogenesis of ITP in KEGG pathway analysis. CONCLUSION Bioinformatics analysis identified differentially expressed proteins in bone marrow that are involved in the TNF-α signalling pathway and are related to the activation of immune function in ITP patients. These findings could provide new ideas for research on the loss of immune tolerance in ITP patients.
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Affiliation(s)
- Dong-Mei Yin
- Department of Blood Transfusion, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
- Department of Blood Transfusion, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Dai Yuan
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jing Wu Rd, Jinan, 250021, Shandong, China
| | - Rui-Jie Sun
- Department of Rheumatology, Clinical Immunology Center, Peking Union Medical College Hospital, Beijing, 100000, China
| | - Hong-Zhi Xu
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jing Wu Rd, Jinan, 250021, Shandong, China
| | - Shou-Yong Hun
- Department of Blood Transfusion, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
- Department of Blood Transfusion, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Xiao-Hui Sui
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jing Wu Rd, Jinan, 250021, Shandong, China
| | - Ning-Ning Shan
- Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China.
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jing Wu Rd, Jinan, 250021, Shandong, China.
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Harsini S, Rezaei N. Autoimmune diseases. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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TCR CDR3 Sequencing as a Clue to Elucidate the Landscape of Dysimmunity in Patients with Primary Immune Thrombocytopenia. J Clin Med 2022; 11:jcm11195665. [PMID: 36233533 PMCID: PMC9571369 DOI: 10.3390/jcm11195665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/21/2022] [Accepted: 09/22/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Primary immune thrombocytopenia (ITP) is an autoimmune disorder. The existence of autoreactive T cells has long been proposed in ITP. Yet the identification of autoreactive T cells has not been achieved, which is an important step to elucidate the pathogenesis of ITP. Methods: ITP patients’ peripheral blood was collected prior to the treatment and one month after initiating dexamethasone treatment per related therapeutic guideline. Serum cytokines were profiled to examine T cell subtypes imbalance using a protein chip. TCR Vβ analysis in CD8+T cells of ITP patients, and TCR CDR3 DNA sequencing of CD4+T and CD8+T cells were performed to determine the autoreactive T cells’ clones. Results: Cytokine profiling revealed imbalanced distribution of T cells subtypes, which was confirmed by CD4+T and CD8+T cells’ oligoclonal expansion of TCR Vβ analysis and TCR CDR3 DNA sequencing. VDJ segments were found to be more frequently presented in ITP patients, when compared with health controls. There was an individualized CD4+T cell or CD8+T cell CDR3 sequence in each ITP patient. Conclusions: The present study revealed that T cell clones expanded in ITP patients’ peripheral blood, and each clone had an individualized TCR CDR3 sequence. The expanded T cell clones preferred to use some specific VDJ segment. Further studies are warranted to get access to individualized treatment such as Car-T in patients with ITP.
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Satoh T, Takiguchi H, Uojima H, Kubo M, Tanaka C, Yokoyama F, Wada N, Miyazaki K, Hidaka H, Kusano C, Kuwana M, Horie R. B cell-activating factor is involved in thrombocytopenia in patients with liver cirrhosis. Ann Hematol 2022; 101:2433-2444. [PMID: 36098792 DOI: 10.1007/s00277-022-04973-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 08/28/2022] [Indexed: 11/26/2022]
Abstract
Liver cirrhosis (LC) involves B cells that produce anti-glycoprotein (GP) IIb/IIIa antibodies, found in primary immune thrombocytopenia (ITP). The role of autoimmunity in the pathology of thrombocytopenia in LC was investigated using 25 LC patients with thrombocytopenia, 18 ITP patients, and 30 healthy controls. Anti-GPIIb/IIIa antibody-producing B cells were quantified using enzyme-linked immunospot assay. Platelet-associated and plasma anti-GPIIb/IIIa antibody, plasma B cell-activating factor (BAFF), and a proliferation-inducing ligand (APRIL) levels were measured using enzyme-linked immunosorbent assay. B cell subset fractions and regulatory T cells (Tregs) were quantified using flow cytometry.The number of anti-GPIIb/IIIa antibody-producing B cells was significantly higher in LC patients than in ITP patients and healthy controls (both p < 0.001). Platelet-associated anti-GPIIb/IIIa antibodies were significantly higher in LC patients than in ITP patients and healthy controls (p = 0.002, p < 0.001, respectively). BAFF levels were significantly higher in LC patients than in ITP patients and healthy controls (p = 0.001 and p < 0.001, respectively), and APRIL levels were significantly higher in LC patients than in healthy controls (p < 0.001). Anti-GPIIb/IIIa antibody-producing B cells and platelet-associated anti-GPIIb/IIIa antibodies were positively correlated with BAFF levels in LC patients. LC patients had more naïve B cells and plasmablasts than healthy controls (p = 0.005, p = 0.03, respectively); plasmablasts were positively correlated with BAFF levels. LC patients had similar Tregs levels as ITP patients and healthy controls. Therefore, excessive BAFF production in LC patients with thrombocytopenia is likely associated with autoimmune B cell response, inducing anti-GPIIb/IIIa antibody production.
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Affiliation(s)
- Takashi Satoh
- Division of Hematology, Kitasato University School of Allied Health Sciences, Sagamihara, Kanagawa, Japan.
- Division of Molecular Hematology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan.
- Regenerative Medicine and Cell Design Research Facility, Kitasato University School of Allied Health Sciences, Sagamihara, Kanagawa, Japan.
| | - Hayato Takiguchi
- Division of Molecular Hematology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Makoto Kubo
- Regenerative Medicine and Cell Design Research Facility, Kitasato University School of Allied Health Sciences, Sagamihara, Kanagawa, Japan
- Division of Immunology, Kitasato University School of Allied Health Sciences, Sagamihara, Kanagawa, Japan
| | - Chisato Tanaka
- Division of Hematology, Kitasato University School of Allied Health Sciences, Sagamihara, Kanagawa, Japan
| | - Fumiko Yokoyama
- Division of Hematology, Kitasato University School of Allied Health Sciences, Sagamihara, Kanagawa, Japan
| | - Naohisa Wada
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Koji Miyazaki
- Department of Transfusion and Cell Transplantation, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Chika Kusano
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Masataka Kuwana
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan
| | - Ryouichi Horie
- Division of Hematology, Kitasato University School of Allied Health Sciences, Sagamihara, Kanagawa, Japan
- Division of Molecular Hematology, Kitasato University Graduate School of Medical Sciences, Sagamihara, Kanagawa, Japan
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12
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Lee‐Sundlov MM, Rivadeneyra L, Falet H, Hoffmeister KM. Sialic acid and platelet count regulation: Implications in immune thrombocytopenia. Res Pract Thromb Haemost 2022; 6:e12691. [PMID: 35425875 PMCID: PMC8994053 DOI: 10.1002/rth2.12691] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/03/2022] [Accepted: 02/10/2022] [Indexed: 12/12/2022] Open
Abstract
Platelets are blood components that survive in circulation for 7 to 10 days in humans. Thus, platelet production by bone marrow (BM) megakaryocytes (MKs), and their removal from the blood circulation is precisely orchestrated to maintain an average platelet count. Abnormalities in both processes can result in thrombocytopenia (low platelet count) or thrombocytosis (high platelet count), often associated with the risk of bleeding or overt thrombus formation, respectively. Platelet glycans, particularly sialic acids, are indicators of platelet count. Loss of platelet sialic acids leads to platelet clearance. A State-of-the-Art lecture titled "Platelet and Megakaryocyte Glycobiology" was presented at the ISTH virtual congress 2021 to discuss (i) the loss of O-glycan sialic acid on BM MKs, revealing the Thomsen-Friedenreich (TF) antigen as a new concept of thrombocytopenia; herein, impaired thrombopoiesis is attributed to activation of immune cells with a plasmacytoid dendritic cell signature; and (ii) upregulation of antibodies against the TF antigen in pediatric patients with immune thrombocytopenia (ITP), positing that glycan alterations such as MK asialylation can lead to immune cell responses. Here, we discuss our findings alongside new data presented at the 2020 and 2021 ISTH congresses on the role of sialic acids and glycans in regulating platelet count. Desialylation is a prominent feature in thrombocytopenia, notably in ITP presentation. We compare similarities between ITP mediated with shear-stress and with storage-related asialylation. We also discuss genes involved in sialic acid synthesis leading to thrombocytopenia. Increased awareness in gene-regulating MK and platelet glycans is a giant leap to understanding the underpinning mechanisms of ITP and other forms of thrombocytopenia.
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Affiliation(s)
| | - Leonardo Rivadeneyra
- Translational Glycomics CenterVersiti Blood Research InstituteMilwaukeeWisconsinUSA
| | - Hervé Falet
- Translational Glycomics CenterVersiti Blood Research InstituteMilwaukeeWisconsinUSA
- Department of Cell Biology, Neurobiology, and AnatomyMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Karin M. Hoffmeister
- Translational Glycomics CenterVersiti Blood Research InstituteMilwaukeeWisconsinUSA
- Departments of Biochemistry and MedicineMedical College of WisconsinMilwaukeeWisconsinUSA
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13
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Youssef MAM, Salah Eldin EM, Osman NS. Revolution of Disturbed Bregs and Bmems Lymphocytes Homeostasis in Children With Chronic ITP After High-dose Dexamethasone Rescue Therapy. J Pediatr Hematol Oncol 2022; 44:e96-e100. [PMID: 33974586 DOI: 10.1097/mph.0000000000002160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 03/04/2021] [Indexed: 11/26/2022]
Abstract
SUMMARY Dexamethasone is approved as second-line therapy in pediatric chronic immune thrombocytopenic purpura (ITP). Several B-cell abnormalities have been described in ITP pathogenesis.This study assessed the effects of high-dose dexamethasone (HD-DXM) on the percentages and absolute counts of CD19+CD24hiCD38hi regulatory (Bregs) and CD19+CD27+ memory B lymphocytes (Bmems) in children with chronic ITP during active bleeding.The study was a prospective case-control, included 20 children with chronic ITP and uncontrolled bleeding. Children received a single daily dose of HD-DXM for 4 days. Blood samples were withdrawn from patients just before HD-DXM therapy and on day 5 to evaluate the platelet counts and flow cytometric analysis of Bregs and Bmem. The patients' platelet counts significantly increased after 5 days of the initiation of therapy (P=0.0001). Bmems percentage and absolute counts were significantly higher in patients before treatment (P=0.0007), and decreased after HD-DXM therapy (P=0.97) compared with the controls. Bregs percentage and absolute counts were significantly lower before treatment (P=0.0003) and increased after HD-DXM (P=0.003). There is a negative correlation between platelet counts and Bregs percentage and absolute count Bmems percentage before and after HD-DXM, whereas a positive correlation between platelets and Bregs before and after dexamethasone has been reported. CONCLUSIONS HD-DXM reestablishes the normal Bregs/Bmems balance. This finding discloses possible involvement of Bregs and Bmems in the pathogenesis of pediatric ITP and provides a novel vision for immune modulation and treatment perspectives.
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Affiliation(s)
| | | | - Naglaa S Osman
- Children's Hospital, Immunology Unit, Faculty of Medicine, Assiut University, Assiut, Egypt
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14
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Kuter DJ. Novel therapies for immune thrombocytopenia. Br J Haematol 2021; 196:1311-1328. [PMID: 34611885 DOI: 10.1111/bjh.17872] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 09/17/2021] [Accepted: 09/19/2021] [Indexed: 01/02/2023]
Abstract
Current therapies for immune thrombocytopenia (ITP) are successful in providing a haemostatic platelet count in over two-thirds of patients. Still, some patients have an inadequate response and there is a need for other therapies. A number of novel therapies for ITP are currently being developed based upon the current pathophysiology of ITP. Many therapies are targetted at reducing platelet destruction by decreasing anti-platelet antibody production by immunosuppression with monoclonal antibodies targetted against CD40, CD38 and the immunoproteasome or physically reducing the anti-platelet antibody concentration by inhibition of the neonatal Fc receptor. Others target the phagocytic system by inhibiting FcγR function with staphylococcal protein A, hypersialylated IgG, polymeric Fc fragments, or Bruton kinase. With a recognition that platelet destruction is also mediated by complement, inhibitors of C1s are also being tested. Inhibition of platelet desialylation may also play a role. Other novel therapies promote platelet production with new oral thrombopoietin receptor agonists or the use of low-level laser light to improve mitochondrial activity and prevent megakaryocyte apoptosis. This review will focus on these novel mechanisms for treating ITP and assess the status of treatments currently under development. Successful new treatments for ITP might also provide a pathway to treat other autoimmune disorders.
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Affiliation(s)
- David J Kuter
- Hematology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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15
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Nomura S, Abe M, Yamaoka M, Ito T. Effect of Cytokine Gene Polymorphisms on Eltrombopag Reactivity in Japanese Patients with Immune Thrombocytopenia. J Blood Med 2021; 12:421-429. [PMID: 34113203 PMCID: PMC8187034 DOI: 10.2147/jbm.s309680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/10/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by low platelet counts resulting from antiplatelet autoantibodies. Analysis of polymorphisms in cytokine-encoding genes is important for understanding the pathophysiology of ITP and selecting appropriate treatments. We investigated associations between polymorphisms in cytokine-encoding genes and responses to therapy in Japanese patients with ITP. METHODS The participants in this study comprised 153 patients with ITP and 70 healthy controls. We extracted data on sex, age, platelet counts, bleeding symptoms, and therapeutic responses, including those to prednisolone (PSL) and eltrombopag. Genomic DNA was isolated from peripheral blood and polymorphisms in TNF-α, IL-10, TGF-β1, and IFN-γ genes were analyzed using the PCR-SSP method. RESULTS Our results showed that the TGF-β1 +869 C/C genotype might be related to ITP in Japanese patients. The IL-10 -592 C/C and A/A, -819 C/C and T/T, and -1082, -819, -592 ATA/ATA genotypes might be associated with reactivity to PSL. Furthermore, the IL-10 -592 C/A -819 C/T genotypes, IL-10 ACC/ATA genotype, and TGF-β1 +869 T/T and T/C genotypes might be linked to the response to eltrombopag. CONCLUSION Our results indicate that analysis of polymorphisms in cytokine-encoding genes could aid in understanding PSL and eltrombopag responsiveness in Japanese patients with ITP.
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Affiliation(s)
- Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan
| | - Misao Abe
- Division of Blood Transfusion, Kansai Medical University, Hirakata, Osaka, Japan
| | - Manabu Yamaoka
- Division of Blood Transfusion, Kansai Medical University, Hirakata, Osaka, Japan
| | - Tomoki Ito
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan
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16
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Immune Thrombocytopenia: Recent Advances in Pathogenesis and Treatments. Hemasphere 2021; 5:e574. [PMID: 34095758 PMCID: PMC8171374 DOI: 10.1097/hs9.0000000000000574] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 04/08/2021] [Indexed: 11/26/2022] Open
Abstract
Immune thrombocytopenia (ITP) is a rare autoimmune disease due to both a peripheral destruction of platelets and an inappropriate bone marrow production. Although the primary triggering factors of ITP remain unknown, a loss of immune tolerance-mostly represented by a regulatory T-cell defect-allows T follicular helper cells to stimulate autoreactive splenic B cells that differentiate into antiplatelet antibody-producing plasma cells. Glycoprotein IIb/IIIa is the main target of antiplatelet antibodies leading to platelet phagocytosis by splenic macrophages, through interactions with Fc gamma receptors (FcγRs) and complement receptors. This allows macrophages to activate autoreactive T cells by their antigen-presenting functions. Moreover, the activation of the classical complement pathway participates to platelet opsonization and also to their destruction by complement-dependent cytotoxicity. Platelet destruction is also mediated by a FcγR-independent pathway, involving platelet desialylation that favors their binding to the Ashwell-Morell receptor and their clearance in the liver. Cytotoxic T cells also contribute to ITP pathogenesis by mediating cytotoxicity against megakaryocytes and peripheral platelets. The deficient megakaryopoiesis resulting from both the humoral and the cytotoxic immune responses is sustained by inappropriate levels of thrombopoietin, the major growth factor of megakaryocytes. The better understanding of ITP pathogenesis has provided important therapeutic advances. B cell-targeting therapies and thrombopoietin-receptor agonists (TPO-RAs) have been used for years. New emerging therapeutic strategies that inhibit FcγR signaling, the neonatal Fc receptor or the classical complement pathway, will deeply modify the management of ITP in the near future.
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Ayoub SE, Hefzy EM, Abd El-Hmid RG, Ahmed NA, Khalefa AA, Ali DY, Ali MA. Analysis of the expression profile of long non-coding RNAs MALAT1 and THRIL in children with immune thrombocytopenia. IUBMB Life 2020; 72:1941-1950. [PMID: 32563217 DOI: 10.1002/iub.2310] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 05/08/2020] [Accepted: 05/12/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS Pediatric immune thrombocytopenia (ITP) is an autoimmune disease; whose etiology is not exactly understood and seems to be highly multifactorial. Long non-coding RNAs (lncRNAs) are key regulators of different actions, which contribute to the development of many autoimmune diseases. To gain a further understanding, we estimated the relative expression of lncRNAs Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and tumor necrosis factor-α (TNF-α) and heterogeneous nuclear ribonucleoprotein L (hnRNPL) immune-regulatory lncRNA (THRIL) in pediatric ITP. METHODS In this case-control study, analysis of the expression profiles of these lncRNAs in blood samples from children with ITP and healthy controls (HCs) using quantitative real-time PCR was done. The association of MALAT1 and THRIL with ITP clinical features and their potential usage as non-invasive circulating biomarkers for ITP diagnosis was also evaluated. The receiver operating characteristic curve was constructed, and an area under the curve was analyzed. RESULTS Both lncRNAs MALAT1 and THRIL were significantly upregulated in ITP patients in comparison to HCs ( p < .0001 and = .001 respectively). In addition, there was a positive significant correlation between the expression level of both biomarkers among patients (r = 0.745, p < .0001). At cutoff points of 1.17 and 1.27 for lncRNAs MALAT1and THRIL, respectively, both biomarkers had an excellent specificity (100% for both) and fair sensitivity (63.6 and 73.3% for lncRNAs MALAT1and THRIL, respectively). Improvement of biomarkers specificity was obtained by evaluation of the combined expression of both biomarkers. Serum lncRNAs MALAT1 and THRIL could be used as potential biomarkers in differentiating childhood ITP patients and HCs.
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Affiliation(s)
- Shymaa E Ayoub
- Department of Medical Biochemistry and Molecular Biology, Fayoum University, Al Fayoum, Egypt
| | - Enas M Hefzy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Fayoum University, Al Fayoum, Egypt
| | - Rehab G Abd El-Hmid
- Department of Pediatric Medicine, Faculty of Medicine, Fayoum University, Al Fayoum, Egypt
| | - Naglaa A Ahmed
- Department of Physiology, Faculty of Medicine, Zagazig University, El Zagazig, Egypt
| | - Abeer A Khalefa
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Fayoum University, Al Fayoum, Egypt
| | - Doaa Y Ali
- Department of Clinical Pathology, Fayoum University, Al Fayoum, Egypt
| | - Marwa A Ali
- Department of Medical Biochemistry and Molecular Biology, Fayoum University, Al Fayoum, Egypt
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18
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Wu YF, Huang WH, Gu MH, Lin SR, Chu SC, Wang TF, Li CC. Higher CD56+ or CD2+ lymphocyte percentage predicts poor steroid response in patients with immune thrombocytopenia. Thromb Res 2019; 183:63-68. [DOI: 10.1016/j.thromres.2019.10.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 08/03/2019] [Accepted: 10/16/2019] [Indexed: 10/25/2022]
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19
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Hall LS, Lennon CS, Hall AM, Urbaniak SJ, Vickers MA, Barker RN. Combination peptide immunotherapy suppresses antibody and helper T-cell responses to the major human platelet autoantigen glycoprotein IIb/IIIa in HLA-transgenic mice. Haematologica 2019; 104:1074-1082. [PMID: 30514805 PMCID: PMC6518892 DOI: 10.3324/haematol.2017.179424] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 11/29/2018] [Indexed: 12/19/2022] Open
Abstract
Platelet destruction in immune thrombocytopenia is caused by autoreactive antibody and T-cell responses, most commonly directed against platelet glycoprotein IIb/IIIa. Loss of self-tolerance in the disease is also associated with deficient activity of regulatory T cells. Having previously mapped seven major epitopes on platelet glycoprotein IIIa that are recognized by helper T cells from patients with immune thrombocytopenia, the aim was to test whether peptide therapy with any of these sequences, alone or in combination, could inhibit responses to the antigen in humanized mice expressing HLA-DR15. None of the individual peptides, delivered by a putative tolerogenic regimen, consistently suppressed the antibody response to subsequent immunization with human platelet glycoprotein IIb/IIIa. However, the combination of glycoprotein IIIa peptides aa6-20 and aa711-725, which contain the predominant helper epitopes in patients and elicited the strongest trends to suppress when used individually, did abrogate this response. The peptide combination also blunted, but did not reverse, the ongoing antibody response when given after immunization. Suppression of antibody was associated with reduced splenocyte T-cell responsiveness to the antigen, and with the induction of a regulatory T-cell population that is more responsive to the peptides than to purified platelet glycoprotein IIb/IIIa. Overall, these data demonstrate that combinations of peptides containing helper epitopes, such as platelet glycoprotein IIIa aa6-20 and aa711-725, can promote in vivo suppression of responses to the major antigen implicated in immune thrombocytopenia. The approach offers a promising therapeutic option to boost T-cell regulation, which should be taken forward to clinical trials.
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Affiliation(s)
- Lindsay S Hall
- Institute of Medical Sciences, Ashgrove Road West, University of Aberdeen
- Scottish National Blood Transfusion Service, Foresterhill Road, Aberdeen, UK
| | - Charlotte S Lennon
- Institute of Medical Sciences, Ashgrove Road West, University of Aberdeen
| | - Andrew M Hall
- Institute of Medical Sciences, Ashgrove Road West, University of Aberdeen
| | - Stanislaw J Urbaniak
- Institute of Medical Sciences, Ashgrove Road West, University of Aberdeen
- Scottish National Blood Transfusion Service, Foresterhill Road, Aberdeen, UK
| | - Mark A Vickers
- Institute of Medical Sciences, Ashgrove Road West, University of Aberdeen
- Scottish National Blood Transfusion Service, Foresterhill Road, Aberdeen, UK
| | - Robert N Barker
- Institute of Medical Sciences, Ashgrove Road West, University of Aberdeen
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20
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Assessment of IL-17F rs763780 gene polymorphism in immune thrombocytopenia. Blood Cells Mol Dis 2018; 75:20-25. [PMID: 30594845 DOI: 10.1016/j.bcmd.2018.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 12/08/2018] [Accepted: 12/12/2018] [Indexed: 12/18/2022]
Abstract
Interleukin-17F rs763780 (7488A/G) gene polymorphism obviously affecting the expression and activity of IL17F and may affect primary immune thrombocytopenia (PIT) susceptibility and its clinical features in Egyptian children and adults. 105 ITP patients divided into (63 pediatric and 42 adult patient) and 112 age and sex matched healthy controls were enrolled in this case control study. All patients were subjected to history taking; clinical examination, CBC, bone marrow aspiration and genotyping of IL17F rs763780 polymorphism by (PCR-RFLP) technique. Our results revealed significant decrease in the mutant heterozygous genotype AG and also in IL-17F mutant allele G frequency in ITP patient group and associated with increased risk for ITP compared with the control group (P = 0.04 and P = 0.005 respectively). Furthermore, the mutant allele G frequency was significantly decreased in childhood onset than adult onset ITP (OR = 0.31, P = 0.02) and also was significantly lower in chronic ITP when compared with newly diagnosed and persistent ITP (P = 0.005). Patients with the AA genotype showed severe thrombocytopenic state at diagnosis than those with the AG genotype (P = 0.04). We concluded from our results that interleukin-17F rs763780 (7488A/G) polymorphism is strongly correlated with susceptibility and severity of ITP.
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21
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Behzad MM, Asnafi AA, Jalalifar MA, Moghtadaei M, Jaseb K, Saki N. Cellular expression of CD markers in immune thrombocytopenic purpura: implications for prognosis. APMIS 2018; 126:523-532. [PMID: 29924452 DOI: 10.1111/apm.12853] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 05/01/2018] [Indexed: 11/30/2022]
Abstract
Immune thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder associated with platelet destruction. Abnormalities in frequency and function of different immune cells can play a crucial role in this disease. The aim of this study was to evaluate the prognostic value of CD markers' expressions by immune cells in ITP. Peripheral blood samples were collected from 25 ITP patients before and after treatment. The expression of CD markers was evaluated by flow cytometry technique. The expression of CD38 and CD56 was significantly lower before treatment than after it (p = 0.025 and p = 0.036, respectively). Furthermore, a positive correlation was found between CD38 expression with platelet count before (r = 0.496, p = 0.012) and after treatment (r = 0.404, p = 0.045). No significant relationship was found between this marker and platelet count while CD4 expression was higher before treatment than after it (p = 0.002). In conclusion, CD38 may have independent prognostic value in ITP and we suggest that it can be a prognostic marker for this disease.
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Affiliation(s)
- Masumeh Maleki Behzad
- Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Amin Asnafi
- Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Ali Jalalifar
- Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mostafa Moghtadaei
- Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kaveh Jaseb
- Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Najmaldin Saki
- Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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22
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Swinkels M, Rijkers M, Voorberg J, Vidarsson G, Leebeek FWG, Jansen AJG. Emerging Concepts in Immune Thrombocytopenia. Front Immunol 2018; 9:880. [PMID: 29760702 PMCID: PMC5937051 DOI: 10.3389/fimmu.2018.00880] [Citation(s) in RCA: 158] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 04/09/2018] [Indexed: 01/19/2023] Open
Abstract
Immune thrombocytopenia (ITP) is an autoimmune disease defined by low platelet counts which presents with an increased bleeding risk. Several genetic risk factors (e.g., polymorphisms in immunity-related genes) predispose to ITP. Autoantibodies and cytotoxic CD8+ T cells (Tc) mediate the anti-platelet response leading to thrombocytopenia. Both effector arms enhance platelet clearance through phagocytosis by splenic macrophages or dendritic cells and by induction of apoptosis. Meanwhile, platelet production is inhibited by CD8+ Tc targeting megakaryocytes in the bone marrow. CD4+ T helper cells are important for B cell differentiation into autoantibody secreting plasma cells. Regulatory Tc are essential to secure immune tolerance, and reduced levels have been implicated in the development of ITP. Both Fcγ-receptor-dependent and -independent pathways are involved in the etiology of ITP. In this review, we present a simplified model for the pathogenesis of ITP, in which exposure of platelet surface antigens and a loss of tolerance are required for development of chronic anti-platelet responses. We also suggest that infections may comprise an important trigger for the development of auto-immunity against platelets in ITP. Post-translational modification of autoantigens has been firmly implicated in the development of autoimmune disorders like rheumatoid arthritis and type 1 diabetes. Based on these findings, we propose that post-translational modifications of platelet antigens may also contribute to the pathogenesis of ITP.
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Affiliation(s)
- Maurice Swinkels
- Department of Hematology, Erasmus University Medical Centre, Rotterdam, Netherlands
| | - Maaike Rijkers
- Department of Plasma Proteins, AMC-Sanquin Landsteiner Laboratory, Amsterdam, Netherlands
| | - Jan Voorberg
- Department of Plasma Proteins, AMC-Sanquin Landsteiner Laboratory, Amsterdam, Netherlands
| | - Gestur Vidarsson
- Department of Experimental Immunohematology, AMC-Sanquin Landsteiner Laboratory, Amsterdam, Netherlands
| | - Frank W G Leebeek
- Department of Hematology, Erasmus University Medical Centre, Rotterdam, Netherlands
| | - A J Gerard Jansen
- Department of Hematology, Erasmus University Medical Centre, Rotterdam, Netherlands.,Department of Plasma Proteins, AMC-Sanquin Landsteiner Laboratory, Amsterdam, Netherlands
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23
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Nookaew I, Wadenvik H, Olsson B, Jernås M. Differential expression of T-cell genes in blood and bone marrow between ITP patients and controls. Thromb Haemost 2017; 109:112-7. [DOI: 10.1160/th12-07-0468] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Accepted: 09/25/2012] [Indexed: 11/05/2022]
Abstract
SummaryPrimary immune thrombocytopenia (ITP) is an autoimmune disease characterised by premature platelet destruction in spleen, liver and bone marrow and a diminished production of platelets. T-cells are important in all forms of autoimmunity including ITP; however, very little is known about T-cells in organs where platelets are destroyed. Our aim was to investigate differences in gene expression in peripheral blood-derived T-cells and bone marrow-derived T-cells between ITP patients and controls. T-cells and subsequent RNA were isolated from blood and bone marrow from chronic ITP patients and healthy controls followed by DNA microarray analysis. There were 1554 differentially expressed genes in peripheral blood-derived T-cells and 976 in bone marrow-derived T-cells between ITP patients and controls and three genes were verified with real-time PCR. Using Gene Ontology functional enrichment analysis we found that genes involved in growth, development, migration, chemotaxis, adhesion and apoptosis were enriched in bone marrow-derived T-cells in ITP. Immune-related genes involved in T-helper cell differentiation, T-cell chemotaxis, migration, immunoglobulin-mediated immune response and classical and alternative pathway complement activation were also enriched in bone marrow-derived T-cells in ITP. Only 213 T-cell genes were differentially expressed in both blood and bone marrow between ITP patients and controls. In conclusion, our findings show that genes involved in major pathophysiologic pathways in ITP such as T-helper cell differentiation, autoantibody response and complement activation are altered in bone marrow-derived T-cells in ITP patients compared with controls. This further supports the concept that bone marrow is an important compartment in ITP.
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24
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Behzad MM, Asnafi AA, Jaseb K, Jalali Far MA, Saki N. Expression of CD markers' in immune thrombocytopenic purpura: prognostic approaches. APMIS 2017; 125:1042-1055. [PMID: 28960510 DOI: 10.1111/apm.12755] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 07/28/2017] [Indexed: 01/19/2023]
Abstract
Immune Thrombocytopenic Purpura (ITP) is a common autoimmune bleeding disorder characterized by a reduction in peripheral blood platelet counts. In this disease, autoantibodies (Auto-Abs) are produced against platelet GPIIb/GPIIIa by B cells, which require interaction with T cells. In this review, the importance of B and T lymphocytes in ITP prognosis has been studied. Relevant literature was identified by a PubMed search (1990-2016) of English-language papers using the terms B and T lymphocyte, platelet, CD markers and immune thrombocytopenic purpura. T and B lymphocytes are the main immune cells in the body. Defective function causes disrupted balance of different subgroups of lymphocytes, and abnormal expression of surface markers of these cells results in self-tolerance dysfunction, as well as induction of Auto-Abs against platelet glycoproteins (PG). Given the role of B and T cells in production of autoantibodies against PG, it can be stated that the detection of changes in CD markers' expression in these cells can be a good approach for assessing prognosis in ITP patients.
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Affiliation(s)
- Masumeh Maleki Behzad
- Research Center of Thalassemia & Hemoglobinopathy, Health research institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Amin Asnafi
- Research Center of Thalassemia & Hemoglobinopathy, Health research institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kaveh Jaseb
- Research Center of Thalassemia & Hemoglobinopathy, Health research institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Ali Jalali Far
- Research Center of Thalassemia & Hemoglobinopathy, Health research institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Najmaldin Saki
- Research Center of Thalassemia & Hemoglobinopathy, Health research institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Zahran AM, Aly SS, Elabd A, Mohamad IL, Elsayh KI. Regulatory and Memory B Lymphocytes in Children With Newly Diagnosed Immune Thrombocytopenia. J Hematol 2017; 6:81-86. [PMID: 32300398 PMCID: PMC7155846 DOI: 10.14740/jh336w] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 08/28/2017] [Indexed: 01/19/2023] Open
Abstract
Background Immune (idiopathic) thrombocytopenic purpura (ITP) is a primary autoimmune disease. It is characterized by a diminished peripheral platelet count (< 100 × 109/L) caused by platelet destruction with an increased risk of mucocutaneous bleeding. The diagnosis of ITP depends on clinical characteristics and the laboratory examinations conducted, as well as the ability to exclude other diseases associated with thrombocytopenia. Antiplatelet autoantibodies are responsible for platelet destruction and probably for inhibition of megakaryopoiesis. B lymphocytes participate in immune responses through production of antibodies, antigen presentation to T cells, and cytokine secretion. The aims of this study were to investigate the levels of Bregs and memory B lymphocytes in newly diagnosed pediatric ITP patients and to correlate their levels with the course of the disease. Methods This study was a case-control study. The study included 30 patients with acute ITP. The patients were recruited from Pediatric Clinical Hematology Unit of Children Hospital, Assiut University. In addition, 20 healthy children of comparable age and sex were taken as controls. The institutional review board approved the study and informed consents were obtained. Results There is a significant alteration of B-cell homeostasis in patients with ITP. Conclusion Analysis of Bregs and memory B cells could serve as prognostic markers and might guide therapy in ITP patients in the future.
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Affiliation(s)
- Asmaa M Zahran
- Clinical Pathology Department, South Egypt Cancer Institute, Assiut, Egypt
| | - Sanaa Shaker Aly
- Clinical and Chemical Pathology Department, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Ahmed Elabd
- Pediatric Department, Faculty of Medicine, South Valley University, Qena, Egypt
| | | | - Khalid I Elsayh
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt
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Feng Q, Xu M, Yu YY, Hou Y, Mi X, Sun YX, Ma S, Zuo XY, Shao LL, Hou M, Zhang XH, Peng J. High-dose dexamethasone or all-trans-retinoic acid restores the balance of macrophages towards M2 in immune thrombocytopenia. J Thromb Haemost 2017; 15:1845-1858. [PMID: 28682499 DOI: 10.1111/jth.13767] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Indexed: 01/08/2023]
Abstract
Essentials M1/M2 imbalance is involved in many autoimmune diseases, and could be restored. The expressions and functions of M1 and M2 were investigated in an in vitro culture system. A preferred M1 polarization is involved in the pathogenesis of immune thrombocytopenia (ITP). High-dose dexamethasone or all-trans-retinoic acid restores M1/M2 balance in ITP patients. SUMMARY Background Immune thrombocytopenia (ITP) is an autoimmune disorder. Deficiency of immune tolerance in antigen-presenting cells and cross-communication between antigen-presenting cells and T cells are involved in the pathogenesis of ITP. Macrophages can polarize into proinflammatory M1 or anti-inflammatory M2 phenotypes in response to different environmental stimuli, and have diverse immunologic functions. Objectives To investigate the M1/M2 imbalance in ITP and whether high-dose dexamethasone (HD-DXM) or all-trans-retinoic acid (ATRA) could restore this imbalance. Methods The numbers of M1 and M2 macrophages in the spleens of ITP patients and patients with traumatic spleen rupture were analyzed by immunofluorescence. Monocyte-derived macrophages were cultured and induced with cytokines and drugs. The expression of M1 and M2 markers and functions of M1 and M2 macrophages before and after modulation by HD-DXM or ATRA were evaluated with flow cytometry and ELISA. Results There was preferred M1 polarization in ITP spleens as compared with healthy controls. Monocyte-derived macrophages from ITP patients had increased expression of M1 markers and impaired immunosuppressive functions. Either HD-DXM or ATRA corrected this imbalance by decreasing the expression of M1 markers and increasing the expression of M2 markers. Moreover, HD-DXM-modulated or ATRA-modulated macrophages suppressed both CD4+ and CD8+ T-cell proliferation and expanded CD4+ CD49+ LAG3+ type 1 T-regulatory cells. HD-DXM or ATRA modulated macrophages to shift the T-cell cytokine profile towards Th2. Treating patients with HD-DXM or ATRA revealed that macrophages induced from responders showed a predominant M2-like phenotype and immunosuppressive function. Conclusions Aberrant macrophage polarization is involved in the pathogenesis of ITP. Either HD-DXM or ATRA is able to correct this imbalance.
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MESH Headings
- Adolescent
- Adult
- Aged
- Biomarkers/metabolism
- CD8-Positive T-Lymphocytes/drug effects
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- Case-Control Studies
- Cell Proliferation/drug effects
- Cells, Cultured
- Coculture Techniques
- Cytokines/metabolism
- Dexamethasone/adverse effects
- Dexamethasone/therapeutic use
- Female
- Humans
- Immunologic Factors/adverse effects
- Immunologic Factors/therapeutic use
- Lymphocyte Activation/drug effects
- Macrophage Activation/drug effects
- Macrophages/drug effects
- Macrophages/immunology
- Macrophages/metabolism
- Male
- Middle Aged
- Phagocytosis/drug effects
- Phenotype
- Purpura, Thrombocytopenic, Idiopathic/drug therapy
- Purpura, Thrombocytopenic, Idiopathic/immunology
- Purpura, Thrombocytopenic, Idiopathic/metabolism
- Spleen/drug effects
- Spleen/immunology
- Spleen/metabolism
- T-Lymphocytes, Helper-Inducer/drug effects
- T-Lymphocytes, Helper-Inducer/immunology
- T-Lymphocytes, Helper-Inducer/metabolism
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Treatment Outcome
- Tretinoin/adverse effects
- Tretinoin/therapeutic use
- Young Adult
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Affiliation(s)
- Q Feng
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
| | - M Xu
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Y Y Yu
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
| | - Y Hou
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
| | - X Mi
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
| | - Y X Sun
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
| | - S Ma
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
| | - X Y Zuo
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
| | - L L Shao
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
| | - M Hou
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China
| | - X H Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
| | - J Peng
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
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Audia S, Mahévas M, Samson M, Godeau B, Bonnotte B. Pathogenesis of immune thrombocytopenia. Autoimmun Rev 2017; 16:620-632. [DOI: 10.1016/j.autrev.2017.04.012] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Accepted: 03/17/2017] [Indexed: 01/19/2023]
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Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood 2017; 129:2829-2835. [PMID: 28416506 PMCID: PMC5813736 DOI: 10.1182/blood-2017-03-754119] [Citation(s) in RCA: 274] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 04/10/2017] [Indexed: 12/25/2022] Open
Abstract
Immune thrombocytopenia (ITP) occurs in 2 to 4/100 000 adults and results in variable bleeding symptoms and thrombocytopenia. In the last decade, changes in our understanding of the pathophysiology of the disorder have led to the publication of new guidelines for the diagnosis and management of ITP and standards for terminology. Current evidence supports alternatives to splenectomy for second-line management of patients with persistently low platelet counts and bleeding. Long-term follow-up data suggest both efficacy and safety, in particular, for the thrombopoietin receptor agonists and the occurrence of late remissions. Follow-up of patients who have undergone splenectomy for ITP reveals significant potential risks that should be discussed with patients and may influence clinician and patient choice of second-line therapy. Novel therapeutics are in development to address ongoing treatment gaps.
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MESH Headings
- Adult
- Female
- Hemorrhage/blood
- Hemorrhage/diagnosis
- Hemorrhage/physiopathology
- Hemorrhage/therapy
- Humans
- Male
- Platelet Count
- Practice Guidelines as Topic
- Purpura, Thrombocytopenic, Idiopathic/blood
- Purpura, Thrombocytopenic, Idiopathic/diagnosis
- Purpura, Thrombocytopenic, Idiopathic/physiopathology
- Purpura, Thrombocytopenic, Idiopathic/therapy
- Receptors, Thrombopoietin/agonists
- Receptors, Thrombopoietin/metabolism
- Splenectomy
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Affiliation(s)
- Michele P Lambert
- Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA; and
| | - Terry B Gernsheimer
- Division of Hematology, University of Washington School of Medicine, Seattle, WA
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Sys J, Provan D, Schauwvlieghe A, Vanderschueren S, Dierickx D. The role of splenectomy in autoimmune hematological disorders: Outdated or still worth considering? Blood Rev 2017; 31:159-172. [DOI: 10.1016/j.blre.2017.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 12/12/2016] [Accepted: 01/03/2017] [Indexed: 01/26/2023]
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Zufferey A, Kapur R, Semple JW. Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP). J Clin Med 2017; 6:jcm6020016. [PMID: 28208757 PMCID: PMC5332920 DOI: 10.3390/jcm6020016] [Citation(s) in RCA: 316] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 02/04/2017] [Indexed: 01/19/2023] Open
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, third-line 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.
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Affiliation(s)
- Anne Zufferey
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
- The Toronto Platelet Immunobiology Group, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
| | - Rick Kapur
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
- The Toronto Platelet Immunobiology Group, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
- Canadian Blood Services, Toronto, ON M5B 1W8, Canada.
| | - John W Semple
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
- The Toronto Platelet Immunobiology Group, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
- Canadian Blood Services, Toronto, ON M5B 1W8, Canada.
- Department of Pharmacology, Medicine, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5B 1W8, Canada.
- Division of Hematology and Transfusion Medicine, Lund University, 221 84 Lund, Sweden.
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Qu MM, Liu XN, Liu XG, Feng Q, Liu Y, Zhang X, Liu S, Zhang L, Li GS, Zhu YY, Lv MY, Peng J, Hou M. Cytokine changes in response to TPO receptor agonist treatment in primary immune thrombocytopenia. Cytokine 2017; 92:110-117. [PMID: 28142109 DOI: 10.1016/j.cyto.2017.01.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 01/08/2017] [Accepted: 01/13/2017] [Indexed: 01/26/2023]
Abstract
Thrombopoietin receptor agonists (TPO-RAs) have been clinically used in primary immune thrombocytopenia (ITP) with favorable outcomes, while their effect on cytokine regulation in ITP remains unknown. In the present study, plasma and mRNA expression levels of interleukin (IL)-2, interferon gamma (IFN-γ), IL-4, IL-17A, and transforming growth factor-β1 (TGF-β1) were determined by ELISA and real-time quantitative PCR in 26 corticosteroid-resistant/relapsed ITP patients receiving eltrombopag or rhTPO therapy and 15 healthy controls (HCs). Results showed that plasma and mRNA levels of IL-2, IFN-γ, IL-4, and IL-17A in ITP patients did not change significantly after TPO-RA treatment, whereas TGF-β1 levels increased remarkably. The pre- and post-treatment plasma and mRNA levels of IFN-γ and IL-2 were significantly higher, while the pre- and post-treatment IL-4 levels as well as the pre-treatment TGF-β1 levels were remarkably lower in ITP patients compared with HCs. There was no significant difference in TGF-β1 levels between TPO-RA-treated ITP patients and HCs. No statistical difference was found in plasma levels of IL-17A between ITP patients before or after treatment and HCs. However, the pre- and post-treatment mRNA expression of IL-17A and retinoic orphan receptor (ROR) γt in ITP patients were higher than that in HCs. Overall, these findings indicated that TPO-RA treatment could promote the secretion of TGF-β1, while it could not correct the Th1 and Th17 polarization in ITP patients. This study might improve our understanding of the mechanism of action of TPO-RAs and provide important information for optimizing therapeutic strategies for ITP.
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Affiliation(s)
- Ming-Ming Qu
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Xue-Na Liu
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Xin-Guang Liu
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China.
| | - Qi Feng
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Yang Liu
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Xu Zhang
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Shuang Liu
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China; Department of Hematology, Taian Central Hospital, Taian, PR China
| | - Lei Zhang
- Department of Orthopedics, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Guo-Sheng Li
- Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Yuan-Yuan Zhu
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Ming-Yun Lv
- Reproductive Center, Rizhao Maternal & Child Health Hospital, Rizhao, PR China
| | - Jun Peng
- Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Ming Hou
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China.
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Nishimoto T, Okazaki Y, Numajiri M, Kuwana M. Mouse immune thrombocytopenia is associated with Th1 bias and expression of activating Fcγ receptors. Int J Hematol 2016; 105:598-605. [PMID: 28028748 DOI: 10.1007/s12185-016-2172-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 12/20/2016] [Accepted: 12/21/2016] [Indexed: 12/13/2022]
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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Affiliation(s)
- Tetsuya Nishimoto
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yuka Okazaki
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Miku Numajiri
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Masataka Kuwana
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. .,Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.
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Abstract
OBJECTIVES Classically, immune thrombocytopenia (ITP) was thought to be caused by the destruction and insufficient production of platelets, as mediated by autoantibodies. More recently other immune mechanisms that contribute to the disease have been discovered. This review attempts to address the main unresolved questions in ITP. METHODS We review the most current knowledge of the pathophysiology of ITP. Immunological effects of available therapies are also described. DISCUSSION The trigger may be a loss of tolerance due to molecular mimicry with cross-reaction of antibodies arising from infectious agents or drugs, genetic factors, and/or platelet Toll receptors. This loss of tolerance activates autoreactive effector B and T lymphocytes, which in turn initiates platelet destruction, mediated by cytotoxic T lymphocytes and the release of pro-inflammatory cytokines (IL-2/IL-17) by T helper (Th) cells (Th1/Th17). Th2 (anti-inflammatory) and regulatory B (Breg) and Treg cells are also inhibited (with decrease in IL-10/TGF-β), which leads to the disease becoming chronic. Some isotypes of autoantibodies may increase the bleeding risk. Corticosteroids, rituximab, and thrombopoietin receptor agonists (A-TPOs) all increase levels of Tregs and TGF-β. The A-TPOs also increase Breg levels, which could explain why complete remission has been seen in some cases. CONCLUSION A better understanding of the immunomodulatory effects of each ITP therapy is needed to best manage the disease.
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Affiliation(s)
- María Perera
- a Haematology Service , University Hospital Doctor Negrín , Las Palmas de Gran Canaria, Spain
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Zhang JM, Feng FE, Wang QM, Zhu XL, Fu HX, Xu LP, Liu KY, Huang XJ, Zhang XH. Platelet-Derived Growth Factor-BB Protects Mesenchymal Stem Cells (MSCs) Derived From Immune Thrombocytopenia Patients Against Apoptosis and Senescence and Maintains MSC-Mediated Immunosuppression. Stem Cells Transl Med 2016; 5:1631-1643. [PMID: 27471307 DOI: 10.5966/sctm.2015-0360] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Accepted: 05/13/2016] [Indexed: 12/12/2022] Open
Abstract
: Immune thrombocytopenia (ITP) is characterized by platelet destruction and megakaryocyte dysfunction. Mesenchymal stem cells (MSCs) from ITP patients (MSC-ITP) do not exhibit conventional proliferative abilities and thus exhibit defects in immunoregulation, suggesting that MSC impairment might be a mechanism involved in ITP. Platelet-derived growth factor (PDGF) improves growth and survival in various cell types. Moreover, PDGF promotes MSC proliferation. The aim of the present study was to analyze the effects of PDGF-BB on MSC-ITP. We showed that MSC-ITP expanded more slowly and appeared flattened and larger. MSC-ITP exhibited increased apoptosis and senescence compared with controls. Both the intrinsic and extrinsic pathways account for the enhanced apoptosis. P53 and p21 expression were upregulated in MSC-ITP, but inhibition of p53 with pifithrin-α markedly inhibited apoptosis and senescence. Furthermore, MSCs from ITP patients showed a lower capacity for inhibiting the proliferation of activated T cells inducing regulatory T cells (Tregs) and suppressing the synthesis of anti-glycoprotein (GP)IIb-IIIa antibodies. PDGF-BB treatment significantly decreased the expression of p53 and p21 and increased survivin expression in MSC-ITP. In addition, the apoptotic rate and number of senescent cells in ITP MSCs were reduced. Their impaired ability for inhibiting activated T cells, inducing Tregs, and suppressing the synthesis of anti-GPIIb-IIIa antibodies was restored after PDGF-BB treatment. In conclusion, we have demonstrated that PDGF-BB protects MSCs derived from ITP patients against apoptosis, senescence, and immunomodulatory defects. This protective effect of PDGF-BB is likely mediated via the p53/p21 pathway, thus potentially providing a new therapeutic approach for ITP. SIGNIFICANCE Immune thrombocytopenia (ITP) is characterized by platelet destruction and megakaryocyte dysfunction. Platelet-derived growth factor (PDGF) improves growth and survival in various cell types and promotes mesenchymal stem cell (MSC) proliferation. PDGF-BB protects MSCs derived from ITP patients against apoptosis, senescence, and immunomodulatory defects. This protective effect of PDGF-BB is likely mediated via the p53/p21 pathway, thus potentially providing a new therapeutic approach for ITP.
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Affiliation(s)
- Jia-Min Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, People's Republic of China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, People's Republic of China
- Collaborative Innovation Center of Hematology, Peking University, Beijing, People's Republic of China
| | - Fei-Er Feng
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, People's Republic of China
| | - Qian-Ming Wang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, People's Republic of China
| | - Xiao-Lu Zhu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, People's Republic of China
| | - Hai-Xia Fu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, People's Republic of China
| | - Lan-Ping Xu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, People's Republic of China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, People's Republic of China
- Collaborative Innovation Center of Hematology, Peking University, Beijing, People's Republic of China
| | - Kai-Yan Liu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, People's Republic of China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, People's Republic of China
- Collaborative Innovation Center of Hematology, Peking University, Beijing, People's Republic of China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, People's Republic of China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, People's Republic of China
- Collaborative Innovation Center of Hematology, Peking University, Beijing, People's Republic of China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, People's Republic of China
- Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, People's Republic of China
- Collaborative Innovation Center of Hematology, Peking University, Beijing, People's Republic of China
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Nomura S. Advances in Diagnosis and Treatments for Immune Thrombocytopenia. Clin Med Insights Blood Disord 2016; 9:15-22. [PMID: 27441004 PMCID: PMC4948655 DOI: 10.4137/cmbd.s39643] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 05/22/2016] [Accepted: 05/24/2016] [Indexed: 01/19/2023]
Abstract
Immune thrombocytopenia (ITP) is an acquired hemorrhagic condition characterized by the accelerated clearance of platelets caused by antiplatelet autoantibodies. A platelet count in peripheral blood <100 × 109/L is the most important criterion for the diagnosis of ITP. However, the platelet count is not the sole diagnostic criterion, and the diagnosis of ITP is dependent on additional findings. ITP can be classified into three types, namely, acute, subchronic, and persistent, based on disease duration. Conventional therapy includes corticosteroids, intravenous immunoglobulin, splenectomy, and watch-and-wait. Second-line treatments for ITP include immunosuppressive therapy [eg, anti-CD20 (rituximab)], with international guidelines, including rituximab as a second-line option. The most recently licensed drugs for ITP are the thrombopoietin receptor agonists (TRAs), such as romiplostim and eltrombopag. TRAs are associated with increased platelet counts and reductions in the number of bleeding events. TRAs are usually considered safe, effective treatments for patients with chronic ITP at risk of bleeding after failure of first-line therapies. Due to the high costs of TRAs, however, it is unclear if patients prefer these agents. In addition, some new agents are under development now. This manuscript summarizes the pathophysiology, diagnosis, and treatment of ITP. The goal of all treatment strategies for ITP is to achieve a platelet count that is associated with adequate hemostasis, rather than a normal platelet count. The decision to treat should be based on the bleeding severity, bleeding risk, activity level, likely side effects of treatment, and patient preferences.
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Affiliation(s)
- Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan
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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; 23:786-792. [PMID: 27329949 DOI: 10.1177/1076029616652726] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Human monocytes are heterogeneous and play an important role in autoimmune diseases. However, the distribution and function of monocyte subsets remain unclear in primary immune thrombocytopenia (ITP). In this study, we determined the frequencies of monocyte subsets in 71 untreated patients with active ITP and 49 healthy controls by flow cytometry. Compared with controls, the frequency of nonclassical monocytes was significantly increased in patients with active ITP but decreased after complete remission. The intermediate subset was also increased in patients with active ITP and produced the highest levels of tumor necrosis factor α and interleukin 1β. Both the nonclassical and intermediate subsets were negatively correlated with the platelet counts. We further determined the correlation between monocyte subsets and the proliferation of platelet-autoreactive T cells. The purified monocyte subsets were cocultured with CD4+ T cells and autologous platelets. The nonclassical subset showed the highest capability of promoting platelet reactive T-cell proliferation and significantly promoted the secretion of interferon γ among the 3 subsets. In conclusion, the nonclassical and intermediate monocyte subsets are both expanded and play different roles in the pathogenesis of ITP.
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Affiliation(s)
- Yanhui Yang
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Xian Zhang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Donglei Zhang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Huiyuan Li
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Li Ma
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Min Xuan
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Hongmei Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Renchi Yang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
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Thrombopoietin receptor agonists shift the balance of Fcγ receptors toward inhibitory receptor IIb on monocytes in ITP. Blood 2016; 128:852-61. [PMID: 27281793 DOI: 10.1182/blood-2016-01-690727] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 06/01/2016] [Indexed: 12/25/2022] Open
Abstract
Elevated expression of the activating Fcγ receptor (FcγR) I and FcγRIIa together with decreased expression of the inhibitory FcγRIIb are involved in the pathogenesis of primary immune thrombocytopenia (ITP). Thrombopoietin receptor agonists (TPO-RAs) have been used clinically for the management of ITP; however, little is known about the effect of TPO-RAs on FcγR modulation in ITP. In this prospective study, we measured the alteration in monocyte FcγR expression from 21 corticosteroid-resistant/relapsed patients with chronic ITP receiving eltrombopag therapy. Results showed that the mRNA and protein levels of FcγRIIb were significantly elevated after 6-week eltrombopag treatment. Concurrently, FcγRI and IIa levels decreased remarkably, whereas FcγRIII expression did not change. In vitro phagocytosis assays indicated that a shift in the balance of FcγR toward inhibitory FcγRIIb on monocytes was accompanied with a considerable decrease in monocyte/macrophage phagocytic capacity. The response to eltrombopag therapy in patients with ITP was associated with FcγR phenotype and functional changes of monocytes/macrophages. Moreover, the plasma transforming growth factor-β1 (TGF-β1) concentrations increased significantly in eltrombopag responders. Modulation of monocyte FcγR balance by TPO-RAs was also found in a murine model of ITP established by transferring splenocytes from immunized CD61 knockout mice into CD61(+) severe combined immunodeficient mice. Romiplostim administration in ITP mice significantly upregulated inhibitory FcγRII expression and downregulated activating FcγRI expression. These findings showed that recovery of platelet counts after TPO-RA treatment in ITP is associated with the restoration of FcγR balance toward the inhibitory FcγRIIb on monocytes, and suggested that thrombopoietic agents have a profound effect on immune modulation in ITP. This study is registered at ClinicalTrials.gov as #NCT01864512.
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Akyol Erikçi A, Karagöz B, Bilgi O. Regulatory T Cells in Patients with Idiopathic Thrombocytopenic Purpura. Turk J Haematol 2016; 33:153-5. [PMID: 27211045 PMCID: PMC5100728 DOI: 10.4274/tjh.2015.0335] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Objective: Immune thrombocytopenic purpura (ITP) is an immune-mediated bleeding disorder in which platelets are opsonized by autoantibodies and destroyed by an Fc receptor-mediated phagocytosis by the reticuloendothelial system within the spleen. Autoimmune processes are also considered in the pathogenesis of this disorder. CD4+CD25+FoxP3+ regulatory T (Treg) cells and CD8+CD28- Treg cells have roles in autoimmune diseases. We investigated these regulatory cells in ITP patients. Materials and Methods: We included 22 ITP patients and 16 age-matched healthy subjects. CD4+CD25+FoxP3+ Treg cells and CD8+CD28- cells were investigated by three-color flow cytometry. The ratios of these cell populations to total lymphocytes were calculated. Statistical analysis was carried out with the Mann-Whitney U test. Results: CD4+CD25+ Treg cells were 9.69±3.70% and 12.99±5.58% in patients with ITP and controls, respectively. CD4+CD25highFoxP3+ cells were 27.72±19.74% and 27.55±23.98% in ITP patients and controls, respectively. The percentages of both of these cell types were not statistically significant when compared to the control group. Conclusion: We did not find any differences in ratios of CD4+CD25+FoxP3+ Treg cells or CD8+CD28- T cells in lymphocytes between patients and healthy subjects. We conclude that these circulatory cells are not different in ITP, but further studies are needed to explore the putative roles of these regulatory cells.
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Affiliation(s)
- Alev Akyol Erikçi
- Gülhane Military Medical Academy, Haydarpaşa Training and Research Hospital, Clinic of Hematology, İstanbul, Turkey, Phone : +90 532 733 03 14, E-mail :
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Min YN, Wang CY, Li XX, Hou Y, Qiu JH, Ma J, Shao LL, Zhang X, Wang YW, Peng J, Hou M, Shi Y. Participation of B-cell-activating factor receptors in the pathogenesis of immune thrombocytopenia. J Thromb Haemost 2016; 14:559-71. [PMID: 26749059 DOI: 10.1111/jth.13246] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 12/20/2015] [Indexed: 12/19/2022]
Abstract
UNLABELLED ESSENTIALS: Dysfunctional B-cell-activating factor (BAFF) system is related to many autoimmune diseases. The regulatory functions of BAFF/BAFF receptors were investigated in an in vitro coculture system. Different regulatory roles of BAFF were investigated via different receptors in immune thrombocytopenia. The upregulated BAFF receptors on autoreactive lymphocytes lead to their hypersensitivity to BAFF. SUMMARY BACKGROUND The pathogenesis of immune thrombocytopenia (ITP) remains enigmatic. B-cell-activating factor (BAFF) and its receptors (BAFF receptor [BAFF-R], transmembrane activator and calcium modulator and cyclophilin ligand interactor [TACI], and B-cell maturation antigen) play central roles in the integrated homeostatic regulation of lymphocytes. OBJECTIVES To investigate the pathologic roles of BAFF receptors in regulating the bioactivities of lymphocytes in ITP. METHODS An in vitro culture system was established by stimulating CD14(-) peripheral lymphocytes with platelet-preloaded dendritic cells in the presence of recombinant human BAFF (rhBAFF; 20 ng mL(-1)). The functions of BAFF receptors were specifically blocked with blocking antibodies. RESULTS BAFF-R, besides prolonging the survival of B cells in both patients and healthy controls, prominently promoted the survival of CD8(+) T cells and the proliferation of B cells in patients with ITP. TACI, as a positive regulator, not only promoted the proliferation of CD4(+) and CD8(+) T cells, but also significantly enhanced the secretion of interleukin-4 in patients with ITP, but not in controls. Besides revealing the pathologic roles of BAFF receptors, these results also indicate that lymphocytes of patients with ITP have enhanced antiapoptotic or proliferative capacity as compared with those from healthy controls when exposed under similar stimulation of rhBAFF. Further study demonstrated that activated autoreactive B cells and CD4(+) T cells from patients with ITP showed significantly higher expression of BAFF-R or TACI than those from healthy controls. CONCLUSIONS Both BAFF-R and TACI are pathogenic participants in ITP. Their dysregulated expression in patients with ITP may lead to hyperreactivity of activated autoreactive lymphocytes in response to rhBAFF, and thus is highly significant in the pathogenesis of ITP.
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Affiliation(s)
- Y-N Min
- Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - C-Y Wang
- Department of General Medicine, Second Hospital of Shandong University, Jinan, Shandong, China
| | - X-X Li
- Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Y Hou
- Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - J-H Qiu
- Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - J Ma
- Department of General Medicine, Medical Research Institute for Tumor Prevention and Cure, Shandong University, Jinan, Shandong, China
| | - L-L Shao
- Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - X Zhang
- Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Y-W Wang
- Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - J Peng
- Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, Shandong, China
| | - M Hou
- Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, Shandong, China
| | - Y Shi
- Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan, Shandong, China
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High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia. Blood 2016; 127:1587-97. [PMID: 26744458 DOI: 10.1182/blood-2015-10-674531] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 12/24/2015] [Indexed: 01/21/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. In this study, the MDSC population was evaluated in adult patients with primary immune thrombocytopenia (ITP), where cell-mediated immune mechanisms are involved in platelet destruction. Our data demonstrated that both the numbers and suppressive functions of MDSCs were impaired in the peripheral blood and spleens of patients with ITP compared with healthy control patients. High-dose dexamethasone (HD-DXM) treatment rescued MDSC numbers in patients with ITP. And DXM modulation promoted the suppressive function of MDSCs induced in vitro. Moreover, the expression of interleukin 10 and transforming growth factor β was significantly upregulated in DXM-modulated MDSCs compared with the unmodulated cultures. DXM-modulated MDSCs inhibited autologous CD4(+)T-cell proliferation and significantly attenuated cytotoxic T lymphocyte-mediated platelet lysis, further indicating enhanced control over T-cell responses. Elevated expression of the transcription factor Ets1 was identified in DXM-modulated MDSCs. Transfection of Ets-1 small interfering RNA efficiently blocked regulatory effects of MDSCs, which almost offset the augmentation of MDSC function by DXM. Meanwhile, splenocytes from CD61 knockout mice immunized with CD61(+)platelets were transferred into severe combined immunodeficient (SCID) mouse recipients (C57/B6 background) to induce a murine model of severe ITP. We passively transferred the DXM-modulated MDSCs induced from bone marrow of wild-type C57/B6 mice into the SCID mouse recipients, which significantly increased platelet counts in vivo compared with those receiving splenocyte engraftment alone. These findings suggested that impaired MDSCs are involved in the pathogenesis of ITP, and that HD-DXM corrected MDSC functions via a mechanism underlying glucocorticoid action and Ets1.
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Bal G, Futschik ME, Hartl D, Ringel F, Kamhieh-Milz J, Sterzer V, Hoheisel JD, Alhamdani MSS, Salama A. Identification of novel biomarkers in chronic immune thrombocytopenia (ITP) by microarray-based serum protein profiling. Br J Haematol 2015; 172:602-15. [PMID: 26628061 DOI: 10.1111/bjh.13861] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 10/06/2015] [Indexed: 01/15/2023]
Abstract
The pathological mechanisms underlying the development of immune thrombocytopenia (ITP) are unclear and its diagnosis remains a process of exclusion. Currently, there are no known specific biomarkers for ITP to support differential diagnosis and treatment decisions. Profiling of serum proteins may be valuable for identifying such biomarkers. Sera from 46 patients with primary chronic ITP and 34 healthy blood donors were analysed using a microarray of 755 antibodies. We identified 161 differentially expressed proteins. In addition to oncoproteins and tumour-suppressor proteins, including apoptosis regulator BCL2, breast cancer type 1 susceptibility protein (BRCA1), Fanconi anaemia complementation group C (FANCC) and vascular endothelial growth factor A (VEGFA), we detected six anti-nuclear autoantibodies in a subset of ITP patients: anti-PCNA, anti-SmD, anti-Ro/SSA60, anti-Ro/SSA52, anti-La/SSB and anti-RNPC antibodies. This finding may provide a rational explanation for the association of ITP with malignancies and other autoimmune diseases. While RUNX1mRNA expression in the peripheral blood mononuclear cells (PBMC) of patients was significantly downregulated, an accumulation of RUNX1 protein was observed in the platelets of ITP patients. This may indicate dysregulation of RUNX1 expression in PBMC and megakaryocytes and may lead to an imbalanced immune response and impaired thrombopoiesis. In conclusion, we provide novel insights into the pathogenic mechanisms of ITP that warrant further exploration.
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Affiliation(s)
- Gürkan Bal
- Institute for Transfusion Medicine, Charité Universitätsmedizin, Berlin, Germany
| | | | - Daniela Hartl
- Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Berlin, Germany
| | - Frauke Ringel
- Institute for Transfusion Medicine, Charité Universitätsmedizin, Berlin, Germany
| | - Julian Kamhieh-Milz
- Institute for Transfusion Medicine, Charité Universitätsmedizin, Berlin, Germany
| | - Viktor Sterzer
- Institute for Transfusion Medicine, Charité Universitätsmedizin, Berlin, Germany
| | - Jörg D Hoheisel
- Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany
| | - Mohamed S S Alhamdani
- Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany
| | - Abdulgabar Salama
- Institute for Transfusion Medicine, Charité Universitätsmedizin, Berlin, Germany
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Tombak A, Boztepe B, Tiftik N, Cömert M, Salim O, Aydın K, Gürkan E, Yücel OK, Saydam G, Sungur MA. Seasonal Association of Immune Thrombocytopenia in Adults. Balkan Med J 2015; 32:347-51. [PMID: 26740892 DOI: 10.5152/balkanmedj.2015.151223] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Accepted: 04/22/2015] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Immune thrombocytopenia (ITP) is an autoimmune disorder. It is characterized by thrombocytopenia due to thrombocyte destruction mediated by autoantibodies; however, cytotoxic and defective regulatory T-lymphocytes play an important role in its pathogenesis. While childhood ITP is usually acute, self-limiting and generally seasonal in nature, ITP in adults is usually chronic; its relation with seasons has not been studied. AIMS We investigated whether months and/or seasons have triggering roles in adults with ITP. STUDY DESIGN Descriptive study. METHODS A retrospective case review of adult patients with primary ITP diagnosed at various University Hospitals in cities where Mediterranean climate is seen was performed. Demographic data, date of referral and treatments were recorded. Corticosteroid-resistant, chronic and refractory cases were determined. Relation between sex, corticosteroid-resistant, chronic and refractory ITP with the seasons was also investigated. RESULTS The study included 165 patients (124 female, mean age=42.8±16.6). Most cases of primary ITP were diagnosed in the spring (p=0.015). Rates of patients diagnosed according to the seasons were as follows: 35.8% in spring, 23% in summer, 20.6% in fall, and 20.6% in winter. With respect to months, the majority of cases occurred in May (18.2%). Time of diagnosis according to the seasons did not differ between genders (p=0.699). First-line treatment was corticosteroids in 97.3%, but 35% of the cases were corticosteroid-resistant. Steroid-resistant patients were mostly diagnosed in the spring (52.1%) (p=0.001). ITP was chronic in 52.7% of the patients and they were also diagnosed mostly in the spring (62.7%) (p=0.149). CONCLUSION This is the first study showing seasonal association of ITP in adults and we have observed that ITP in adults is mostly diagnosed in the spring. The reason why more patients are diagnosed in the spring may be due to the existence of atmospheric pollens reaching maximum levels in the spring in places where a Mediterranean climate is seen.
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Affiliation(s)
- Anıl Tombak
- Department of Hematology, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Burcu Boztepe
- Department of Internal Medicine, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Naci Tiftik
- Department of Hematology, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Melda Cömert
- Department of Hematology, Ege University Faculty of Medicine, İzmir, Turkey
| | - Ozan Salim
- Department of Hematology, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Kaniye Aydın
- Department of Internal Medicine, Çukurova University Faculty of Medicine, Adana, Turkey
| | - Emel Gürkan
- Department of Hematology, Çukurova University Faculty of Medicine, Adana, Turkey
| | - Orhan Kemal Yücel
- Department of Hematology, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Güray Saydam
- Department of Hematology, Ege University Faculty of Medicine, İzmir, Turkey
| | - Mehmet Ali Sungur
- Department of Biostatistics, Düzce University Faculty of Medicine, Düzce, Turkey
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Nomura S. Chronic immune thrombocytopenia and semaphorin 5A. Thromb Res 2015; 136:843-4. [PMID: 26381436 DOI: 10.1016/j.thromres.2015.08.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 08/29/2015] [Indexed: 10/23/2022]
Affiliation(s)
- Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, 2-3-1 Shin-machi, Hirakata, Osaka 573-1191, Japan.
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Song I, Kim J, Kwon K, Koo S, Jo D. Expression of CD154 (CD40L) on stimulated T lymphocytes in patients with idopathic thrombocytopenic purpura. Hematology 2015; 21:187-92. [DOI: 10.1179/1607845415y.0000000032] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Affiliation(s)
- Ikchan Song
- Department of Hemato-Oncology, Chungnam National University Hospital, 282 Moonhwa-ro, Joong-gu, Daejeon 301-721, South Korea
| | - Jimyung Kim
- Department of Laboratory Medicine, Chungnam National University Hospital, 282 Moonhwa-ro, Joong-gu, Daejeon 301-721, South Korea
| | - Kyechul Kwon
- Department of Laboratory Medicine, Chungnam National University Hospital, 282 Moonhwa-ro, Joong-gu, Daejeon 301-721, South Korea
| | - Sunhoe Koo
- Department of Laboratory Medicine, Chungnam National University Hospital, 282 Moonhwa-ro, Joong-gu, Daejeon 301-721, South Korea
| | - Dukyeon Jo
- Department of Hemato-Oncology, Chungnam National University Hospital, 282 Moonhwa-ro, Joong-gu, Daejeon 301-721, South Korea
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Bakchoul T, Sachs UJ. Platelet destruction in immune thrombocytopenia. Understanding the mechanisms. Hamostaseologie 2015; 36:187-94. [PMID: 25982994 DOI: 10.5482/hamo-14-09-0043] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Accepted: 05/04/2015] [Indexed: 01/19/2023] Open
Abstract
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by isolated thrombocytopenia. A dysfunctional proliferation of autoreactive T cells is suggested to be responsible for the loss of tolerance to self-platelet antigens in ITP patients. Autoreactive T cells induce uncontrolled proliferation of autoantibody producing B cells leading to persistent anti-platelet autoimmunity in some ITP patients. The autoimmune response causes an increased destruction of platelets by antibody-mediated phagocytosis, complement activation but also by T cell mediated cytotoxicity. In addition, abnormalities in thrombopoiesis and insufficient platelet production due to antibody or T cell mediated megakaryocyte inhibition and destruction contribute to the pathophysiology of ITP. These various effector cell responses may account for the heterogeneity in the clinical manifestation of ITP and also, to success or failure of different treatment strategies. A better understanding of the mechanisms behind ITP will hopefully allow for better diagnostic and, particularly, therapeutic strategies in the future.
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Affiliation(s)
- Tamam Bakchoul
- Prof. Dr. med. Tamam Bakchoul, Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany, Tel. +49/(0)38 34/86 54 58, Fax +49/(0)38 34/86 54 89, E-mail:
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Li JQ, Hu SY, Wang ZY, Lin J, Jian S, Dong YC, Wu XF, Lan D, Cao LJ. MicroRNA-125-5p targeted CXCL13: a potential biomarker associated with immune thrombocytopenia. Am J Transl Res 2015; 7:772-780. [PMID: 26064444 PMCID: PMC4455351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 02/20/2015] [Indexed: 06/04/2023]
Abstract
BACKGROUND Immune thrombocytopenia (ITP) is an acquired and autoimmune disease of adults and children characterized by decreased platelet production. CXC chemokine ligand-13 (CXCL13) participates in multiple immunological responses. However, it is still unknown the relationship between CXCL13 and ITP. METHODS Plasma CXCL13 was detected in ITP (n = 30) children. CD4+ T cells was isolated from peripheral blood mononuclear cells (PBMCs) from healthy volunteers. Treated CD4+ T cells with dexamethasone and/or miR-125-5p mimic/inhibitor, to observe the regulation of CXCL13. RESULTS Compared with controls, ITP children had elevated plasma CXCL13, the concentration of which was reduced after treatment. In vitro, dexamethasone decreased CXCL13 level in in dose- dependent and in time-dependent manner. MiR-125-5p mimic decreased CXCL13 level and miR-125-5p inhibitor increased CXCL13 level in CD4+ T cells. CXCL13 was implied to be target gene of miR-125-5p. MiR-125-5p inhibitor also canceled dexamethasone induced decrease of CXCL13. CONCLUSION CXCL13 is the target gene of miR-125-5p, which is possibly involved in the pathological process of ITP.
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Affiliation(s)
- Jian-Qin Li
- Department of Hematology, Soochow University Affiliated Children’s HospitalSuzhou 215003, Jiangsu, China
| | - Shao-Yan Hu
- Department of Hematology, Soochow University Affiliated Children’s HospitalSuzhou 215003, Jiangsu, China
| | - Zhao-Yue Wang
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversitySuzhou 215016, Jiangsu, China
| | - Jing Lin
- Department of Hematology, Soochow University Affiliated Children’s HospitalSuzhou 215003, Jiangsu, China
| | - Su Jian
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversitySuzhou 215016, Jiangsu, China
| | - Yong-Chao Dong
- Department of Hematology, Soochow University Affiliated Children’s HospitalSuzhou 215003, Jiangsu, China
| | - Xiao-Fang Wu
- Department of Hematology, Soochow University Affiliated Children’s HospitalSuzhou 215003, Jiangsu, China
| | - Dai Lan
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversitySuzhou 215016, Jiangsu, China
| | - Li-Juan Cao
- Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversitySuzhou 215016, Jiangsu, China
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Sun T, Zhang D, Yang Y, Zhang X, Lv C, Fu R, Lv M, Liu W, Chen Y, Liu W, Huang Y, Xue F, Liu X, Zhang L, Li H, Yang R. Interleukin 35 may contribute to the loss of immunological self-tolerance in patients with primary immune thrombocytopenia. Br J Haematol 2015; 169:278-85. [PMID: 25640666 DOI: 10.1111/bjh.13292] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 12/03/2014] [Indexed: 01/31/2023]
Abstract
Primary immune thrombocytopenia (ITP) is an autoimmune disorder. Interleukin-35 (IL35) can suppress T cell proliferation and elicit the development of inducible regulatory T cells (Tregs). Previous studies have shown decreased plasma IL35 levels and dysfunctional T cells in patients with ITP. In this study, we determined whether decreased IL35 levels correlate with T cell dysfunction in ITP patients. Plasma IL35 levels were found to be lower in ITP patients than in healthy controls, were positively correlated with platelet levels and the percentage of peripheral circulating Tregs, and negatively correlated with the levels of T helper-1 cells in ITP patients. We also evaluated the effects of IL35 on cytokines contributing to T cell proliferation. IL35 promoted the secretion of interleukin 10 (IL10) and transforming growth factor-β1 but reduced the levels of interferon-γ and IL17A (also termed IL17). Moreover, IL35 inhibited the proliferation of CD4+ and CD8+ T cells but induced the differentiation and proliferation of Tregs in ITP. In summary, IL35 appears to contribute to the loss of immunological self-tolerance in ITP patients by modulating T cells and immunoregulatory cytokines.
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MESH Headings
- Adult
- Aged
- Case-Control Studies
- Cytokines/biosynthesis
- Female
- Humans
- Immune Tolerance
- Interleukins/blood
- Interleukins/metabolism
- Leukocytes, Mononuclear/immunology
- Leukocytes, Mononuclear/metabolism
- Lymphocyte Activation
- Male
- Middle Aged
- Purpura, Thrombocytopenic, Idiopathic/immunology
- Purpura, Thrombocytopenic, Idiopathic/metabolism
- T-Lymphocytes, Helper-Inducer/immunology
- T-Lymphocytes, Helper-Inducer/metabolism
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Young Adult
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Affiliation(s)
- Tiantian Sun
- State Key Laboratory of Experimental Haematology, Institute of Haematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
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Zhong H, Bussel J, Yazdanbakhsh K. In vitro TNF blockade enhances ex vivo expansion of regulatory T cells in patients with immune thrombocytopenia. Br J Haematol 2014; 168:274-83. [PMID: 25252160 DOI: 10.1111/bjh.13126] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 07/29/2014] [Indexed: 01/09/2023]
Abstract
Tumour necrosis factor-α (TNF) is an inflammatory cytokine that is elevated in a number of autoimmune diseases including immune thrombocytopenia (ITP), a bleeding disorder characterized by low platelet counts. In vitro TNF blockade increases expansion of the regulatory T cell (Treg) IKZF2 (also termed Helios) subset in T cell-monocyte cocultures from healthy donors, but its role on proliferative responses of Tregs in ITP patients, who have altered immunoregulatory compartment, remains unclear. TNF in CD4+ T cells from patients with chronic ITP were elevated and negatively correlated with peripheral Treg frequencies, suggesting a possible inhibitory effect of TNF on ITP Tregs. In vitro antibody neutralization with anti-TNF in T cell-monocyte cocultures resulted in a robust expansion of pre-existing ITP Tregs, higher than in healthy controls. Similar to the effects of anti-TNF antibodies, TNF blockade with antibodies against TNFRSF1B (anti-TNFRSF1B, previously termed anti-TNFRII) almost doubled ITP Treg expansion whereas neutralization with anti-TNFRSF1A (anti-TNFRI) antibodies had no effect on proliferative responses of Tregs. In addition, TNFRSF1B levels on ITP Tregs were significantly elevated, which may explain the increased susceptibility of patient Tregs to the actions of TNF blockade. Altogether, these data raise the possibility that TNF blockers, through their ability to increase Treg proliferation, may be efficacious in ITP patients.
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Affiliation(s)
- Hui Zhong
- Laboratory of Complement Biology, New York Blood Center, New York, NY, USA
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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. [PMID: 25212676 DOI: 10.1007/s12185-014-1661-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 08/31/2014] [Accepted: 09/01/2014] [Indexed: 11/25/2022]
Abstract
Immune thrombocytopenia (ITP) is an autoimmune disorder caused by IgG anti-platelet autoantibodies. Thrombopoietin (TPO) receptor agonists are highly effective in inducing the recovery of platelet counts in ITP patients. Although these agents are thought to promote platelet production without affecting the autoimmune pathogenesis of the disease, a small subset of ITP patients exhibits sustained platelet recovery after treatment termination. To investigate mechanisms involved in this sustained recovery, we evaluated the effects of short-term TPO treatment using a mouse ITP model generated by Foxp3(+) T regulatory cell (Treg) depletion. After treatment, platelet recovery was sustained, along with complete suppression of both anti-platelet autoantibody production and T-cell responses to platelet autoantigens. TPO treatment also promoted the peripheral induction of Foxp3(+) Tregs in conjunction with elevated circulating TGF-β levels. In summary, thrombopoietic agents are capable of inducing immune tolerance to platelet autoantigens, thereby suppressing the autoimmune pathogenesis of ITP.
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Affiliation(s)
- Tetsuya Nishimoto
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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