摘要
研究背景
系统性红斑狼疮(Systemic lupus erythematosus, SLE)是一种典型的自身免疫性疾病,以大量自身抗体产生、补体激活和免疫复合物沉积为主要特征,导致组织和器官损伤。目前SLE的病因仍未阐明,也无特异性的治疗方法。只有深入研究其发病机制,才能有望寻找到更有效的治疗策略。
已有研究表明,辅助性T细胞(T help cells, Th)产生的细胞因子在SLE及其它自身免疫疾病的发病机制中起着重要作用。活化的自身反应性Th细胞促使B细胞分化、产生自身抗体。包含自身抗体的免疫复合物和炎性Th细胞导致组织和器官的损伤。人类自身免疫性疾病的动物模型,包括实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis, EAE)和胶原诱导的关节炎(collagen-induced arthritis, CIA)被认为是典型的CD4+Th1细胞介导的疾病。然而,以往关于Th1细胞功能和自身免疫性炎症的文献存在矛盾。IL-12、γ干扰素(Interferon-gamma, IFN-γ)是促使Th0向Th1转化并活化Th1功能的关键细胞因子。有研究发现,缺乏IL-12/ IFN-γ的小鼠能够发生EAE和CIA。而缺乏IL-12和IL-23(一种在Th17分化形成过程中起重要作用的关键因子)所共有的p40亚单位的小鼠不会发生EAE和CIA,而且给小鼠注入针对这种p40亚单位的抗体后,明显抑制了这种自身免疫性疾病的发展。
最近的一项关于IL-23在Th17中的作用研究解决了以往研究存在的矛盾。Th17是新近发现的一种Th细胞的亚型,能够选择性地分泌一些前炎症细胞因子,主要为IL-17,因此命名为Th17细胞。一些研究利用基因敲除或是针对IL-23的p19和p40亚单位的抗体的动物模型实验发现,IL-23而非IL-12在自身免疫性疾病的发病机制中起着重要作用。首先,缺乏IL-23 p19而含IL-12p35的小鼠不会发生EAE和CIA;其次,应用抗-IL-23p19亚单位的单克隆抗体(mAb)或抗-IL-12p40 mAb抑制了多种炎症性细胞因子(如,IL-17、IL-6、IFN-γ、IL-1β和TNF)的产生,从而缓解了EAE。最后,过继性转移髓磷脂神经胶质细胞特异的产生IL-17的T细胞,而不是产生IFN-γ的T细胞,能够诱发受试鼠发生EAE。与Th17在自身免疫性炎症中的作用类似,IL-17基因敲除小鼠不易发生EAE和CIA,或者是病情较轻。此外,给予CIA和EAE小鼠模型注入抗-IL-17 mAb明显减轻了病情。最近,McGeachy等的一项研究进一步证实,Th17的致病性是由IL-23介导的,而不是TGF-β和IL-6。事实上,不仅IL-23,其受体IL-23R在Th细胞分化为Th17细胞的过程中也起着重要作用。研究表明,编码IL-23R基因区域的基因(single nucleotide polymorphism, SNP)与很多自身免疫性疾病,如crohn’s病、类风湿关节炎(rheumatoid arthritis, RA)和Graves’眼病等,具有相关性。由此可见,IL-23--Th17轴而不是IL-12--Th1轴,在自身免疫性疾病的发生、发展中起着关键作用。
既往研究表明,IL-17能够促进SLE中的炎症反应,诱发一系列前炎症因子(包括IFN-γ、IL-2和单核细胞-集落刺激因子)产生增加。Dong等发现IL-17可能通过诱发IgG、抗dsDNA抗体和外周血单核细胞IL-6的过度产生,从而导致狼疮肾炎。Hsu等进一步证实,IL-17可以通过诱导自发性生发中心形成而促进自身免疫性疾病的发生。
以上这些证据均显示,Th17可能在SLE的发病中起着重要作用。然而目前关于Th17细胞及其相关细胞因子在SLE中的作用研究还很有限,本课题组根据最新的研究进展,提出假设:SLE中可能存在Th17细胞数量的异常及其相关细胞因子表达水平的异常,而且这些异常很可能与疾病活动度,不同的临床和实验室特征有关。深入研究Th17及其细胞因子在SLE发病中的作用,将有望找到新的生物学标记和治疗靶点。
目的
(1)比较SLE患者和正常对照之间,SLE合并肾炎患者和未合并肾炎患者之间血清Th17相关细胞因子(包括IL-17、IL-21、IL-22、IL-23)表达水平差异,分析SLE患者血清Th17相关细胞因子与SLE疾病活动指数及临床与实验室特征的关联,并探讨SLE患者血清Th17细胞因子水平之间的关联。
(2)比较SLE患者和正常对照之间,SLE合并肾炎患者和未合并肾炎患者之间Th17通路相关细胞因子与趋化因子mRNA表达水平差异。
方法
病例来自于安徽医科大学附属省立医院风湿免疫科和安徽医科大学第一附属医院风湿免疫科的SLE患者。SLE的诊断依据1997年美国风湿病学会修订的SLE分类标准。正常对照为:不符合SLE诊断标准;无重大疾病史;未长期使用激素或免疫抑制剂;本人或直系的亲属无自身免疫性疾病。收集57例SLE患者,30例正常对照用于血清Th17相关细胞因子(包括IL-17、IL-21、IL-22、IL-23)表达水平。另外收集25例SLE患者、15例正常对照用于Th17相关细胞因子mRNA表达水平检测。问卷调查收集一般情况和临床资料,并进行SLE疾病活动指数(SLE disease activity index,SLEDAI)评分。获得研究对象知情同意后,抽取外周静脉血。
采用ELISA试剂盒检测SLE患者和正常对照之间,SLE合并肾炎患者和未合并肾炎患者之间血清Th17相关细胞因子(包括IL-17、IL-21、IL-22、IL-23)表达水平。
采用Th17 Pathway Q-PCR array检测Th17相关细胞因子mRNA表达水平。采用SPSS 10.0进行统计分析。
结果
(1)SLE与正常对照之间、SLE肾炎和非肾炎患者之间、活动期和非活动期SLE患者之间血清Th17相关细胞因子(包括IL-17、IL-21、IL-22、IL-23)表达水平的比较
与正常对照相比,SLE患者血清IL-17水平显著升高(P<0.001),血清IL-21(P=0.026)和IL-22(P<0.001)水平显著降低,IL-23水平无显著变化(P=0.348);SLE肾炎和非肾炎患者之间、活动期和非活动期SLE患者之间均无显著性差异。(2)SLE患者血清Th17相关细胞因子(包括IL-17、IL-21、IL-22、IL-23)表达水平与SLE疾病活动指数(SLEDAI)之间的关系
SLE患者血清IL-17、IL-21、IL-22、IL-23水平与SLEDAI均无显著性关联(P>0.05)。
(3)SLE患者血清Th17相关细胞因子与临床与实验室检查指标的关联SLE患者血清IL-21水平与患者的贫血存在显著关联,存在贫血的患者血清IL-21水平显著降低(P=0.03);SLE患者血清IL-22水平与血尿存在显著关联,在有血尿的患者中血清IL-22水平显著降低(P=0.05);SLE患者血清IL-23水平与IgG升高之间存在显著关联,在IgG升高的患者中血清IL-23水平显著升高(P=0.03)。未发现血清IL-17水平与SLE患者的临床和实验室特征之间存在关联。
(4)SLE患者血清Th17细胞因子水平之间的关联
血清IL-17与IL-23呈显著相关(r=0.461,P<0.001);血清IL-21与IL-23之间呈显著相关(r=0.320,P=0.015);其他细胞因子之间未发现显著相关。(5)SLE患者和正常对照之间,SLE合并肾炎患者和未合并肾炎患者之间Th17通路相关细胞因子与趋化因子mRNA表达水平比较
与正常对照相比,SLE患者CCL2, CXCL1, ICAM1, IL10, IL21, IL5, IL8, ISG20, JAK2, MMP9, SOCS3的mRNA表达水平显著上调,CD28, CD4, CD40LG, S1PR1, IL17RE, IL23R, RORC的mRNA表达水平显著下调;与SLE非肾炎患者相比,SLE合并肾炎患者JAK2的的mRNA表达水平显著下调。
结论
SLE患者存在Th17通路相关因子血清水平表达异常以及mRNA水平表达异常,表明Th17通路调节异常可能在SLE的发病中起重要作用,进一步证实了我们前期提出的观点——Th17可能作为SLE的一个潜在治疗靶点。
Backgroud
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by a diverse array of autoantibody production, complement activation and immune complex deposition, causing tissue and organ damage. The etiology and pathogenetic mechanisms of SLE have not been clearly elucidated. At present, there is no cure for SLE and treatment is aimed at controlling symptoms; despite this, exploration into the disease mechanisms might lead to the development of improved therapeutic approaches.
Abnormal T helper (Th) cell cytokines have been shown to be involved in the pathogenesis of SLE and other autoimmune diseases. Activated autoreactive Th cells provide aid to autoreactive B cells to differentiate and produce pathogenic autoantibodies. Both autoantibody-containing immune complexes and direct effects of inflammatory Th cells promote tissue injury and organ damage. Models of human autoimmune disease, including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA), have been recognized as prototypic Th1 CD4+ T cell-mediated diseases. Nevertheless, in these studies there are contradictions regarding the link between Th1 function and autoimmune inflammation. Mice that lacked components of the interleukin (IL)-12–interferon (IFN)-γaxis developed EAE and CIA of normal or even increased magnitude. By contrast, mice that lacked the p40 subunit shared by IL-12 and IL-23 were resistant to EAE and CIA, and antibodies against this p40 subunit significantly suppressed the development of autoimmune disease.
These paradoxes have now been clarified by the recent discovery of the functional activities of IL-23 in the development of Th17 cells, a novel subset of Th cells that selectively secrete several proinflammatory cytokines, mainly IL-17. The definitive role of IL-23, but not IL-12, in the pathogenesis of autoimmune disease came from several studies using gene knockout mice or antibodies against the p19 and p40 subunits of IL-23 in autoimmune murine models. Firstly, mice lacking IL-23p19 but not IL-12p35 were shown to be resistant to EAE and CIA. Secondly, administration of anti-IL-23p19 monoclonal antibody (mAb) or anti-IL-12p40 mAb inhibited the production of multiple inflammatory cytokines, including IL-17, IL-6, IFN-γ, IL-1[beta] and TNF and, as a result, ameliorated EAE. Thirdly, adoptive transfer of myelin oligodendrocyte-specific IL-17-producing T cells but not IFN-γ-producing T cells induced EAE in recipient mice. Consistent with the role of Th17 lineage in autoimmune inflammation, IL-17-deficient mice either were resistant or showed reduced severity to EAE and CIA induction. Moreover, administration of anti-IL-17 mAb in CIA and EAE models significantly reduced disease severity. Recently, McGeachy et al further established that full acquisition of pathogenic function by effector Th17 cells is mediated by IL-23 rather than by transforming growth factor-[beta] and IL-6. In fact, not only IL-23 but also its receptor (IL-23R) guide T cells toward the Th17 phenotype. Single nucleotide polymorphisms in regions coding for IL-23R have been shown to be associated with several autoimmune diseases, including Crohn's disease, rheumatoid arthritis and Graves' ophthalmopathy. Collectively, the IL-23–Th17 axis, rather than the IL-12–Th1 axis, is crucial to autoimmune disease development.
IL-17 is the defining cytokine of Th17, IL-17 has been implicated in a variety of autoimmune diseases, such as EAE and CIA are directly linked with IL-17 production, largely through demonstrations that the cytokine is overexpressed in these conditions. Moreover, the absence or neutralization of this cytokine can block the initiation of disease. Previous studies have shown that the increased production of IL-17 exert a synergistic effect on the inflammatory reactions to induce increased production of a panel of proinflammatory cytokines including IFN-γ, IL-2 and granulocyte monocyte-colony stimulating factor in SLE. Dong et al. found that IL-17 might play an important role in the pathogenesis of lupus nephritis through the induction of IgG, anti-dsDNA overproduction and IL-6 overexpression of PBMC in patients with lupus nephritis (LN). Recently, Hsu et al. further confirmed that IL-17 can promote autoimmune disease by promoting the formation of spontaneous germinal centers. These data suggest that Th17 may play an important role in SLE.
Objective
(1) To compare the serum Th17 related cytokines (including IL-17, IL-21, IL-22, IL-23) levels between patients with SLE and normal controls, to analyze it’s associations with activity and disease manifestations; additionally, to explore the correlations within the 4 Th17 related cytokines.
(2) To compare the mRNA expression levels of Th17 pathway related genes between SLE patients and normal controls, as well as the difference between SLE patients with nephritis and those without nephritis.
Methods
SLE patients were recruited at the Department of Rheumatology of Auhui Provincial Hospital and First Affiliated Hospital, Anhui Medical University. Diagnosis of SLE was established according to the 1997 revised criteria of American College Rheumatology (ACR). Disease activity was evaluated using the SLE Disease Activity Index (SLEDAI) score. Age and sex-matched healthy volunteers were included as normal controls, all of them were without evidence of rheumatologic conditions. In total, 57 SLE patients and 30 normal controls were included in the study of serum Th17 related cytokines (including IL-17, IL-21, IL-22, IL-23) levels; 25 SLE patients and 15 normal controls were included in the evaluation of the mRNA expression levels of Th17 pathway related genes. The demographic and clinical data were collected by questionnaire or hospital records. Before study, all subjects gave their written consent to participate. Venous blood from all studied subjects was collected in tube.
The serum levels of Th17 related cytokines were detected by ELISA. The mRNA levels of Th17-related cytokines using Quantitative RT-PCR Array (Human Th17 for Autoimmunity & Inflammation PCR Array). The data were analyzed by Statistical Package for Social Sciences version 10.01 software (SPSS, Chicago, IL, USA).
Results
(1) Comparisons of serum Th17 related cytokines (including IL-17, IL-21, IL-22, IL-23) levels between patients with SLE and normal controls, SLE patients with nephritis and SLE patients without nephritis, more active SLE and less active SLE: compared with normal controls, the serum IL-17 level was significantly increased (P<0.001), the serum IL-21 (P=0.026) and IL-22 (P<0.001) level were significantly decreased. No significant differences were found between SLE patients with nephritis and SLE patients without nephritis, more active SLE and less active SLE.
(2) Correlations between serum Th17 related cytokines (including IL-17, IL-21, IL-22, IL-23) levels and SLEDAI: no significant association were found between serum Th17 related cytokines (including IL-17, IL-21, IL-22, IL-23) levels and SLEDAI.
(3) Association of serum Th17 related cytokines (including IL-17, IL-21, IL-22, IL-23) levels and clinical data of SLE patients: serum IL-21 level were significantly associated with anemia (P=0.030) ; serum IL22 level were significantly associated with blood urine (P=0.05) ; serum IL-23 level were significantly associated with elevation of IgG (P=0.03) ; no significant association were found between serum IL-17 level and clinical data.
(4) Correlations within serum Th17 related cytokines (including IL-17, IL-21, IL-22, IL-23) levels: serum IL-17 level were significantly associated with serum IL-23 level (r=0.461,P<0.001); serum IL-21 level were significantly associated with serum IL-23 level (r=0.320,P=0.015).
(5) Comparisons of the mRNA expression levels of Th17 pathway related genes between SLE patients and normal controls, as well as the difference between SLE patients with nephritis and those without nephritis: compared with normal controls, mRNA expression of 11 genes (CCL2, CXCL1, ICAM1, IL10, IL21, IL5, IL8, ISG20, JAK2, MMP9, SOCS3) were upregulated and 7 genes (CD28, CD4, CD40LG, S1PR1, IL17RE, IL23R, RORC) were downregulated in SLE patients; compared with SLE patients without nephritis, mRNA expression of JAK2 was downregulated in SLE patients with nephritis.
Conclusions
In conclusion, SLE patients and normal controls showed different serum Th17 related cytokines levels; in addition, SLE patients have distinct Th17 pathway gene expression profiles, indicating that Th17 pathway is indeed implicated in the pathogenesis of SLE, which further support our viewpoint that Th17 cells might be a promising therapeutic target for SLE.
引文
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[1]叶冬青(主编).红斑狼疮.北京:人民卫生出版社, 2006.
[2] Cook HT, Botto M. Mechanisms of Disease: the complement system and the pathogenesis of systemic lupus erythematosus. Nat Clin Pract Rheumatol. 2006;2:330-7.
[3] Datta SK, Zhang L, Xu L. T-helper cell intrinsic defects in lupus that break peripheral tolerance to nuclear autoantigens. J Mol Med 2005;83:267-78.
[4] Harrington LE, Hatton RD, Mangan PR et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6: 1123–32.
[5] Park H, Li Z, Yang XO et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6: 1133–41.
[6] Pernis AB. Th17 cells in rheumatoid arthritis and systemic lupus erythematosus. J Intern Med 2009;265:644-52.
[7] Wong CK, Ho CY, Li EK, et al. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 2000;9:589–93.
[8] Wong CK, Lit LC, Tam LS, et al. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol 2008;127:385-93.
[9] Zhao XF, Pan HF, Yuan H, et al. Increased serum interleukin 17 in patients with systemic lupus erythematosus. Mol Biol Rep 2010; 37:81-5.
[10] Kwan BC, Tam LS, Lai KB, et al. The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus. Rheumatology (Oxford). 2009; 48:1491-7.
[11] Kang HK, Liu M, Datta SK. Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatoryT cells and contraction of inflammatory Th17 cells. J Immunol 2007;178:7849-58.
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