CD47、TSP-1及细胞因子与儿童特发性血小板减少性紫癜关系的研究
摘要
目的:原发性血小板减少性紫癜(idiopathic thrombocytopenicpurpura,ITP)是一种由于外周血小板破坏增多而引起的儿童常见出血性疾病。目前对其免疫致病机制虽有一定的了解,但仍有很多环节缺乏统一的认识,其具体发病机理尚未完全阐明。CD47又叫整合素相关蛋白(integrin-associated protein,IAP),是一种广泛表达的抗原,存在于所有组织的不同细胞。2005年Olsson等在小鼠模型中发现CD47/SIRPα(inhibitory receptor signal regulator proteinα)可以阻断巨噬细胞对血小板的吞噬作用,并且这种阻断作用与CD47的表达呈正比。血小板反应素-1(thrombospondin-1,TSP-1)对骨髓巨核细胞的生成有抑制作用,其与CD47的结合与血小板聚集功能有关,还有下调IL-12(interleukin-12)的作用。IL-4、IL-12是维持Th1/Th2(helper T lymphocyte,Th)平衡的关键因子。因此我们对10例ITP患儿检测血小板和血浆CD47荧光强度、血清TSP-1、IL-4、IL-12水平,旨在研究CD47、TSP-1与ITP的关系,探讨Th1/Th2在ITP发病中的变化及意义,以进一步提高对ITP发病机制的认识,为临床治疗、评估病情及预后提供理论依据。
方法:选择急性初发ITP患儿10例,其中男7例,女3例,年龄1.5～12岁,血小板(10～30)×10~9/L,均符合ITP的诊断标准,病程在1周以内。正常对照组选门诊健康体检儿童10例,其中男6例,女4例,年龄3～10岁。用流式细胞术检测外周血中血小板CD47荧光强度和血浆CD47的荧光强度,ELISA(enzyme linked immunosorbent assay)法检测血清TSP-1、IL-4、IL-12水平。ITP患儿在治疗前后分别检测,治疗后采血标准为血小板上升至100×10~9/L以上。治疗方法:①大剂量丙种球蛋白0.4g/(kg.d)静滴,连用5天;②同时应用地塞米松0.2～0.4mg/(kg.d),连用3～5天后口服强的松维持治疗,逐渐减量停药。
结果:1.ITP患儿血小板CD47荧光强度(1947±40)U,较正常对照组(1937±64)U无明显差异(P=0.071,t=0.139)。
2.ITP患儿血浆CD47荧光强度(4021±398)U,较正常对照组(3419±371)U高,差异显著(P=0.003,t=3.496);ITP患儿血浆CD47荧光强度含量治疗后(3743±420)U,与治疗前比较差异显著(P＜0.001,t=21.614),与正常对照组比较无显著差异(P=1.831,t=0.084)。
3.ITP患儿血清TSP-1含量(185.41±24.91)ng/ml,较正常对照组(154.71±37.71)ng/ml高,差异显著(P=0.046,t=2.148);ITP患儿治疗后血清TSP-1含量(168.15±26.33)ng/ml,与治疗前比较有显著差异(P＜0.001,t=8.468),与正常对照组比较无显著差异(P=0.368,t=0.924)。
4.ITP患儿血清IL-4含量(47.12±6.31)pg/ml,较正常对照组(55.12±6.35)pg/ml低,差异显著(P=0.011,t=2.825);ITP患儿治疗后血清IL-4含量(48.13±6.18)pg/ml,与治疗前比较差异显著(P＜0.001,t=6.245),与正常对照组比较差异显著(P=0.023,t=2.494)。
5.ITP患儿血清IL-12含量(74.97±2.28)pg/ml,较正常对照组(70.70±3.02)pg/ml高,差异显著(P=0.002,t=3.566);ITP患儿治疗后血清IL-12含量(73.40±2.03)pg/ml,与治疗前比较差异显著(P=0.010,t=3.244),与正常对照组比较差异显著(P=0.031,t=2.347)。
结论:1.ITP发病与CD47、TSP-1有关。
2.ITP患儿Th1/Th2功能异常,Th1处于优势状态。
3.经过治疗ITP患儿血小板恢复正常,免疫功能有所恢复,但尚未恢复到正常,提示免疫功能紊乱仍然存在,有继续应用免疫抑制剂的必要。
4.临床上可将血清中IL-4、IL-12水平作为评估病情及预后的指标之一。
Objective:Idiopathic thrombocytopenic purpura is a common hemorrhagic diseases of children caused by increased peripheral platelet destruction. Currently we have certain understanding about the immune mechanism of ITP, but there are still a lot of links which lack of unity of understanding. Specific pathogenesis of ITP has not yet been fully clarified. CD47 (integrin-associated protein) is a ubiquitously expressed 50kD transmem-brane glycoprotein that is found on all kinds of cells. In 2005, Olsson found that platelet CD47 and macrophage SIRPα(inhibitory receptor signal regulator proteinα) play an important role in regulating normal platelet homeostasis and autoimmune elimination of opsonized platelets in experimental mice ITP, which suggests a gene-dose effect of CD47 in this system. Up to now,we know that TSP-1 inhibits the growth of bone marrow megacaryocyte. The binding of TSP-1 and CD47 is related to platelet aggregation. Meanwhile, it selectively downregulates the production of human IL-12.IL-4 and IL-12 are key factors which maintain the balance of Th1/Th2. CD47 expression was tested in 10 ITP children by quantitative flow cytometry on platelets and in plasma.The levels of serum TSP-1, IL-4,IL-12 were also tested in ITP group, so as to find the connection between CD47, TSP-1 and ITP, discover the change and significance of Th1/Th2 in the outbreak of ITP, expand our understanding of the cause and the process of ITP, and provide some theoretical help for doctors to treat,estimate ITP and predict an adverse prognosis.
Methods: According to the ITP standard, 10 acute ITP children (7 boys and 3 girls from 1. 5 to 12 years old) were included in our research group. Their thrombocyte number was (10～30)×10~9/L. They all had ITP for the first time and had been ill for 1 to 7 days. 10 healthy donors (6 boys and 4 girls from 3 to 10 years old) were as control. The leves of TSP-1, IL-14 and IL-12 in serum were measured by using ELISA.Flow cytometry was used to analyse CD47 on platelets and in the plasma.They were detected before and after treatment respectively. Methods of treatment were as follow:①The patients were injected human immunoglobulin intravenously for 5 days. The dose was 0.4g/(kg.d) ;②At the same time the patients were injected dexamethasone 0.2～0.4 mg/(kg.d) for 3～5days and then, dexamethasone was substitued by taking prednisone orally. The dose of prednisone decreased gradually. Blood samples were collected when the number of thrombocyte increased to 100×10~9/L.
Results: 1.CD47 expression on platelets was predominantly identical in the normal group (1937±64) U and ITP children (1947±40) U, with no significant difference observed ( P=0.071, t=0.139) .
2. CD47 detected in the plasma of the normal group was (3419±371) U. Significantly higher levels of CD47 [(4021±398) U] was observed in the plasma of ITP children (P=0.003, t=3.496) ; After treatment,CD47 observed in the plasma of ITP children was (3743±420)U, which was obviously lower than ITP children before treatment (P<0.001, t=21.614). CD47 detected in the plasma of the normal group was no significant difference compared with ITP children after treatment (P=1.831, t=0.084).
3. The serum TSP-1 content of the ITP children was (185.41±24.91) ng/ml, which was obviously higher than the normal group[( 154.71±37.71) ng/ml] ( P=0.046, t=2.148). After treatment the serum TSP-1 content of the ITP children was (168.15±26.33) ng/ml, which was obviously lower than ITP children before treatment ( P<0.001, t=8.468) .The serum TSP-1 content of the normal group was no significant difference compared with ITP children after treatment (P=0.368, t=0.924) .
4. The serum IL-4 content of the ITP children was (47.12±6.31) pg/ml, which was obviously lower than the normal group[(55.12±6.35) pg/ml] ( P=0.011, t=2.825) . After treatment the serum IL-4 content of the ITP children was (48.13±6.18) pg/ml , which was obviously higher than ITP children before treatment (P<0.001, t=6.245). The serum IL-4 content of the normal group was obviously higher than ITP children after treatment (P=0.023, t=2.494).
5. The serum IL-12 content of the ITP children was (74.97±2.28 ) pg/ml, which was obviously higher than the normal group[ (70.70±3.02) pg/ml] ( P=0.002, t=3.566) . After treatment the serum IL-12 content of the ITP children was (73.40±2.03) pg/ml, which was obviously lower than ITP children before treatment ( P=0.010, t=3.244) .The serum IL-12 content of the normal group was obviously lower than ITP children after treatment (P=0.031, t=2.347).
Conclusions: 1. CD47、TSP-1 are related to the cause of ITP.
2. Th1/Th2 in the ITP children is abnormal. The strengthened activity of Th1 and its being in a dominate state put the cells of Th2 in a depressed state.
3. After injected human immunoglobulin and dexamethasone intravenously, the number of thrombocyte increases and becomes normal. The immune function of ITP patient restored partially. The patient's immune function is still in disorder and it is necessary to continue to use immune remedy.
4. In clinic, the level of IL-12 and IL-4 can be used to estimate ITP and predict an adverse prognosis.
方法:选择急性初发ITP患儿10例,其中男7例,女3例,年龄1.5～12岁,血小板(10～30)×10~9/L,均符合ITP的诊断标准,病程在1周以内。正常对照组选门诊健康体检儿童10例,其中男6例,女4例,年龄3～10岁。用流式细胞术检测外周血中血小板CD47荧光强度和血浆CD47的荧光强度,ELISA(enzyme linked immunosorbent assay)法检测血清TSP-1、IL-4、IL-12水平。ITP患儿在治疗前后分别检测,治疗后采血标准为血小板上升至100×10~9/L以上。治疗方法:①大剂量丙种球蛋白0.4g/(kg.d)静滴,连用5天;②同时应用地塞米松0.2～0.4mg/(kg.d),连用3～5天后口服强的松维持治疗,逐渐减量停药。
结果:1.ITP患儿血小板CD47荧光强度(1947±40)U,较正常对照组(1937±64)U无明显差异(P=0.071,t=0.139)。
2.ITP患儿血浆CD47荧光强度(4021±398)U,较正常对照组(3419±371)U高,差异显著(P=0.003,t=3.496);ITP患儿血浆CD47荧光强度含量治疗后(3743±420)U,与治疗前比较差异显著(P＜0.001,t=21.614),与正常对照组比较无显著差异(P=1.831,t=0.084)。
3.ITP患儿血清TSP-1含量(185.41±24.91)ng/ml,较正常对照组(154.71±37.71)ng/ml高,差异显著(P=0.046,t=2.148);ITP患儿治疗后血清TSP-1含量(168.15±26.33)ng/ml,与治疗前比较有显著差异(P＜0.001,t=8.468),与正常对照组比较无显著差异(P=0.368,t=0.924)。
4.ITP患儿血清IL-4含量(47.12±6.31)pg/ml,较正常对照组(55.12±6.35)pg/ml低,差异显著(P=0.011,t=2.825);ITP患儿治疗后血清IL-4含量(48.13±6.18)pg/ml,与治疗前比较差异显著(P＜0.001,t=6.245),与正常对照组比较差异显著(P=0.023,t=2.494)。
5.ITP患儿血清IL-12含量(74.97±2.28)pg/ml,较正常对照组(70.70±3.02)pg/ml高,差异显著(P=0.002,t=3.566);ITP患儿治疗后血清IL-12含量(73.40±2.03)pg/ml,与治疗前比较差异显著(P=0.010,t=3.244),与正常对照组比较差异显著(P=0.031,t=2.347)。
结论:1.ITP发病与CD47、TSP-1有关。
2.ITP患儿Th1/Th2功能异常,Th1处于优势状态。
3.经过治疗ITP患儿血小板恢复正常,免疫功能有所恢复,但尚未恢复到正常,提示免疫功能紊乱仍然存在,有继续应用免疫抑制剂的必要。
4.临床上可将血清中IL-4、IL-12水平作为评估病情及预后的指标之一。
Objective:Idiopathic thrombocytopenic purpura is a common hemorrhagic diseases of children caused by increased peripheral platelet destruction. Currently we have certain understanding about the immune mechanism of ITP, but there are still a lot of links which lack of unity of understanding. Specific pathogenesis of ITP has not yet been fully clarified. CD47 (integrin-associated protein) is a ubiquitously expressed 50kD transmem-brane glycoprotein that is found on all kinds of cells. In 2005, Olsson found that platelet CD47 and macrophage SIRPα(inhibitory receptor signal regulator proteinα) play an important role in regulating normal platelet homeostasis and autoimmune elimination of opsonized platelets in experimental mice ITP, which suggests a gene-dose effect of CD47 in this system. Up to now,we know that TSP-1 inhibits the growth of bone marrow megacaryocyte. The binding of TSP-1 and CD47 is related to platelet aggregation. Meanwhile, it selectively downregulates the production of human IL-12.IL-4 and IL-12 are key factors which maintain the balance of Th1/Th2. CD47 expression was tested in 10 ITP children by quantitative flow cytometry on platelets and in plasma.The levels of serum TSP-1, IL-4,IL-12 were also tested in ITP group, so as to find the connection between CD47, TSP-1 and ITP, discover the change and significance of Th1/Th2 in the outbreak of ITP, expand our understanding of the cause and the process of ITP, and provide some theoretical help for doctors to treat,estimate ITP and predict an adverse prognosis.
Methods: According to the ITP standard, 10 acute ITP children (7 boys and 3 girls from 1. 5 to 12 years old) were included in our research group. Their thrombocyte number was (10～30)×10~9/L. They all had ITP for the first time and had been ill for 1 to 7 days. 10 healthy donors (6 boys and 4 girls from 3 to 10 years old) were as control. The leves of TSP-1, IL-14 and IL-12 in serum were measured by using ELISA.Flow cytometry was used to analyse CD47 on platelets and in the plasma.They were detected before and after treatment respectively. Methods of treatment were as follow:①The patients were injected human immunoglobulin intravenously for 5 days. The dose was 0.4g/(kg.d) ;②At the same time the patients were injected dexamethasone 0.2～0.4 mg/(kg.d) for 3～5days and then, dexamethasone was substitued by taking prednisone orally. The dose of prednisone decreased gradually. Blood samples were collected when the number of thrombocyte increased to 100×10~9/L.
Results: 1.CD47 expression on platelets was predominantly identical in the normal group (1937±64) U and ITP children (1947±40) U, with no significant difference observed ( P=0.071, t=0.139) .
2. CD47 detected in the plasma of the normal group was (3419±371) U. Significantly higher levels of CD47 [(4021±398) U] was observed in the plasma of ITP children (P=0.003, t=3.496) ; After treatment,CD47 observed in the plasma of ITP children was (3743±420)U, which was obviously lower than ITP children before treatment (P<0.001, t=21.614). CD47 detected in the plasma of the normal group was no significant difference compared with ITP children after treatment (P=1.831, t=0.084).
3. The serum TSP-1 content of the ITP children was (185.41±24.91) ng/ml, which was obviously higher than the normal group[( 154.71±37.71) ng/ml] ( P=0.046, t=2.148). After treatment the serum TSP-1 content of the ITP children was (168.15±26.33) ng/ml, which was obviously lower than ITP children before treatment ( P<0.001, t=8.468) .The serum TSP-1 content of the normal group was no significant difference compared with ITP children after treatment (P=0.368, t=0.924) .
4. The serum IL-4 content of the ITP children was (47.12±6.31) pg/ml, which was obviously lower than the normal group[(55.12±6.35) pg/ml] ( P=0.011, t=2.825) . After treatment the serum IL-4 content of the ITP children was (48.13±6.18) pg/ml , which was obviously higher than ITP children before treatment (P<0.001, t=6.245). The serum IL-4 content of the normal group was obviously higher than ITP children after treatment (P=0.023, t=2.494).
5. The serum IL-12 content of the ITP children was (74.97±2.28 ) pg/ml, which was obviously higher than the normal group[ (70.70±3.02) pg/ml] ( P=0.002, t=3.566) . After treatment the serum IL-12 content of the ITP children was (73.40±2.03) pg/ml, which was obviously lower than ITP children before treatment ( P=0.010, t=3.244) .The serum IL-12 content of the normal group was obviously lower than ITP children after treatment (P=0.031, t=2.347).
Conclusions: 1. CD47、TSP-1 are related to the cause of ITP.
2. Th1/Th2 in the ITP children is abnormal. The strengthened activity of Th1 and its being in a dominate state put the cells of Th2 in a depressed state.
3. After injected human immunoglobulin and dexamethasone intravenously, the number of thrombocyte increases and becomes normal. The immune function of ITP patient restored partially. The patient's immune function is still in disorder and it is necessary to continue to use immune remedy.
4. In clinic, the level of IL-12 and IL-4 can be used to estimate ITP and predict an adverse prognosis.
引文
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9.李秋,杨锡强,李永柏,等.过敏性紫癜T淋巴细胞功能状态的研究.中华儿科杂志,2001,39(3):157.
10.曾巧慧,梅志勇,钟凤仪,等.白介素12、白介素4及γ-干扰素在过敏性紫癜儿童中的表达及意义.中国小儿血液,2005,10(6):247-249.
11.Hiroyuki T,Hiroshi Y.Type Ⅰ and Type Ⅱ T-cell Profiles in Aplastic Anemia and Refractory Anaemia.American Journal of Hematology,2000,64:271-274.
12.Selleri C,Maciejewski JP,Catalano L,et al.Effects of cyclosporine on hematopoietic and immune functions in patients with hypoplastic myelodysplasia:in vitro and in vivo studies.Cancer,2002,95(9):1911-1922.
13.何广胜,邵宗鸿,吴德沛,等.重型再生障碍性贫血和骨髓增生异常综合征骨髓中T辅助细胞亚群的变化.现代免疫学,2004,24(5):417-423.
14.Yothda P,Mintz P,Grigoriadou K,et al.Analysis of T-cell defects in the specific immune response against acute lymphoblastic leukemia cells.Exp Hematol,1999,27:1375-1383.
15.游伟文,杜新,张琼丽,等.白血病患者Th、Tc细胞IFN-γ、IL-4表达研究.中国热带医学,2007,7(6):874-875.
16.Trinchieri.Interleukin-12:a proinflammatory cytokine with immuno-regulatory functions that bridge innate resistance and antigen-specific adaptive immunity.Annu-Rev-Immunol,1995,13251-13276.
17.Formby.Immunologic response in pregnancy.Its role in endocrine disorders of pregnancy and influence on the course of maternal autoimmune diseases.Endocrinol-Metab-Clin-North-Am,1995,24(1):187-205.
18.Gergely L,Aleksza M,Varoczy L,et al.Intracellular IL-4/IFN-gamma producing peripheral T lymphocyte subsets in B cell non-Hodgkin's lymphoma patients.Eur J Haematol,2004,72(5):336-341.
19.李丽,张巧花,侯淑玲,等.三氧疗法对非霍奇金淋巴瘤患者Th1/Th2细胞亚群漂移的影响.中国免疫学杂志,2008,24:274-封4.
20.Andersson J.Cytokines in idiopathic thrombocytopenic purpura (ITP).Acta Paediatr Suppl,1998,424:61-64.
21.孟德润,王静波,戴海滨.Th2和Tc2细胞在慢性ITP发病机制中的作用.中华血液学杂志,1999,20(3):150-152.
22.Kaito K,Otsubo H,Usui N,et al.Th1/Th2 lymphocyte balance in patients with aplastic anemia.Rinsho Byori,2004,52(7):569-573.
23.张强,翟志敏,李庆,等.再生障碍性贫血患者外周血Th1/Th2水平测定及其临床意义.实用医学杂志,2008,24(18):3176-3178.
24.Oh S,Hodge JW,Ahlers JD,et al.Selective induction of high avidity CTL by altering The balance of signals from APC.Immunol,2003,170(5):2523-30.
25.Barcellini W,Clerici G,Montesano R,et al.In vitro quantification of anti-red blood cell antibody production in idiopathic autoimmune haemolytic anaemia:effect of mitogen and cytokine stimulation.Haematol,2000,111(2):452-460.
1.Mitchison NA.T-cell-B-cell cooperation.Nat RevImmunol,2004,4(4):308-312.
2.Carcao MD,Blanchette VS,Wakefield CD,et al.Fcgamma Receptor Ⅱa and Ⅲa polymorphisms in childhood immune thrombocytopenic purpura.Br J Haematol,2003,120(1):135-141.
3.Canetti,Hu B,Curtis JL,et al.Syk activation is a leukotriene B4-regulated event involved in macrophage phagocytosis of IgG-coated targets but not apoptotic cells.Blood,2003,102(5):1877-1883.
4. Hu B, Punturieri A, Todt J, et al. Recognition and phagocytosis of apoptotic T cells by resident murine tissue macrophages require multiple signal transduction events. J Leukoc Biol, 2002,71(5) :881-889.
5.Youinou P,Lydyard PM.CD5~+ B cells in nonorgan-specific auto immune diseases:a fresh look. Lupus, 2001, 10:523-525.
6.Seidi OA,Semra YK, Sharief MK.Expression of CD5 on B lymphocytes correlates with disease activity in patients with multiple sclerosis.J Neuroimmunol,2002, 133(1):205-210.
7.Mountz JD,Wu J,Cheng J, et al.Autoimmune disease: A problem of defective apoptosis.Arthritis Rheum, 1994,37(10):1415- 1420.
8.Seidi OA, Sharief MK. The expression of apoptosis-regulatory proteins in B lymphocytes from patients with multiple sclerosis.J Neuroimmunol,2002,130(1):202-210.
9.Mcmillan R, Wang L, Tomer A, et al.Suppression of in vitro-megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood, 2004, 103(4): 1364-1369.
10.Takahashi R,Sekine N, Nakatake T.Influence of monoclonal antiplatelet glycoprotein antibodies on in vitro human megakaryocyte colony formation and proplatelet formation. Blood, 1999,93(6) : 1951-1958.
11. Chang M, Nakagawa PA, Williams SA, et al. Immune thrombocyto-penic purura(ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryoctopoiesis in vitro.Blood,2003,102(3):887-895.
12.Houwerzijl EJ,Blom NR,van der Want JJ,et al.Ultrastructural study shows morphologic features of apoptosis and paraapopto-sis in megakaryocytes from patients with idiopathic thrombocy-topenic purura.Blood,2004,103(2):500-506.
13.Cines DB, Blancbhette VS. Immune thrombocytopenic purpura. N Engl J Med,2002,346(13):995-1008.
14.Kuwana M, Kaburaki J, lkeda Y, et al. Autoreactive T Cells to platelet GP II b-IIIa in immune thrombocytopenia purpura Role in production, of anti-platelet antoantibody. J Clin Invest, 1998,102(7) : 1393-1402.
15. Yan J, Mammla MJ. Autoreactive T cells revealed in the normal repertoire: escape from negative selection and peripheral tolerance.J Immunol, 2002, 168(7):3188-3194.
16.Semple JW.Immune pathophysiology of antoimmune thrombocy-topenic purpura. Blood Rev,2002,16(1):9-12.
17. McFarland J. Pathophysiology of platelet destrucion in immune (idiopathic) thrombocytopenic purpura. Blood Rev, 2002,16(1): 1-2.
18.Semple JW,Miles Y,Cosgrave D, et al. Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplat-elet T-cell reactivity. Blood,1996,87(10):4245-4254.
19.Liang B,Mamula MJ.Molecular mimicry and the role of B lymphocytes in the processing of autoantigens.Cell Mol Life Sci,2000,57(4):561-568.
20.Bettaieb A, Oksenhendler E, Duedari N, et al. Cross-reactive antibodies between HIV-gpl20 and platelet gpIIIa (CD61) in HIV-related immune thrombocytopenic purpura. Clin Exp Immunol, 1996, 103(1) : 19-23.
21. Kuwana M, Kaburaki J, Kitasato H, et al. Imnamodominant epitopes on glycoprotein II b-IIIa recognized by autoreactive T cells patients with immune thrombocytopenic purpura. Blood,2001, 98(1):130-139.
22.Bowditch RD,Tani P,Fong KC,et al.Characterization of autoantigenic epitopes on platelet glycoprotein II b/I11 a using random peptide libraries. Blood, 1996, 88(12) : 4579-4584.
23. Olsson B, Andersson PO, Jernas M, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocyto-penic purpura. Nat Med,2003,9(9):1123-1124.
24.Yoshimura C,Nomura S,Nagahama M,et al.Plasma-soluble Fas (APO-1,CD95) and soluble Fas ligand in immune thrombocyto-penic purpura.Eur J Haematol, 2000,64(4):219-224.
25.Jin F,Balthasar JP.Mechanisms of intravenous immunoglobulin action in immune thrombocytopenic purpura. Hum Immunol,2005, 66(5):403-410.
26. Debes A, Bauer M, Kremer S, et al. Tolerability and safety of the intravenous immunoglobulin Octagam (R): a 10-year prospective observational study.Pharmacoepidemiol Drug Saf,2007,16 (9): 1038-1047.
27.Cooper N,Heddle NM, Haas M, et al.Intravenous (IV) anti-D and IV immunoglobulin achieve acute platelet increases by different mechanisms: modulation of cytokine and platelet responses to IV anti-D by FcgammaRIIa and FcgammaRIIIa polymorphisms. Br J Haematol,2004,124(5):511-518.
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1.Mosmann TR,Cherwinski H,Bond MW,et al.Two types of murine helper T cell clone.I.Definition according to profiles of lymphokine activities and secreted proteins.J Immunol,1986,136(7):2348-2357.
2.Romagnani S.Human TH1 and TH2 subsets:doubt no more.Immunol Today,1991,12(8):256-257.
3.Butter C,Lun A,Splettstoesser T,et al.Monclonal anti-inter-leukin -5 treatment suppresses eosinophil but not T-cell functions.Eur Resir J,2003,21(5):799.
4.Hirano T.Ineterleukin-6.London:Academic Press,1991:171-183.
5.Kinoshita T,Ito H,Miki C.Serum interleukin 6 levels reflects the tumor proliferative activity in patients with colorectal carcinoma.Cancer,1999,85(12):2526-2531.
6.Tangerine B,Savino W,Delespesse G,et al.Proc Natl Acad Sci USA,1995,4:150.
7.Wigginton J,Gruys E,Geiselhart L.IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy.J Clin Invest,2001,108(1):51-62.
8.陈永胜,袁旭影,马永威.过敏性紫癜白介素2,自然杀伤细胞及B细胞活性的研究.中华儿科杂志,1993,31(3):155.
9.李秋,杨锡强,李永柏,等.过敏性紫癜T淋巴细胞功能状态的研究.中华儿科杂志,2001,39(3):157.
10.曾巧慧,梅志勇,钟凤仪,等.白介素12、白介素4及γ-干扰素在过敏性紫癜儿童中的表达及意义.中国小儿血液,2005,10(6):247-249.
11.Hiroyuki T,Hiroshi Y.Type Ⅰ and Type Ⅱ T-cell Profiles in Aplastic Anemia and Refractory Anaemia.American Journal of Hematology,2000,64:271-274.
12.Selleri C,Maciejewski JP,Catalano L,et al.Effects of cyclosporine on hematopoietic and immune functions in patients with hypoplastic myelodysplasia:in vitro and in vivo studies.Cancer,2002,95(9):1911-1922.
13.何广胜,邵宗鸿,吴德沛,等.重型再生障碍性贫血和骨髓增生异常综合征骨髓中T辅助细胞亚群的变化.现代免疫学,2004,24(5):417-423.
14.Yothda P,Mintz P,Grigoriadou K,et al.Analysis of T-cell defects in the specific immune response against acute lymphoblastic leukemia cells.Exp Hematol,1999,27:1375-1383.
15.游伟文,杜新,张琼丽,等.白血病患者Th、Tc细胞IFN-γ、IL-4表达研究.中国热带医学,2007,7(6):874-875.
16.Trinchieri.Interleukin-12:a proinflammatory cytokine with immuno-regulatory functions that bridge innate resistance and antigen-specific adaptive immunity.Annu-Rev-Immunol,1995,13251-13276.
17.Formby.Immunologic response in pregnancy.Its role in endocrine disorders of pregnancy and influence on the course of maternal autoimmune diseases.Endocrinol-Metab-Clin-North-Am,1995,24(1):187-205.
18.Gergely L,Aleksza M,Varoczy L,et al.Intracellular IL-4/IFN-gamma producing peripheral T lymphocyte subsets in B cell non-Hodgkin's lymphoma patients.Eur J Haematol,2004,72(5):336-341.
19.李丽,张巧花,侯淑玲,等.三氧疗法对非霍奇金淋巴瘤患者Th1/Th2细胞亚群漂移的影响.中国免疫学杂志,2008,24:274-封4.
20.Andersson J.Cytokines in idiopathic thrombocytopenic purpura (ITP).Acta Paediatr Suppl,1998,424:61-64.
21.孟德润,王静波,戴海滨.Th2和Tc2细胞在慢性ITP发病机制中的作用.中华血液学杂志,1999,20(3):150-152.
22.Kaito K,Otsubo H,Usui N,et al.Th1/Th2 lymphocyte balance in patients with aplastic anemia.Rinsho Byori,2004,52(7):569-573.
23.张强,翟志敏,李庆,等.再生障碍性贫血患者外周血Th1/Th2水平测定及其临床意义.实用医学杂志,2008,24(18):3176-3178.
24.Oh S,Hodge JW,Ahlers JD,et al.Selective induction of high avidity CTL by altering The balance of signals from APC.Immunol,2003,170(5):2523-30.
25.Barcellini W,Clerici G,Montesano R,et al.In vitro quantification of anti-red blood cell antibody production in idiopathic autoimmune haemolytic anaemia:effect of mitogen and cytokine stimulation.Haematol,2000,111(2):452-460.
1.Mitchison NA.T-cell-B-cell cooperation.Nat RevImmunol,2004,4(4):308-312.
2.Carcao MD,Blanchette VS,Wakefield CD,et al.Fcgamma Receptor Ⅱa and Ⅲa polymorphisms in childhood immune thrombocytopenic purpura.Br J Haematol,2003,120(1):135-141.
3.Canetti,Hu B,Curtis JL,et al.Syk activation is a leukotriene B4-regulated event involved in macrophage phagocytosis of IgG-coated targets but not apoptotic cells.Blood,2003,102(5):1877-1883.
4. Hu B, Punturieri A, Todt J, et al. Recognition and phagocytosis of apoptotic T cells by resident murine tissue macrophages require multiple signal transduction events. J Leukoc Biol, 2002,71(5) :881-889.
5.Youinou P,Lydyard PM.CD5~+ B cells in nonorgan-specific auto immune diseases:a fresh look. Lupus, 2001, 10:523-525.
6.Seidi OA,Semra YK, Sharief MK.Expression of CD5 on B lymphocytes correlates with disease activity in patients with multiple sclerosis.J Neuroimmunol,2002, 133(1):205-210.
7.Mountz JD,Wu J,Cheng J, et al.Autoimmune disease: A problem of defective apoptosis.Arthritis Rheum, 1994,37(10):1415- 1420.
8.Seidi OA, Sharief MK. The expression of apoptosis-regulatory proteins in B lymphocytes from patients with multiple sclerosis.J Neuroimmunol,2002,130(1):202-210.
9.Mcmillan R, Wang L, Tomer A, et al.Suppression of in vitro-megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood, 2004, 103(4): 1364-1369.
10.Takahashi R,Sekine N, Nakatake T.Influence of monoclonal antiplatelet glycoprotein antibodies on in vitro human megakaryocyte colony formation and proplatelet formation. Blood, 1999,93(6) : 1951-1958.
11. Chang M, Nakagawa PA, Williams SA, et al. Immune thrombocyto-penic purura(ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryoctopoiesis in vitro.Blood,2003,102(3):887-895.
12.Houwerzijl EJ,Blom NR,van der Want JJ,et al.Ultrastructural study shows morphologic features of apoptosis and paraapopto-sis in megakaryocytes from patients with idiopathic thrombocy-topenic purura.Blood,2004,103(2):500-506.
13.Cines DB, Blancbhette VS. Immune thrombocytopenic purpura. N Engl J Med,2002,346(13):995-1008.
14.Kuwana M, Kaburaki J, lkeda Y, et al. Autoreactive T Cells to platelet GP II b-IIIa in immune thrombocytopenia purpura Role in production, of anti-platelet antoantibody. J Clin Invest, 1998,102(7) : 1393-1402.
15. Yan J, Mammla MJ. Autoreactive T cells revealed in the normal repertoire: escape from negative selection and peripheral tolerance.J Immunol, 2002, 168(7):3188-3194.
16.Semple JW.Immune pathophysiology of antoimmune thrombocy-topenic purpura. Blood Rev,2002,16(1):9-12.
17. McFarland J. Pathophysiology of platelet destrucion in immune (idiopathic) thrombocytopenic purpura. Blood Rev, 2002,16(1): 1-2.
18.Semple JW,Miles Y,Cosgrave D, et al. Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplat-elet T-cell reactivity. Blood,1996,87(10):4245-4254.
19.Liang B,Mamula MJ.Molecular mimicry and the role of B lymphocytes in the processing of autoantigens.Cell Mol Life Sci,2000,57(4):561-568.
20.Bettaieb A, Oksenhendler E, Duedari N, et al. Cross-reactive antibodies between HIV-gpl20 and platelet gpIIIa (CD61) in HIV-related immune thrombocytopenic purpura. Clin Exp Immunol, 1996, 103(1) : 19-23.
21. Kuwana M, Kaburaki J, Kitasato H, et al. Imnamodominant epitopes on glycoprotein II b-IIIa recognized by autoreactive T cells patients with immune thrombocytopenic purpura. Blood,2001, 98(1):130-139.
22.Bowditch RD,Tani P,Fong KC,et al.Characterization of autoantigenic epitopes on platelet glycoprotein II b/I11 a using random peptide libraries. Blood, 1996, 88(12) : 4579-4584.
23. Olsson B, Andersson PO, Jernas M, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocyto-penic purpura. Nat Med,2003,9(9):1123-1124.
24.Yoshimura C,Nomura S,Nagahama M,et al.Plasma-soluble Fas (APO-1,CD95) and soluble Fas ligand in immune thrombocyto-penic purpura.Eur J Haematol, 2000,64(4):219-224.
25.Jin F,Balthasar JP.Mechanisms of intravenous immunoglobulin action in immune thrombocytopenic purpura. Hum Immunol,2005, 66(5):403-410.
26. Debes A, Bauer M, Kremer S, et al. Tolerability and safety of the intravenous immunoglobulin Octagam (R): a 10-year prospective observational study.Pharmacoepidemiol Drug Saf,2007,16 (9): 1038-1047.
27.Cooper N,Heddle NM, Haas M, et al.Intravenous (IV) anti-D and IV immunoglobulin achieve acute platelet increases by different mechanisms: modulation of cytokine and platelet responses to IV anti-D by FcgammaRIIa and FcgammaRIIIa polymorphisms. Br J Haematol,2004,124(5):511-518.
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