英夫利西单抗治疗克罗恩病黏膜愈合的血清差异蛋白质表达研究
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摘要
目的:寻找与英夫利西单抗(infliximab,IFX)治疗克罗恩病(Crohn’s disease,CD)黏膜愈合(mucosal healing,MH)相关的血清蛋白质生物标志物。方法:采集7例经IFX治疗获得MH的CD患者治疗前(0周,A组)和治疗后(14周,B组)的血清,以及7例未获得MH的CD患者(0周为C组,14周为D组)的血清。采用荧光标记双向差异凝胶电泳的方法,比较A组与B组之间、C组与D组之间、A组与C组之间以及B组与D组之间的蛋白质组学差异,并对差异表达的蛋白质斑点进行基质辅助激光解吸/电离飞行时间串联质谱初步鉴定和生物信息学分析。结果:(1)A组与B组、C组与D组、A组与C组以及B组与D组之间比较分别存在36、3、10和31个差异表达的蛋白质斑点,共计存在44个显著差异表达的蛋白质斑点。(2)上述各组之间的差异斑点分别初步鉴定出17、2、2和15种蛋白质,共计存在19种差异表达的蛋白质,包括载脂蛋白E、载脂蛋白A-I、补体因子H等。(3)基于STRING数据库绘制了蛋白质网状功能图。结论:IFX治疗获得MH的CD患者治疗前后的血清蛋白质表达谱存在差异,获得MH和未获得MH的患者血清表达谱亦存在差异,其中19种蛋白质有可能成为预测CD患者使用IFX获得MH的生物标志物。
AIM: To identify the serum proteins that might serve as biomarkers for predicting mucosal healing( MH) in the patients with Crohn's disease( CD) treated with infliximab( IFX). METHODS: We collected serum samples before treatment( 0 week,group A) and 14 weeks after treatment( group B) from 7 CD patients with IFX treatment who had achieved MH,as well as the serum samples from 7 CD patients who had not achieved MH( 0 week,group C; 14 weeks,group D). Two-dimensional fluorescence difference gel electrophoresis was applied to analyze and compare the results of serum profiles between groups A and B,C and D,A and C,B and D. Matrix-assisted laser desorption / ionization time-of-flight tandem mass spectrometry and bioinformatics tools were utilized to preliminarily identify and figure out the differentially expressed proteins. RESULTS:( 1) In total,there were 44 differentially expressed spots,36,3,10 and 31 differentially expressed spots were detected while comparing A with B,C with D,A with C and B with D,respectively.( 2) Among those spots,17,2,2 and 15 proteins were identified,respectively. In total,there were 19 differentially expressed proteins,including apolipoprotein E,apolipoprotein A-I,complement factor H,and so on.( 3) Protein functional association networks were carried out based on STRING database. CONCLUSION: The serum protein profiles obviously change after IFX treatment in MH CD patients,and the serum protein profiles of MH patients are different from that of nonMH patients after IFX treatment. The 19 proteins we identified may serve as potential biomarkers for predicting MH in CD patients with IFX treatment.
AIM: To identify the serum proteins that might serve as biomarkers for predicting mucosal healing( MH) in the patients with Crohn's disease( CD) treated with infliximab( IFX). METHODS: We collected serum samples before treatment( 0 week,group A) and 14 weeks after treatment( group B) from 7 CD patients with IFX treatment who had achieved MH,as well as the serum samples from 7 CD patients who had not achieved MH( 0 week,group C; 14 weeks,group D). Two-dimensional fluorescence difference gel electrophoresis was applied to analyze and compare the results of serum profiles between groups A and B,C and D,A and C,B and D. Matrix-assisted laser desorption / ionization time-of-flight tandem mass spectrometry and bioinformatics tools were utilized to preliminarily identify and figure out the differentially expressed proteins. RESULTS:( 1) In total,there were 44 differentially expressed spots,36,3,10 and 31 differentially expressed spots were detected while comparing A with B,C with D,A with C and B with D,respectively.( 2) Among those spots,17,2,2 and 15 proteins were identified,respectively. In total,there were 19 differentially expressed proteins,including apolipoprotein E,apolipoprotein A-I,complement factor H,and so on.( 3) Protein functional association networks were carried out based on STRING database. CONCLUSION: The serum protein profiles obviously change after IFX treatment in MH CD patients,and the serum protein profiles of MH patients are different from that of nonMH patients after IFX treatment. The 19 proteins we identified may serve as potential biomarkers for predicting MH in CD patients with IFX treatment.
引文
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[10]Haberman Y,Tickle TL,Dexheimer PJ,et al.Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature[J].J Clin Invest,2014,124(8):3617-3633.
[11]Gazouli M,Anagnostopoulos AK,Papadopoulou A,et al.Serum protein profile of Crohn’s disease treated with infliximab[J].J Crohns Colitis,2013,7(10):e461-e470.
[12]曾花,蔡道章,陈郁鲜,等.人膝骨关节炎血清生物学标志物的筛选[J].中国病理生理杂志,2012,28(5):884-888.
[2]Schnitzler F,Fidder H,Ferrante M,et al.Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn’s disease[J].Inflamm Bowel Dis,2009,15(9):1295-1301.
[3]中华医学会消化病学分会炎症性肠病学组.炎症性肠病诊断与治疗的共识意见(2012年·广州)[J].中华内科杂志,2012,51(10):818-831.
[4]Hebuterne X,Lemann M,Bouhnik Y,et al.Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn’s disease following treatment with certolizumab pegol[J].Gut,2013,62(2):201-208.
[5]Renz H,von Mutius E,Brandtzaeg P,et al.Gene-environment interactions in chronic inflammatory disease[J].Nat Immunol,2011,12(4):273-277.
[6]Colombel JF,Sandborn WJ,Reinisch W,et al.Infliximab,azathioprine,or combination therapy for Crohn’s disease[J].N Engl J Med,2010,362(15):1383-1395.
[7]Levy E,Rizwan Y,Thibault L,et al.Altered lipid profile,lipoprotein composition,and oxidant and antioxidant status in pediatric Crohn disease[J].Am J Clin Nutr,2000,71(3):807-815.
[8]Takeuchi T,Nakanishi T,Tabushi Y,et al.Serum protein profile of rheumatoid arthritis treated with anti-TNF therapy(infliximab)[J].J Chromatogr B Analyt Technol Biomed Life Sci,2007,855(1):66-70.
[9]Serada S,Fujimoto M,Ogata A,et al.i TRAQ-based proteomic identification of leucine-rich alpha-2 glycoprotein as a novel inflammatory biomarker in autoimmune diseases[J].Ann Rheum Dis,2010,69(4):770-774.
[10]Haberman Y,Tickle TL,Dexheimer PJ,et al.Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature[J].J Clin Invest,2014,124(8):3617-3633.
[11]Gazouli M,Anagnostopoulos AK,Papadopoulou A,et al.Serum protein profile of Crohn’s disease treated with infliximab[J].J Crohns Colitis,2013,7(10):e461-e470.
[12]曾花,蔡道章,陈郁鲜,等.人膝骨关节炎血清生物学标志物的筛选[J].中国病理生理杂志,2012,28(5):884-888.