高迁移率族蛋白B1在系统性红斑狼疮患者血清中的表达及临床意义
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:探讨高迁移率族蛋白B1(HMGB1)在系统性红斑狼疮(SLE)患者血清中的表达和临床意义。
     方法:选择65例SLE患者,并按SLE疾病活动指数(SLEDAI)分组,其中活动组50例与非活动组15例;按照肾脏有无受累进行分组,其中狼疮肾炎(LN)组38例和SLE非肾炎组27例。25例健康人作为对照组。采用酶联免疫吸附(ELISA)法分别检测各组血清中HMGB1水平。采用统计学方法分析HMGB1水平与SLE病情活动性和狼疮肾损害之间的关系。
     结果:⑴SLE组血清HMGB1水平高于健康对照组(P<0.05)。⑵SLE活动组血清HMGB1水平高于非活动组(P<0.05)。⑶LN组血清HMGB1水平高于SLE非肾炎组(P<0.05)。⑷SLE血清HMGB1水平与SLEDAI评分呈正相关(P<0.05)。⑸SLE血清HMGB1水平与抗ds-DNA抗体水平呈正相关(P<0.05)。⑹SLE血清HMGB1水平与免疫指标血清C3水平呈负相关(P<0.05)。⑺LN组血清HMGB1水平与肾损害指标尿ALB、尿IgG、尿IgA、尿IgM、尿α2-MG及24小时尿蛋白定量均呈正相关性(P<0.05)。
     结论:血清HMGB1水平在SLE组高于健康对照组,活动组高于非活动组,LN组高于SLE非肾炎组,SLE血清HMGB1水平与抗ds-DNA抗体水平正相关,提示HMGB1参与了SLE、LN疾病病理发生过程,其致炎作用可能与抗ds-DNA抗体合成有关。血清HMGB1水平与SLEDAI积分呈正相关,血清HMGB1水平能反映出疾病的活动状态,可作为SLE、LN疾病活动性指标之一。此外,患者血清HMGB1水平还可作为SLE患者肾小球损害的监测指标之一。
Objective: To investigate the expression and clinical significance of serum high mobility group box1 protein(HMGB1)in patients with systemic lupus erythematosus(SLE).
     Method: The levels of serum HMGB1 were measured in 65 SLE Chinese patients and 25 healthy persons by the method of enzyme-linked immunosorbent assay (ELISA),65 SLE patients were divided into different groups according to the SLE disease activity index (SLEDAI) score and renal involvement :50 patients at active phase and 15 at stable stage; 38 patients with nephritis and 27 patients without nephritis. And the correlation between HMGB1 levels and SLE other disease activity parameters and renal injury was analyzed.
     Results:⑴The levels of serum HMGB1 in SLE patients were significantly higher than that in normal controls (P<0.05).⑵The levels of serum HMGB1 in SLE patients with active lupus were significantly higher than that of in those without active lupus(P<0.05).⑶The levels of serum HMGB1 in lupus nephritis patients were significantly higher than that of in those without lupus nephritis (P<0.05).⑷The levels of serum HMGB1 was significantly positively correlated with SLE disease activity index (SLEDAI) scores(P<0.05).⑸The levels of serum HMGB1 was positively correlated with anti ds-DNA antibody levels(P<0.05).⑹The levels of serum HMGB1 was significantly negatively correlated with C3 levels(P<0.05).⑺The levels of serum HMGB1 in lupus nephritis were positively correlated with these renal injury’s clinical indexes (including urine ALB,urine IgG,urine IgA,urine IgM,urineα2-MG) and 24 hours urine protein(24hUpro)(P<0.05).
     Concluions: The levels of serum HMGB1 were significantly elevated in SLE patients compared with that of in healthy person, the levels of serum HMGB1 in active SLE were higher than that in those without active lupus, and higher in LN than those without LN. The levels of serum HMGB1 was significantly correlated with anti ds-DNA antibody levels, which reveals HMGB1 participate in the pathogenesis of SLE and LN, and the way of inflammation inducing effects maybe correlated with the synthesis of anti ds-DNA antibody. Besides, the levels of serum HMGB1 are positively correlated with SLEDAI scores. HMGB1 can display the state of disease activity and it is also suggested that HMGB1 can be one of the indicator of the disease activity and renal injury in patients with SLE.
引文
[1]WangH, BloomO, ZhangM, et al .HMG as a late mediator of endotoxin lethality in mice [J].Science, 1999, 285(5425):248-51.
    [2]Sunden-cunliberg J, Norrby-teglund A, Rouhiainen A, et al.Persistent elevation of high mobility group box-1protein (HMGB1) in patients with severe sepsis and septic shock [J].CritC are Med, 2005, 33(3):564-73.
    [3]KimooJY, ParkJS, StrassheimD, et a1.HMGB1 contributes to the development of acute lung injury after hemorrhage[J].Am J Physiol Lung cell Mol Physiol, 2005, 288(5): L958-65.
    [4]Li W, Samaa E, Wang H. Role of HMGB1 in cardiovascular diseases [J]. Curr Opin Pharmacol, 2006, 6(2):130-135.
    [5]Huang Y, Yin H, Han J, et.al.Extracellular HMGBl Functions as an innate immune mediator implicated in murine cardiac allograft acute rejection [J]. Am J Transplant, 2007, Apr, 7(4):799-808.
    [6]MoserB, Szabolcs MJ, Ankersmit HJ, et al.Blockade of RAGE suppresses allo imunune reactions invitro and delays allograft rejection in murine heart transplantation[J].AmJ Transplant,2007,7(2):293-302.
    [7]Nakano T, Laic Y, Goto S,et al.Role of anti nuclear antibodies in experimental and clinical liver transplantation[J].Transplant Proc,2006,38(10):3605-3606.
    [8]Monica EK,Popovic K,Harris HE,et a1.Increased extracellular levels of the novel proinflammatory eytokine high mobility group box chromosomal protein 1 in minor salivary glands of patients with sjtigren syndrome[J]. Arthritis Rheum, 2006,54(7): 2289-2294.
    [9]Ulfgrena K,Grundtman C,Borg K,et a1.Down regulation of the aberrant expression of the inflammation mediator high mobility group box chromosomal protein 1 in muscle tissue of patients with polymyositis and dermatomyositis treated with corticosteroids [J].Arthritis Rheum,2004,50(5):1589-1594.
    [10]Taira T,Matsuyama W,Mitsuyama H,et a1.Increased serum high mobility group box1 level in Churg Strauss Syndrome.Clinical and Experimental [J].Immunology,2007, 148(2):241-247.
    [11]Li J,Kokkola R,Tabibzadeh S,et al. Structural basis for the proinflammatory cytokine activity of mobility group box 1.Mol Med,2003,9,(1-2):37-45.
    [12]Knapp S, Muller S, Digilio G, et al. The long acidic tail of high mobility group box 1(HMGB1) protein forms an extended and flexible structure that interacts with specific residues within and between the HMG boxes.Biochemistry, 2004, (38):11992-11997.
    [13]Ulloa L,Franak M,Andersson U,et al. High mobility group box chromosomal protein 1 as a nuclear protein,cytokine and potential therapeutic target in arthritis. Arthr Rheum,2003, 48:876-881.
    [14]Mullins GE,Sunden-Cullbergy J,Johansson AS,et a1.Activation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group box chromosomal protein 1 [J].Scand Immunol,2004,60(6):566-573.
    [15]AnderssonU,WangH,PalmbladK,eta1.High mobility group1 protein(HMG-1)stimulates proinflammatory cytokine synthesis in human monocytes.Exp Med, 2000, 192(4): 565-570.
    [16]Scaffidi P,Misteli T,Bianchi ME.Release of chmmatin pmtein HMGB1 by necrotic cells triggers inflammation.Nature,2002,418(6894):191-195.
    [17]Muller S,Scandi P,Degryse B,et a1.The double life of HMGB1 chromatin protein: architectural factor and extracellular signal[J].EMBO,2001,20(16):4337-4340.
    [18]BonaldlT,Langst G,Strohner R,et a1.The DNA chaperone HMGB1 facilitates ACF/CHRAC-dependent nucleosome sliding[J].EMBO,2002,21(24):6865-6873.
    [19]Urbonaviciute V, Furnrohrb G, Weber C, et al. Factors masking HMGB1 in human serum and plasma [J].Leukoc Biol, 2007, 81:67-74.
    [20]Jiang W, Pisetskyd S, et a1.Expression of high mobility group protein 1 in the sera of patients and mice with systemic lupus erythematosus. Ann Rheum Dis, 2008, 67:727-728.
    [21]Urbonaviciute V, FurrnrohrbG, Meister S, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE[J].Exp Med,2008,205: 3007-3018.
    [22]Tian J,Avalosa M, Maos Y,et al.Toll-like receptor 9-dependent activation by DNA- containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol, 2007, May 8(5):487-496.
    [23]Qing X, Pitashny M, Thomasd B, et al .Pathogenic anti-DNA antibodies modulate gene expression in mesangial cells: involvement of HMGB1 in anti DNA antibody-induced renal injury. Immunol Lett, 2008,Nov 16,121(1):61-73.
    [24]刘淑霞、郝军,等.高迁移率族蛋白及其TOLL样受体4在系统性红斑狼疮肾脏损害中的作用[J].中国免疫学杂志, 2008,24(10):948-951.
    [1]Wang ,Bloomo,Zhangm ,et al .HMGB-1 as a late mediator of endotoxin lethality in mice[J].Science,1999,285(5425):248-251.
    [2]Sunden-cuilbergJ, Norrby-teglundA, RouhiainenA, et al.Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock[J].CritC are Med,2005,33(3):564-573.
    [3]KimjY, ParkjS, Strassheim D, et a1.HMGB1 contributes to the Development of acute lung injury after hemorrhage[J].Am J Physiol Lung cell Mol Physiol, 2005,288 (5):L958-65.
    [4]LiW, SamaaE, Wang H.Role of HMGB1 in cardiovascular diseases [J].Curr Opin Pharmacol,2006,6(2):130-135.
    [5]HuangY, Yin H, Han J, et al.Extracellular HMGBl Functions as an innate immune mediator implicated in Murine Cardiac Allograft Acute Rejection[J]. AmJ Transplant, 2007,Apr,7(4):799-808.
    [6]Moser B, SzabolcS MJ, AnkersmithJ, et al.Blockade of RAGE suppresses alloimunune reactions invitro and delays allograft rejection in murine heart transplantation[J].AmJ T ransplant,2007,7(2):293-302.
    [7]Nakano T, LaicY, Goto S,et al.Role of antinuclear antibodies in experimental and clinical liver transplantation[J].Transplant Proc,2006,38(10):3605-3606.
    [8]Monica EK,Popovic K,Harris HE,et a1.Increased extracellular levels of the novel proinflammatory eytokine high mobility group box chromosomal protein 1 in minor salivary glands of patients with sjtigren syndrome[J] .Arthritis Rheum,2006,54(7): 2289-2294.
    [9]Ulfgren AK,Grundtman C,Borg K,et a1.Down regulation of the aberrant expression of the inflammation mediator high mobility group box chromosomal protein 1 in muscle tissue of patients with polymyositis and dermatomyos it is treated with corticosteroids [J].Arthritis Rheum,2004,50(5):1589-1594.
    [10]Taira T,Matsuyama W, Mitsuyama H,et a1. Increased serum high mobility group box1 level in Churg Strauss syndrome. Clinical and Experimental. Immunology, 2007, 148 (2):241-247.
    [11]Bentley DR,Deloukas P,Dunham A,et a1.Thephysical maps for sequencing humanchromosomesl,6,9,10,13,20 and x[J].Nature,2001,409(6822):942-943.
    [12]Li J,Kokkola R,Tabibzadeh S,et al,.Structural basis for the proinflammatory cytokine activity of mobility group box 1.Mol Med,2003,9,(1-2):37-45.
    [13]Knapp S, Muller S, Digilio G, et al. The long acidic tail of high mobility group box 1(HMGB1) protein forms an extended and flexible structure that interacts with specific residues within and between the HMG boxes.Biochemistry, 2004, 43(38): 11992-11997.
    [14]Ulloa L,Franak M,Andersson U,et al. High mobility group box chromosomal protein 1 as a nuclear protein,cytokine and potential therapeutic target in arthritis[J]. Arthr. Rheum, 2003,48:876-881.
    [15]Yang H,Wang H,Christopher J,et al. The cytokine activity of HMGB1.Journal of Leukocyte Biology,2005,78(1):1-8.
    [16]Andersson U,Tracey KJ.HMGB1 in sepsis.Scand J Infect Dis,2003,35(9):577-584.
    [17]Bonaldi T,Talmno F,Scaffidi P,et a1.Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion[J].EMBO,2003,22(20):5551-5560.
    [18]Scaffidi P,Misteli T,Bianchi ME.Release of chmmatin pmtein HMGB1 by necrotic cells triggers inflammation.Nature,2002,418(6894):191-195.
    [19]Muller S,Scandi P,Degryse B,et a1.The double life of HMGB1 chromatin protein: architectural factor and extracellular signal[J].EMBO,2001,20(16):4337-4340.
    [20]BonaldlT,Langst G,Strohner R,et a1.The DNA chaperone HMGB1 facilitates ACF/CHRAC-dependent nucleosome sliding[J].EMBO,2002,21(24):6865-6873.
    [21]Guazzi S,Strangio A,Franzi AT,et al. HMGB-l an architectural chromatin protein and extrace1lular signa1ling factor,has a spatially and temporal1y restricted expression pattern in mouse brain. Gene ExPr Patterns,2003,3(1):29-33.
    [22]Calogero S,Grassi F,Aguzzi A,et al. The lack of chromosomal protein Hmgbl does not disrupt cell growth but causes 1etha1 hypoglycaemia in new born mice. Nature Genet,1999,22(3):276-280.
    [23]KokkolaR, Sundberg E, UlfTen Alc,et a1.High mobility group box chromosomal protein1:a novel pro-inflammatory mediator in synovitis.Arthritis Rheum, 2002,46:2598-2603.
    [24]Mullins GE,Sunden-Cullbergy J,Johansson AS,et a1.Activation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group boxchromosomal protein 1 [J].Scand Immunol,2004,60(6):566-573.
    [25]AnderssonU,WangH,PalmbladK,eta1.High mobility group1 protein(HMG-1)stimulates pminflammatory cytokine synthesis in human monocytes.Exp Med, 2000, 192(4): 565-570.
    [26] Ann Marie Schmidt,David M Stern, et a1.RAGE: A New Target for the Prevention and Treatment of the Vascular and Inflammatory Complications of Diabetes Trends Endocrinol Metab,2000,11(9):368- 375.
    [27]Srikrishna G, Huttunen HJ, Johansson L, Weigle B, Yamaguchi Y, Rauvala H, Freeze H,et al,N-Glycans on the receptor for advanced glycation end products influence amphoterin binding and neurite outgrowth[J].Neurochem, 2002,80:998–1008.
    [28]ParkJS,SvetkauskaiteD,HeQ,et a1.Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein.[J] Biol Chem, 2004, 279(9): 7370-7377.
    [29]Sunden-Cullberg J,Norrby-Teglund L,Rouhiainen A,et a1.Persistent elevation of high mobility group box1 pmtein(HMGB 1)in patients with severe sepsis and septic shock.Crit Care Med,2005,33(3):564.
    [30]费军,余洪俊,梁华平,等.多发伤患者血清高迁移率蛋白-1水平与ISS、APACHE lI评分的相关性研究.创伤外科杂志,2006,8(3):205.
    [31]彭建平,范学工,刘洪波,等,慢性乙型肝炎患者高迁移率族蛋白1mRNA的表达及其临床意义.世界华人消化杂志,2005,13(2):167- 172.
    [32]Taguchi A,Blood DC,et a1.Blockade of RAGE amphoterin signalling suppresses tumour growth and metastasis[J].Nature,2000,405(6784):354-360.
    [33]Rovere Querini P,Capobianco A,Seaffidi P,et a1.HMGB1 is an endogenous immune adjuvant released by necrotic cels[J].EMB0 Rep,2004,5(8):825-830.
    [34]Volp K,Brezniceanu ML,Boser S,et a1.Increased expression of high mobility group box 1(HMGB1)is associated with all elevated level of the anti apoptotic c-IAP2 protein in human colon carcinomas[J].Gut,2006,55(2):234-242.
    [35]Kuniyasu H,Sasaki T,Sasahira T,et a1.Depletion of tumor-infiltrating macrophages is associated with an protein expression in colon caneer[J]. Pathobiology, 2004,71 (3):129-136.
    [36]Meyer B,Murua Escobar H,Hauke S,et a1.Expression pattern of the HMGB1gene in sarconlas of the dog[J].Anticancer Res,2004,24(2B):707-710.
    [37]Ynan F,Gu L,Gno S,et a1.Evidence for involvement of HMGB1 protein in human DNA mismatch repair[J].J Biol Chem,2004,279(201):20935—20940.
    [38]Breznieeanu ML,Volp K,Btisser S,et a1.HMGB1 inhibits cell death in yeast and main Tlalian cells and is abundantly expressed in human breast carcinomal[J].FASEB J,2003,17(10):1295-1297.
    [39]Abraham E,Arcaroli J,Carmody A,et a1.HMGB1as a mediator of acute lung inflammation[J].Immunol,2000,165(6):2950-2954.
    [40]Rouhiainen A,Kuja Panula J,Wilkman E,et a1.Regulation of moB-ocyte migration by amphoterin(HMGB1).Blood,2O04,104(4):1174-1182.
    [41]Lin X,Yang H,Sakuragi T,et a1.Alpha chemokine receptor blockade reduces high mobility group box 1 protein induced lung inflammarion and injury and improves survivalin sepsis[J].Am J Physiol Lung CellMol Physiol,2005,289(4):L583-590.
    [42]Oqawa EN,Ishizaka A,Tasaka S,et a1.Contribution of high mobility group box1 to the development of ventilator-induced lung injury[J].Am J Respir Crit Care Med,2006, 174(4):400-407.
    [43]Sitzer M,Trostdorf F.The unstable carotid stenosis:definition and biological processes.Hamostaseologie,2003,23:61-66.
    [44]Cipollone F, Fazia M, Mincione G, et a1.Increased expression of transforming growth factor-betal as a stabilizing factor in human atherosclerotic plaques. Stroke,2004, 35:2253-2257.
    [45]Formato M,Farina M,Spirito R,et a1.Evidence for a proinflammatory and proteolytic environment in plaques from endarterectomy segments of human carotid arteries. Arterioseler Thromb Vasc Bio1,2004,24:l29-135.
    [46]Fiuza C,Bustin M,Talwar S,et a1.Inflammation-promoting activity of HMGBl on human microvascular endothelial cells.Blood,2003,101:2652-2660.
    [47]李树合、周定标、袁晓玲,等.颈动脉粥样硬化不稳定斑块异质性的病理研究及高分辨MRI影像特点分析.中华神经外科杂志,2006,22:485-488.
    [48]Ranganna K,Yousefipour Z,Yatsu FM,et al.Gene expression profile of butyrate-inhibited vascular smooth muscle cell proliferation.Mol Cell Biochem, 2003, 254: 21-36.
    [49]Kalinina N,Agrotis A,Antropova Y,et a1.Increased expression of the DNA.binding cytokine HMGB1 in human atherosclerotic lesions:role of activated macrophages and cytokines.Arterioscler Th romb Vasc Biol,2004,24:2320-2325.
    [50]AnderssonU,Harrish E.HMGB 1 is a potent trigger of arthritis[J] .Intern Med, 2004, 255: 344-350.
    [51] Pullerits R,Jonsson M,Verdrengh M,et a1.High mobility group box chromosomal protein 1,a DNA binding cytokine Induces arthritis . Arthritis Rheum, 2003, 48:1693-1700.
    [52]Kokkolar,Andersson A,Mullins G,et a1.RAGE is the major receptor for the proinflam matory activity of HM GB1 in rodent macrophages [J].Scand J Immunol, 2005, 61(1):1-9.
    [53]Kokkolar,LiJ,Sundberg E,et a1.Successful treatment of collagen induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity [J].Arthritis Rheum ,2003,48(7):2052-2 058.
    [54]Afklint E,Grundtman C,Engstrom M,et a1.Intraarticular glucocorticoid treatment reduces inflammation in synovial cell infiltrations moreefficiently than in synovial blood vessels.Arthritis Rheum,2005,52(12):3880-3889.
    [55]Taniguchi N,Kawahara K,Yone K,et a1.High mobility group box1 chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine.Arthritis Rheum,2003,48(4):971-981.
    [56]Jiang W,Pisetsky DS.Mechanisms of Disease:the role of high mobility group protein 1 in the pathogenesis of inflammatory arthritis.Nat Clin Pract Rheumatol, 2007, 3(1): 52-58.
    [57]郑毅、董馨等,类风湿关节炎滑膜中高迁移率族蛋白1的表达.中华风湿病学杂志,2005,9(11):684-686.
    [58]Urbonaviciute V, Furnrohr BG, Weber C et al.Factors masking HMGB1 in human serum and plasma[J].Leukoc Biol,2007,81:67–74.
    [59]Jiang W, Pisetsky DS.Expression of high mobility group protein 1 in the sera of patients and mice with systemic lupus erythematosus. Ann Rheum Dis, 2008, 67:727–728.
    [60]Urbonaviciute V, Furrnrohr BG, Meister S et al.Induction of inflammatory and immuneresponses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE[J].Exp Med,2008,205:3007-3018.
    [61]Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature,2002,7(11),418:191–195.
    [62]Hvashi A, Nagafuchi H, Itol, et al. Lupus antibodies to the HMGB1 chromosomal protein:epitope mapping and association with disease activity.Mod Rheumatol, 2009,19(3):283-292.
    [63]Dumitriu E,Bianchi ME,Bacci M,et a1.The secretion of HMGB1 is required for the migration of maturing dendritic cells[J].Leukoc Biol,2007,81(1):84-91.
    [64]Popovic K,Ek M,Espinosa A,et a1.Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus [J].Arthritis Rheum,2005,52(11):3639—3645.
    [65]Qing X, Pitashny M, Thomasd B et al.Pathogenic anti-DNA antibodies modulate gene expression in mesangial cells: involvement of HMGB1 in anti-DNA antibody-induced renal injury. Immunol Lett,2008,Nov 16,121:61–73.
    [66]刘淑霞、郝军,等.高迁移率族蛋白及其TOLL样受体4在系统性红斑狼疮肾脏损害中的作用[J].中国免疫学杂志, 2008,24(10):948-951.
    [67]Ulloa L,Ochani M,Yang H,et a1.Ethyl Pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation.Proc Nat1 Acad Sci USA,2002,99:12351-12356.
    [68]Mao SY, Xu Y, Zhang J, et al. Antagonizing HMGB1 inhibits proteinuria in a murine model of lupus-like disease[J]. Immunol 2007,178:131-24.

© 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