IL-21和BAFF在免疫性血小板减少性紫癜血清中表达水平及其意义
详细信息    本馆镜像全文|  推荐本文 |  |   获取CNKI官网全文
摘要
目的
     探讨免疫性血小板减少性紫癜(ITP)患者血清中白介素-21(IL-21)与B细胞激活因子(BAFF)表达水平及临床意义
     方法
     46例ITP患者中(ITP组),男性14例,女性32例,年龄16-74岁,中位年龄36岁。进一步按照ITP患者发病时间及出血严重程度进行分组,其中新诊断ITP组17例、持续性ITP组5例、慢性ITP组20例、重症组3例、难治性ITP组1例。另选择同时期住院的10例其他原因血小板减少患者(NITP组),其中男性4例,女性6例,年龄16-57岁,中位年龄40岁。以性别和年龄相符合的20例健康体检者(健康对照组),男性10例,女性10例,年龄16~70岁,中位年龄39岁。采用酶联免疫吸附法(ELISA)检测ITP患者治疗前及治疗后、NITP患者以及健康体检者血清中IL-21、BAFF表达水平。
     结果
     1.ITP组治疗前血清IL-21表达水平明显高于健康对照组(551.79±48.15pg/ml vs 480.2±28.28pg/ml,p<0.01);但与NITP组无明显统计学差异(551.79±48.15pg/ml vs 567.27±92.64 pg/ml, p=0.619);
     2.ITP组治疗前血清BAFF表达水平明显高于健康对照组(721.03±117.7pg/ml vs 512.5±86.91pg/ml, p<0.01);但与NITP患者组无明显统计学差异(721.03±117.7pg/ml vs 782.0±138.08pg/ml, p=0.128);
     3.ITP组治疗后血清中IL-21和BAFF表达水平明显下降(分别为468.05±30.11pg/ml,548.57±88.33pg/ml),并与健康对照组比较无统计学意义;
     4.按ITP患者疾病分期中(新诊断ITP、持续性ITP、慢性ITP、重症ITP、难治性ITP),各亚组血清IL-21、BAFF表达水平与疾病严重程度分期呈正相关(r分别为0.833、0.785,P均<0.01);
     5.ITP组血清IL-21表达水平与出血分级、血小板计数之间无相关关系(r=—0.246,p=0.099;r=—0.028,p=0.856);ITP组血清BAFF水平与出血分级、血小板计数之间亦无相关关系(r=0.03,p=0.845;r=0.028,p=0.856);
     6.1TP组血清IL-21与BAFF表达水平呈正相关关系(r=0.659,p<0.01);
     7.ITP患者在大剂量地塞米松治疗组与标准剂量糖皮质激素治疗组治疗前后血清IL-21、BAFF表达水平无明显统计学意义。
     结论
     ITP患者血清中IL-21和BAFF表达明显升高,且二者与疾病严重程度呈正相关,给予糖皮质激素后血清IL-21和BAFF表达水平明显下降,提示IL-21和BAFF可能参与了ITP疾病进程。
Objective:To investigate the expression of IL-21、BAFF in immune thrombocyto-penic purpura (ITP) and its significance
     Methods:46 cases of ITP patients(ITP group) were recruited:male 14, female 32, aged 16 to 74 years, median age was 36 years.The ITP patients were divided into different groups according to time of onset and severity of bleeding, of which 17 patients newly diagnosed ITP, persistent ITP group of 5 patients,20 cases of chronic ITP,3 patients of severe ITP,1 case of refractory ITP group.10 patients with non-ITP thrombocytopenic patients (NITP group) in the same period hospitalized were aslo recruited:4 males and 6 females, aged 16 to 57 years, the median age 40 years.20 healthy subjects (control group) were recruited:10 males and 10 females, aged 16 to 70 years, the median age 39 years. The levels of IL-21 and BAFF in serum of ITP patients before and after treatment, NITP patients and healthy subjects were measured by enzyme-linked immunosorbent assay (ELISA).
     Resulrs:1.Compared with the normal controls, the level of serum IL-21 in the patients of untreated immune thrombocytopenic purpura were significantly higher (551.79±48.15pg/ml vs 480.2±28.28pg/ml, p<0.01), but no significant difference with NITP group (551.79±48.15pg/ml vs 567.27±92.64 pg/ml, p=0.619);
     2. Compared with the normal controls, the levels of serum BAFF in the patients of untreated immune thrombocytopenic purpura were significantly higher (721.03±117.7pg/ml vs 512.5±86.91pg/ml, p<0.01); but no significant difference with NITP group (721.03±117.7pg/ml vs 782.0±138.08pg/ml, p=0.128);
     3. The levels of serum IL-21 and BAFF in the patients with ITP after treatment,were significantly decreased (468.05±30.11pg/ml,548.57±88.33pg/ml respectively), and no significant difference with the control group;
     4.In the disease respectively stage with ITP (the newly diagnosed ITP, persistent ITP, chronic ITP, severe ITP, refractory ITP), the levels of serum IL-21, BAFF and disease severity was positively correlated (r=0.833,0.785;P<0.01).
     5.There were no significant correlation between the levels of serum IL-21 in patients and the bleeding grade level or the peripheral blood platelet count (r=-0.0246,-0.028respectively); Aslo, there were no significant correlation between the levels of serum BAFF in patients and the bleeding grade level or the peripheral blood platelet count (r= 0.03,0.028 respectively);
     6.The levels of serum IL-21 with ITP patients showed a positive correlation and regression with the levels of serum BAFF in all subjects(r=0659, p<0.01);
     7. The levels of serum IL-21 or BAFF with the ITP patients in the high-dose dexamethasone treatment group and the standard dose glucocorticoid treatment group,were not statistically significant.
     Conclusion:The levels of serum IL-21 and BAFF were significantly increased in ITP patients.Also,the relationship of IL-21 and BAFF was positively correlated. Furthermore, the levels of serum IL-21 and BAFF were significantly decreased after glucocorticoid treatment.The result suggests that IL-21 and BAFF may play a important role in ITP.
引文
[1]Axel Matzdorff,Aristoteles Giagounidis,Andreas Greinacher,et al.Diagnostik und Therapie der Immunthrombozytopenie[J].Onkologie,2010,33(3):2-20.
    [2]Alan T Nurden.Sustaining platelet counts in chronic ITP[J].The lancet,2011,377:358-360.
    [3]Douglas B Cines, James B Bussel, Howard A Liebman,et al.The ITP syndrome:pathogenic and clinical diversity[J].20091.13:6511-6521.
    [4]Wu KH, Peng CT, Li TC,et al. Interleukin 4, interleukin 6 and interleukin 10 polymorphisms in children with acute and chronic immune thrombocytopenic purpura[J]. Br J Haematol,2005,128(6):849-52.
    [5]Julia Parrish-Novak,Stacey R Dillon.Andrew Nelson,et al.Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function[J]. Nature,2000, 408:57-63.
    [6]Rosanne Spolski,Warren J Leonard.IL-21 and T follicular helper cells [J]. International Immunology,2009,22(1):7-12.
    [7]Hidetoshi Nara,Tadashi Onoda,Mizanur Rahman,et al.WSB-1, a novel IL-21 receptor binding molecule, enhances the maturation of IL-21 receptor[J].Cellular Immun-ology, 2011,269:54-59.
    [8]Alicia D Henn,Jonathan Rebhahn,Miguel ABrown,et al.Modulation of Single-Cell IgG Secretion Frequency and Rates in Human Memory B Cells by CpG DNA, CD40L, IL-21, and Cell Division[J].J Immunol,2009,183:3177-3187.
    [9]Helene Decaluwe,Morgan Taillardet,Erwan Corcuff,et al.γc deficiency precludes CD8+T cell memory despite formation of potent T cell effectors[J]. PNAS,2010,107 (20): 9311-9316.
    [10]Jing Li,Hai-Feng Pan,Han Cen,et al.Interleukin-21 as a potential therapeutic target for systemic lupus erythematosus[J].Mol Biol Rep,2010 Nov 24.
    [11]Feng-Lai Yuan,Wei Hu,Wei-Guo Lu,et al.Targeting interleukin-21 in rheumatoid arthritis[J].Mol Biol Rep,2011,38(3):1717-21.
    [12]Daniela de Toteroa,Matteo Capaiaa.Marina Fabbi,et al.Heterogeneous expression and function of IL-21 R and susceptibility to IL-211 mediated apoptosis in follicular lymphoma cells[J].Experimental Hematology,2010,38:373-383.
    [13]Christian W Eskelund,LineNederby,AnnaH Thysen,et al.Interleukin-21 and rituximab enhance NK cell functionality inpatients with B-cell chronic lymphocytic leukaemia[J].Leuk Res,2011 Feb25.
    [14]Bjorn Lamprecht,Stephan Kreher,Ioannis Anagnostopoulos,et al.Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3a[J].Blood,2008,112(8):3339-3347.
    [15]Paul A. Moore,Ornella Belvedere,Amy Orr,et al.BLyS:Member of the Tumor Necrosis Factor Family and B Lymphocyte Stimulator[J]. Science,1999,285:260-263.
    [16]Claudia Bossen,Pascal Schneider.BAFF, APRIL and their receptors:Structure, function and signaling[J].Seminars in Immunology,2006,18:263-275.
    [17]G A Lied,A Berstad.Functional and Clinical Aspects of the B-Cell-Activating Factor (BAFF): A Narrative Review[J].Scandinavian Journal of Immunology,2011,73:1-7.
    [18]Arnaud Van Den Broeck,John Cambier.B cells talk to their progenitors[J]. Blood,2011, 17(11):2985-2986.
    [19]Carrie A Fletcher,Joanna R Grooma,Blanche Woehl,et al.Development of autoimmune nephritis in genetically asplenic and splenectomized BAFF transgenic mice[J].Journal of Autoimmunity,2011,36:125-134.
    [20]Klaus Warnatz,Ulrich Salzera,Marta Rizzi,et al.B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans[J]. PNAS,2009, 106(33):13945-13950.
    [21]Thomas D6rner,Annett M Jacobi,Jisoo Lee,et al.Abnormalities of B cell subsets in patients with systemic lupus erythematosus[J].Journal of Immunological Methods,2011,363:187-197.
    [22]Rita A Moural,Rita Casca~-ol.lne~ s Perpe'tuo.et al.Cytokine pattern in very early rheumatoid arthritis favours B-cell activation and survival[J].Rheumatology,2011,50: 278-282.
    [23]Xavier Mariettea,Jacques-Eric Gottenberg.Pathogenesis of Sjo gren's syndrome and therapeutic consequences[J].Current Opinion in Rheumatology,2010,22:471-477.
    [24]Lucius Bader,Wenche Koldingsnes,Johannes Nossent.B-lymphocyte activating factor levels are increased in patients with Wegener's granulomatosis and inversely correlated with ANCA titer[J].Clin Rheumatol,2010.29:1031-1035.
    [25]S Morimoto, S Nakano, T Watanabe,et al.Expression of B-cell activating factor of the tumour necrosis factor family (BAFF) in T cells in active systemic lupus erythematosus:the role of BAFF in T cell-dependent B cell pathogenic autoantibody production[J]. Rheumatology, 2007,46:1083-1086.
    [26]Zhu X, Ma D, Zhang J,et al. Elevated interleukin-21 correlated to Th17 and Th1 cells in patients with immune thrombocytopenia[J].J Clin Immunol,2010,30(2):253-9.
    [27]Semple JW.ITP has elevated BAFF expression[J]. Blood,2009,114(26):5248-9.
    [28]Francesco Rodeghiero,Roberto Stasi,Terry Gernsheimer,et al.Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group[J]. Blood,2009,113(11):2386-2393.
    [29]Maria Gabriella Mazzucconi,Paola Fazi,Sayla Bernasconi,et al.Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura:a GIMEMA experience [J]. Blood,2007,109(4):1401-1407.
    [30]Howard A Liebman.Immune Thrombocytopenia(ITP):An Historical Perspective[M]. publication ASH 50th Anniversary.
    [31]B H CHONG.Primary immune thrombocytopenia:understanding pathogenesis is the key to better treatments[J].Journal of Thrombosis and Haemostasis,2008,7:319-321.
    [32]Adam Cuker,Douglas B Cines.Immune Thrombocytopenia[J].Hematology Am Soc Hematol Educ Program,2010,2010:377-84.
    [33]Daoxin Ma,Xiaojuan Zhu,Ping Zhao,et al.Profile of Th17 cytokines (IL-17, TGF-β,IL-6) and Thl cytokine (IFN-y) in patients with immune thrombo-cytopenic Purpura[J].Ann Hematol,2008,87:899-904.
    [34]刘俊庆,杨林花,陈剑芳,等.特发性血小板减少性紫癜患者B细胞活化因子的表达及其基因多态性[J].中华血液学杂志,2010,31(9):586-589.
    [35]Bethan Psailal,James B Bussel.Fc receptors in immune thrombocytopenias:a target for immunomodulation[J].The Journal of Clinical Investigation,2008,118(8):2677-2681.
    [36]Lisa M Sedger,Arna Katewa,Ann K Pettersen,et al.Extreme lymphoproliferative disease and fatal autoimmune thrombocytopenia in FasL and TRAIL double-deficient mice[J]. Blood, 2010,115,(16):3258-3268.
    [37]Jin H, R Carrio, A Yu,et al.Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis[J].J Immunol,2004,173(1):657-665.
    [38]Kim L Good,Vanessa L Bryant.Stuart G Tangye.Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21[J].J Immunol, 2006,177,5236-5247.
    [39]Sudhanshu Agrawal,Sudhir Gupta.Erratum to:TLR1/2, TLR7, and TLR9 Signals Directly Activate Human Peripheral Blood Naive and Memory B Cell Subsets to Produce Cytokines, Chemokines.and Hematopoietic Growth Factors[J].J Clin Immunol,2011,31:136.
    [40]Katsutoshi Ozaki,Ai Hishiya,Keiko Hatanaka,et al.Overexpression of Interleukin-21 Induces Expansion of Hematopoietic Progenitor Cells[J]. International Journal of Hematology,2006, 84:224-230.
    [41]Stephan Borte,Qiang Pan-Hammarstrom,Chonghai Liu,et al.Interleukin-21 restores immun-oglobulin production ex vivo in patients with common variable immunodeficiency and selective IgA deficiency[J].Blood,2009,114(19):4089-4098.
    [42]Schiemann B, Gommerman JL, Vora K,et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway[J].Science,2001; 293(5537):2111-2114.
    [43]Fletcher CA, Groom JR. Woehl B,et al. Development of autoimmune nephritis in genetically asplenic and splenectomized BAFF transgenic mice[J].J Autoimmun,2011,36(2):125-34.
    [44]Kristen L Hoek,Gianluca Carlesso,Emily S Clark,et al. Absence of Mature Peripheral B Cell Populations in Mice with Concomitant Defects in B Cell Receptor and BAFF-R Signaling[J]. J Immunol 2009,183:5630-5643.
    [45]Bing Hel,Raul Santamaria,Weifeng Xu,et al. TACI triggers immunoglobulin class switching by activating B cells through the adaptor protein MyD88[J].Nat Immunol,2010,11(9):836-845.
    [46]S Kracker,PGardes, F Mazerolles,et al. Immunoglobulin class switch recombination defi-ciencies[J]. Clinical Immunology,2010,135:193-203.
    [47]Brian P O'Connor,Vanitha S Raman,Loren D Erickson.et al. BCMA Is Essential for the Survival of Long-lived Bone Marrow Serum Cells[J].J Exp Med,2004.199(1):91-8.
    [48]Christopher G Maynel, Faye E Nashold,Yoshiteru Sasaki,et al. Altered BAFF-receptor signaling and additional modifier loci contribute to systemic autoimmunity in A/WySnJ mice[J]. Eur J Immunol,2009.39:589-599.
    [49]Stacey Walters,Kylie E Webster,Andrew Sutherland,et al. Increased CD4+Foxp3+T Cells in BAFF-Transgenic Mice Suppress T Cell Effector Responses[J].J Immunol 2009,182; 793-801.
    [50]Aikaterini Thanou-Stavraki.Amr H Sawalha.An update on belimumab for the treatment of lupus[J].Biologics:Targets and Therapy,2011,5:33-43.
    [51]Brian P O'Connor,Vanitha S Raman,Loren D. Erickson,et al.BCMA Is Essential for the Survival of Long-lived Bone Marrow Serum Cells[J].J Exp Med,2004,199(1):91-97.
    [52]Florian Emmerich,Gurkan Bal,Alaa Barakat,et al.High-level serum B-cell activating factor and promoter polymorphisms in patients with idiopathic thrombocytopenic purpura[J].British Journal of Haematology.2006,136:309-314.
    [53]Xiao-juan Zhu,Yan Shi,Jun Peng.et al.The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia[J].BLOOD,2009,114:5362-5367.
    [1]PGottlieb.Except:Paul Gottlieb Werlhof.JAMA[J].1968,206(13):2892.
    [2]Blanchette M,Freedman J.The history of idiopathic thrombocytopenic purpura [J]. Transfusion Science,1998,19(3):231-236.
    [3]Chong BH.Primary immune thrombocytopenia:understandingpathogenesis is the key to better treatments[J].Journal of Thrombosis and Haemostasis,2009,7:319-321.
    [4]Ma D,Zhu X,Zhao P,et al.Profile of Th17 cytokines (IL-17, TGF-beta,1L-6) and Th1 cytokine (IFN-gamma) in patients with immune thrombocytopenic purpura [J].Ann Hematol, 2008,87(11):899-904.
    [5]Zhu X,Ma D,Zhang J, Peng J et al.Elevated interleukin-21 correlated to Th17 and Thl cells in patients with immune thrombocytopenia[J].J Clin Immunol.2010 Mar;30(2):253-9.
    [6]Semple JW.ITP has elevated BAFF expression[J].Blood,2009,114(26):5248-9.
    [7]Psaila B, Bussel JB.Fc receptors in immune thrombocytopenias:a target for immuno dulation[J].J Clin Invest.2008.18(8):2677-81.
    [8]Peerschke El, Andemariam B, Yin W,et al.Complement activation on platelets correlates with a decrease in circulating immature platelets in patients with immune thrombocytopenic purpura[J].Br J Haematol,2010,148(4):638-45.
    [9]Sedger LM, Katewa A, Pettersen AK,et al.Extreme lymphoproliferative disease and fatal autoimmune thrombocytopenia in FasL and TRAIL double-deficient mice[J].Blood,010, 15(16):58-68.
    [10]Hanrrington WJ,Minnich V,Hollingsworth W,et al.Demonsstration of a thrombocytopenic factor in the blood of patients wit thrombocytopenic purpura[J].J Lab Clin,1951,38(1):1-10.
    [11]Shulman NR,Marder VJ,Weinrach RS.Similarities between known antiplatelet antibobodies and the factor responsible for thrombocytopentic in idiopathic purpura J],Physiologic, 965.124(2):499-542.
    [12]Stasi R,Evangelista ML,Stipa E,et al.Idiopathic thrombocytopenic purpuraxurrent concepts in pathophysiology and management[J].Thromb Haemost,2008;99:4-13.
    [13]Kuwana M,Kaburaki J, Ikeda Y. Autoreactive T cells to platelet GPⅡb/Ⅲa in immune thrombocytopenic purpura. Role in production of anti-platelet autoanti-body[J].J Clin Invest, 1998,102:1393-402.
    [14]Machino Y, Ohta H, Suzuki E,et al.Effect of immunoglobulin G (IgG) interchain disulfide bond cleavage on efficacy of intravenous immunoglobulin for immune thrombocytopenic purpura (ITP) [J].Clin Exp Immunol,2010,1365-2249.
    [15]Ruiz-Argiielles A, Llorente L.The role of complement regulatory proteins (CD55 and CD59) in the pathogenesis of autoimmune hemocytopenias[J].Autoimmun Rev,2007,6(3):155-61.
    [16]Kuter DJ, Gernsheimer TB.Thrombopoietin and platelet production in chronic immune thrombocytopenia[J].Hematol Oncol Clin North Am.2009.23(6):1193-1211.
    [17]Nugent D, McMillan R, Nichol JL,et al.Pathogenesis of chronic immune thrombo-cytopenia: increased platelet destruction and/or decreased platelet production[J].Br J Haematol,009,146 6):585-596.
    [18]Rank A, Weigert O, Ostermann H.Management of chronic immune thrombo-cytopenic purpura:targeting insufficient megakaryopoiesis as a novel therapeutic principle^]. Biologics,2010,4:139-145.
    [19]Frank HJ.Primary thrombocytopenic purpura,(Idiopathic) [J].Pa Dent J (Harrisb),970,37(8): 94-295.
    [20]Houwerzijl EJ,Blom NR,van der Want JJ,et al.Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura[J].Blood,2004,103:500-506.

© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号

地址:北京市海淀区学院路29号 邮编:100083

电话:办公室:(+86 10)66554848;文献借阅、咨询服务、科技查新:66554700