糖皮质激素治疗对系统性红斑狼疮患者外周单个核细胞TLR7和TLR9表达的影响及相关因素分析
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摘要
目的探讨糖皮质激素治疗对系统性红斑狼疮(SLE)患者外周血单个核细胞(PBMC)中Toll样受体(TLR7、TLR9)转录水平的影响及其可能的影响因素。方法收集40例SLE患者(激素治疗组24例,初次诊断组16例)以及健康对照组(19例)的临床资料和外周血,分离PBMC,通过定量PCR法检测TLR7和TLR9基因的转录水平,通过统计学分析组间的差异和相关变量分析。结果激素治疗组和初次诊断组SLE患者PBMC的TLR7和TLR9基因转录水平均高于健康对照组,差异具有统计学意义(P <0.05)。初次诊断组TLR7表达高于激素治疗组(P <0.05),但TLR9的增高差异无统计学意义。TLR7和TLR9的转录水平均与SLE的活动指数成正相关关系。TLR7还与抗Sm抗体滴度正相关,而TLR9与年龄、抗dsDNA抗体滴度、补体C4以及糖皮质激素治疗日均剂量等因素相关。通过线性回归模型进一步筛选变量提示TLR7主要与SLE活动指数相关,而TLR9的可能相关变量依次为SLE活动指数、补体C4和糖皮质激素治疗剂量。结论 TLR7和TLR9基因转录增高与SLE的病情活动具有正相关关系。影响TLR9表达的主要因素还包括近期糖皮质激素治疗剂量和补体C4水平。
Objective To investigate the effect of glucocorticoid therapy on the transcriptional level of Toll-like receptors(TLR7,TLR9)in peripheral blood mononuclear cells of patients with systemic lupus erythematosus(SLE)and its possible influencing factors. Methods 40 patients with SLE(24 under treatment and 16 newly diagnosed)and 19 healthy controls were recruited. Peripheral blood mononuclear cells(PBMCs)were isolated and the transcriptional expression of TLR7 and TLR9 were measured by quantitative PCR. Their expression levels were statistically analyzed with clinical data to achieve candidate relative factors. Results The TLR7 and TLR9 transcriptional levels of PBMCs in the glucocorticoid-treated group and the newly diagnosed group were significantly higher than those in the healthy control(P < 0.05). The expression of TLR7 but not TLR9 were significantly lower in the treated group than the newly diagnosed group(P < 0.05). The transcriptional levels of TLR7 and TLR9 were positively correlated with SLE disease activity index(SLEDAI). TLR7 was also positively correlated with antiSmith antibody titer. TLR9 was associated with age,anti-dsDNA antibody titer,complement C4,and glucocorticoid dose. In the multivariate model,TLR7 was associated with SLEDAI,while TLR9 was associated with SLEDAI,complement C4 and glucocorticoid dose. Conclusions The expression of TLR7 and TLR9 is positively correlated with disease activity in SLE. Other related factors including glucocorticoid dose and complement C4 levels are involved in the TLR9 expression.
Objective To investigate the effect of glucocorticoid therapy on the transcriptional level of Toll-like receptors(TLR7,TLR9)in peripheral blood mononuclear cells of patients with systemic lupus erythematosus(SLE)and its possible influencing factors. Methods 40 patients with SLE(24 under treatment and 16 newly diagnosed)and 19 healthy controls were recruited. Peripheral blood mononuclear cells(PBMCs)were isolated and the transcriptional expression of TLR7 and TLR9 were measured by quantitative PCR. Their expression levels were statistically analyzed with clinical data to achieve candidate relative factors. Results The TLR7 and TLR9 transcriptional levels of PBMCs in the glucocorticoid-treated group and the newly diagnosed group were significantly higher than those in the healthy control(P < 0.05). The expression of TLR7 but not TLR9 were significantly lower in the treated group than the newly diagnosed group(P < 0.05). The transcriptional levels of TLR7 and TLR9 were positively correlated with SLE disease activity index(SLEDAI). TLR7 was also positively correlated with antiSmith antibody titer. TLR9 was associated with age,anti-dsDNA antibody titer,complement C4,and glucocorticoid dose. In the multivariate model,TLR7 was associated with SLEDAI,while TLR9 was associated with SLEDAI,complement C4 and glucocorticoid dose. Conclusions The expression of TLR7 and TLR9 is positively correlated with disease activity in SLE. Other related factors including glucocorticoid dose and complement C4 levels are involved in the TLR9 expression.
引文
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[15]张伟迅,朱俊萍,何秋水. Toll样受体7作为新靶点在过敏性及自身免疫性疾病中的研究进展[J].国际免疫学杂志,2017,40(2):210-215.
[16] WONG C K,WONG P T,TAM L S,et al. Activation profile of Toll-like receptors of peripheral blood lymphocytes in patients with systemic lupus erythematosus[J]. Clin Exp Immunol,2010,159(1):11-22.
[17] GHALY N R,KOTB N A,NAGY H M,et al. Toll-like receptor 9 in systemic lupus erythematosus,impact on glucocorticoid treatment[J]. J Dermatolog Treat,2013,24(6):411-417.
[18] RAAFAT,II,EL GUINDY N,SHAHIN R M H,et al. Tolllike receptor 7 gene single nucleotide polymorphisms and the risk for systemic lupus erythematosus:A case-control study[J].Z Rheumatol,2018,77(5):416-420.
[19] MAHTO H,PANDA A K. TLR9(rs187084)polymorphism is neither under selection pressure and nor predisposed to systemic lupus erythematosus[J]. Lupus,2018,27(3):520-521.
[20] SKONIECZNA K,WOZNIACKA A,CZAJKOWSKI R,et al. X-linked TLR7 gene polymorphisms are associated with diverse immunological conditions but not with discoid lupus erythematosus in Polish patients[J]. Postepy Dermatol Alergol,2018,35(1):26-32.
[21] WANG D,ZHANG C,ZHOU Z,et al. TLR9 polymorphisms and systemic lupus erythematosus risk:An update meta-analysis study[J]. Rheumatol Int,2016,36(4):585-595.
[22] LORENZ G,LECH M,ANDERS H J. Toll-like receptor activation in the pathogenesis of lupus nephritis[J]. Clin Immunol,2017,185:86-94.
[23] LIU Y,SETO N L,CARMONA-RIVERA C,et al. Accelerated model of lupus autoimmunity and vasculopathy driven by tolllike receptor 7/9 imbalance[J]. Lupus Sci Med,2018,5(1):e000259.
[24] YUAN Y,YANG M,WANG K,et al. Excessive activation of the TLR9/TGF-beta1/PDGF-B pathway in the peripheral blood of patients with systemic lupus erythematosus[J]. Arthritis Res Ther,2017,19(1):70.
[25] BOSSALLER L,CHRIST A,PELKA K,et al. TLR9 deficiency leads to accelerated renal disease and myeloid lineage abnormalities in pristane-induced murine lupus[J]. J Immunol,2016,197(4):1044-1053.
[26] GUIDUCCI C,GONG M,XU Z,et al. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus[J]. Nature,2010,465(7300):937-941.
[27] ROZKOVA D,HORVATH R,BARTUNKOVA J,et al. Glucocorticoids severely impair differentiation and antigen presenting function of dendritic cells despite upregulation of Toll-like receptors[J]. Clin Immunol,2006,120(3):260-271.
[2] CHEN J Q,SZODORAY P,ZEHER M. Toll-like receptor pathways in autoimmune diseases[J]. Clin Rev Allergy Immunol,2016,50(1):1-17.
[3] ZHOU Z,MA J,XIAO C,et al. Phenotypic and functional alterations of pDCs in lupus-prone mice[J]. Sci Rep,2016,6:20373.
[4] MIYAKE K,SHIBATA T,OHTO U,et al. Mechanisms controlling nucleic acid-sensing Toll-like receptors[J]. Int Immunol,2018,30(2):43-51.
[5]刘江琦,刘志强,邱书奇. MicroRNA-150免疫调节作用的研究进展[J].实用医学杂志,2017,33(19):163-165.
[6] CELHAR T,MAGALHAES R,FAIRHURST A M. TLR7 and TLR9 in SLE:when sensing self goes wrong[J]. Immunol Res,2012,53(1-3):58-77.
[7] KOMATSUDA A,WAKUI H,IWAMOTO K,et al. Up-regulated expression of Toll-like receptors mRNAs in peripheral blood mononuclear cells from patients with systemic lupus erythematosus[J]. Clin Exp Immunol,2008,152(3):482-487.
[8] DEVARAPU S K,ANDERS H J. Toll-like receptors in lupus nephritis[J]. J Biomed Sci,2018,25(1):35.
[9] NASR A S,FAWZY S M,GHEITA T A,et al. Expression of Tolllike receptors 3 and 9 in Egyptian systemic lupus erythematosus patients[J]. Z Rheumatol,2016,75(5):502-507.
[10] KLONOWSKA-SZYMCZYK A,WOLSKA A,ROBAK T,et al.Expression of toll-like receptors 3,7,and 9 in peripheral blood mononuclear cells from patients with systemic lupus erythematosus[J]. Mediators Inflamm,2014,2014:381418.
[11]史家欣,李家树.糖皮质激素抗炎作用机制的研究进展[J].实用医学杂志,2014,30(6):983-984.
[12] GIES V,SCHICKEL J N,JUNG S,et al. Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus[J]. JCI Insight,2018,3(5). pii:96795.
[13] TSUBATA T. Negative regulation of B cell responses and self-tolerance to RNA-related lupus self-antigen[J]. Proc Jpn Acad Ser B Phys Biol Sci,2018,94(1):35-44.
[14] JENKS S A,CASHMAN K S,ZUMAQUERO E,et al. Distinct effector B cells induced by unregulated toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus[J]. Immunity,2018,49(4):725-739 e6.
[15]张伟迅,朱俊萍,何秋水. Toll样受体7作为新靶点在过敏性及自身免疫性疾病中的研究进展[J].国际免疫学杂志,2017,40(2):210-215.
[16] WONG C K,WONG P T,TAM L S,et al. Activation profile of Toll-like receptors of peripheral blood lymphocytes in patients with systemic lupus erythematosus[J]. Clin Exp Immunol,2010,159(1):11-22.
[17] GHALY N R,KOTB N A,NAGY H M,et al. Toll-like receptor 9 in systemic lupus erythematosus,impact on glucocorticoid treatment[J]. J Dermatolog Treat,2013,24(6):411-417.
[18] RAAFAT,II,EL GUINDY N,SHAHIN R M H,et al. Tolllike receptor 7 gene single nucleotide polymorphisms and the risk for systemic lupus erythematosus:A case-control study[J].Z Rheumatol,2018,77(5):416-420.
[19] MAHTO H,PANDA A K. TLR9(rs187084)polymorphism is neither under selection pressure and nor predisposed to systemic lupus erythematosus[J]. Lupus,2018,27(3):520-521.
[20] SKONIECZNA K,WOZNIACKA A,CZAJKOWSKI R,et al. X-linked TLR7 gene polymorphisms are associated with diverse immunological conditions but not with discoid lupus erythematosus in Polish patients[J]. Postepy Dermatol Alergol,2018,35(1):26-32.
[21] WANG D,ZHANG C,ZHOU Z,et al. TLR9 polymorphisms and systemic lupus erythematosus risk:An update meta-analysis study[J]. Rheumatol Int,2016,36(4):585-595.
[22] LORENZ G,LECH M,ANDERS H J. Toll-like receptor activation in the pathogenesis of lupus nephritis[J]. Clin Immunol,2017,185:86-94.
[23] LIU Y,SETO N L,CARMONA-RIVERA C,et al. Accelerated model of lupus autoimmunity and vasculopathy driven by tolllike receptor 7/9 imbalance[J]. Lupus Sci Med,2018,5(1):e000259.
[24] YUAN Y,YANG M,WANG K,et al. Excessive activation of the TLR9/TGF-beta1/PDGF-B pathway in the peripheral blood of patients with systemic lupus erythematosus[J]. Arthritis Res Ther,2017,19(1):70.
[25] BOSSALLER L,CHRIST A,PELKA K,et al. TLR9 deficiency leads to accelerated renal disease and myeloid lineage abnormalities in pristane-induced murine lupus[J]. J Immunol,2016,197(4):1044-1053.
[26] GUIDUCCI C,GONG M,XU Z,et al. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus[J]. Nature,2010,465(7300):937-941.
[27] ROZKOVA D,HORVATH R,BARTUNKOVA J,et al. Glucocorticoids severely impair differentiation and antigen presenting function of dendritic cells despite upregulation of Toll-like receptors[J]. Clin Immunol,2006,120(3):260-271.
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