Advances in Clinical Medicine
Vol.
14
No.
04
(
2024
), Article ID:
85711
,
8
pages
10.12677/acm.2024.1441316
系统性红斑狼疮患者外周血滤泡辅助性T细胞和滤泡调节性T细胞表达变化及意义
安平,邢倩*
青岛大学附属青岛市市立医院,山东 青岛
收稿日期:2024年3月27日;录用日期:2024年4月21日;发布日期:2024年4月29日

摘要
目的:检测系统性红斑狼疮(SLE)患者外周血中滤泡辅助性T细胞(Tfh)细胞亚型和效应记忆Tfh细胞(Tfh-EM)以及滤泡调节性T细胞(Tfr)的表达,并探讨其在SLE患者发病中的临床意义。方法:流式细胞术分别检测30例SLE患者和26例健康对照的外周血中Tfh (CD4+CXCR5+)细胞亚型Tfh1 (CD4+CXCR5+CXCR3+CCR6−)、Tfh2 (CD4+CXCR5+CXCR3−CCR6−)、Tfh17 (CD4+CXCR5+CXCR3−CCR6+)、Tfh-EM (CD4+CXCR5+ICOS+PD-1+)和Tfr (CD4+CD25+CXCR5+CD127low)的水平。收集入组SLE患者的临床资料及实验室指标,采用酶联免疫吸附试验(ELISA)法检测各组受试者外周血中白细胞介素21 (IL-21)。结果:SLE组与健康对照组相比,外周血中Tfh-EM细胞、Tfh17细胞、总Tfh细胞的表达和外周血中IL-21水平较健康对照组表达升高(P均 < 0.05)。SLE组Tfh/Tfr高于健康对照组(P = 0.020)。外周血Tfh-EM细胞在SLE组中高病情活动度的表达高于低疾病活动度的患者(P = 0.024)。Tfh-EM细胞与抗ds-DNA抗体存在正相关(ρ = 0.444, P = 0.018),Tfr细胞的比率与疾病活动度SLEDAI-2K评分呈负相关(ρ = −0.392, P = 0.039)。结论:SLE组Tfh表达升高致Tfh/Tfr比值失衡,Tfh-EM细胞、Tfh17表达异常可能参与了SLE的发生和发展。
关键词
系统性红斑狼疮,滤泡性T调节细胞,滤泡性T辅助细胞

Changes in Expression and Significance of Follicular Helper T Cells and Follicular Regulatory T Cells in Peripheral Blood of Patients with Systemic Lupus Erythematosus
Ping An, Qian Xing*
Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao Shandong
Received: Mar. 27th, 2024; accepted: Apr. 21st, 2024; published: Apr. 29th, 2024

ABSTRACT
Objective: To investigate the expression of follicular helper T cell (Tfh) subtypes and effector memory Tfh cells (Tfh-EM) in the peripheral blood of patients with systemic lupus erythematosus (SLE), as well as the expression of follicular regulatory T cells (Tfr), and to explore their clinical significance in the onset of SLE. Methods: Flow cytometry was utilized to analyze the levels of Tfh (CD4+CXCR5+) cell subtypes, including Tfh1 (CD4+CXCR5+CXCR3+CCR6−), Tfh2 (CD4+CXCR5+CXCR3− CCR6−), Tfh17 (CD4+CXCR5+CXCR3−CCR6+), Tfh-EM (CD4+CXCR5+ICOS+PD-1+), and Tfr (CD4+CD25+ CXCR5+CD127low) in the peripheral blood of 30 SLE patients and 26 healthy controls. Clinical data and laboratory parameters of the SLE patients were collected, and enzyme-linked immunosorbent assay (ELISA) was employed to measure the levels of interleukin-21 (IL-21) in the peripheral blood of each participant. Results: The expression of Tfh-EM cells, Tfh17 cells, total Tfh cells in peripheral blood and the level of IL-21 in peripheral blood were elevated in the SLE group compared to healthy controls (P all < 0.05). Tfh/Tfr was higher in the SLE group than in healthy controls (P = 0.020), Peripheral blood Tfh-EM cells were expressed higher in the SLE group with high disease activity than in patients with low disease activity (P = 0.024). There was a positive correlation between Tfh-EM cells and anti-ds-DNA antibodies (ρ = 0.444, P = 0.018), and the ratio of Tfr cells was negatively correlated with the SLEDAI-2K score of disease activity (ρ = −0.392, P = 0.039). Conclusion: Elevated Tfh expression in the SLE group resulted in an imbalance of the Tfh/Tfr ratio, and abnormal expression of Tfh-EM cells, Tfh17, may be involved in the occurrence and development of SLE.
Keywords:Systemic Lupus Erythematosus, Follicular Regulatory T Cells (Tfr), Follicular Helper T Cells (Tfh)
Copyright © 2024 by author(s) and Hans Publishers Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
1. 背景
系统性红斑狼疮(Systemic lupus erythematosus, SLE)是一种累及多器官的自身免疫性疾病,其特征为自身抗体与自身抗原结合形成免疫复合物沉积造成组织器官的损伤 [1] 。系统性红斑狼疮的确切发病机制仍有待阐明,目前认为自身反应性淋巴细胞参与了系统性红斑狼疮的发病 [2] 。
滤泡辅助T细胞((Follicular helper T cells, Tfh)是CD4+T细胞的一个异质亚群,专门刺激生发中心(Germinal Center, GC)的形成和选择GC中的高亲和性B细胞。它们存在于GC附近,其记忆区也在血液中循环 [3] [4] 。在系统性疾病和其他自身免疫性疾病中,循环Tfh细胞数量的增加已得到证实 [5] 。Tfh细胞进一步分为Tfh1、Tfh2和Tfh17,其在SLE中的作用尚不明确。血液中高表达PD-1和ICOS的CD4+CXCR5+ T细胞亚型视为Tfh效应记忆(T follicular helper effector memory, Tfh-EM)细胞 [6] ,当再次遇到致病原或抗原时,Tfh-EM迅速分化为Tfh细胞并促进抗体的产生,也是通过分泌IL-21辅助B细胞的分化 [7] ,因此Tfh-EM反映了机体的免疫状态并参与自身免疫病的发病机制 [4] [6] [8] [9] 。
最近研究发现的调节性T细胞(Regulatory T Cells Treg)亚群为滤泡调节T细胞(Follicular Regulatory T Cells Tfr) [10] 。Tfr细胞位于GC中,可通过控制Tfh和GC B细胞的数量来抑制GC反应 [3] [11] [12] 。Tfh和Tfr细胞在调节GC反应中的作用相反,它们之间的作用平衡对免疫平衡至关重要。受损的Tfr区间可增强Tfh的活性,导致自反应性B细胞的扩增和自身抗体的产生 [13] 。
本研究检测系统性红斑狼疮患者和健康对照人群外周血中Tfh及其亚群和Tfr细胞的比率及其与疾病活动度、临床指标的相关性,探讨Tfh和Tfr细胞在SLE发病中的可能作用。
2. 研究方法
2.1. 样本收集
本研究选取在青岛市市立医院风湿免疫科收治的30例SLE患者作为SLE组,平均年龄(46.00 ± 10.76),其中男7例,女23例。所有SLE患者均符合美国风湿病学会(ACR) 1997年诊断标准,排除合并其他自身免疫系统疾病者,合并肝、肾、心脏功能障碍等严重疾病者,合并肿瘤、感染性疾病者,不配合医生治疗者,1月内泼尼松 ≥ 100 mg/d或等效能皮质激素治疗 ≥ 14天者。选择同期在本院健康体检的志愿者26例作为对照组,平均年龄(45.73 ± 10.77),其中男6例、女20例。各组受试者性别、年龄无统计学差异。该研究获得青岛市市立医院医学伦理委员会批准,所有参与研究的受试者均签署了同意书。
2.2. 实验方法
采用Elisa试剂盒(武汉云克隆生物有限公司)检测血浆IL-21水平浓度的表达水平,根据试剂商的说明,按照标准流程检测,单位为ρB/(ng·L−1)。
流式细胞术:外周血Tfh及其亚型定义:Tfh:CD4+CXCR5+,Tfh-EM:CD4+CXCR5+ICOS+PD-1+ (PD-1+Tfh),Tfh1:CD4+CXCR5+CXCR3+CCR6−,Tfh2:CD4+CXCR5+CXCR3−CCR6−,Tfh17:CD4+CXCR5+ CXCR3−CCR6+,Tfr:CD4+CD25+CXCR5+CD127low,征得同意后从入组人员处采用受试者3 ml新鲜外周血于EDTA抗凝管中,经过溶血剂处理,分成多管后分别加入CD4-FITC,CD25-PE-Cy7,CXCR5-PE,CD127-APC,CXCR3-PE-Cy5.5,CD185 (CXCR5)-PE和CD278 (ICOS)-PE-Cy5.5等抗体,后经避光孵育,加入pbs,多次离心后,上流式细胞仪(美国贝克曼公司)检测细胞的表达水平。
2.3. 统计学方法
采用SPSS 25.0统计学软件对数据进行处理分析,使用GraphPad Prism9进行作图。正态分布数据以平均数±标准差表示。非正态分布数据以中位数(四分位数间距)表示。两组间比较采用独立样本t检验;不服从正态分布计量资料组间比较采用非参数检验(Mann-Whitney U检验)。相关性分析采用Spearman秩相关分析。P < 0.05认为有统计学意义。
3. 结果
3.1. SLE组与HC组外周血Tfr、Tfh及其其亚群细胞比率比较
SLE与健康对照组外周血Tfr和Tfh及其亚型的细胞比率相比(见表1),外周血中Tfh-EM细胞、Tfh17细胞、总Tfh细胞的比率表达高于健康对照组(P < 0.05),而Tfh1和Tfh2的比率在系统性红斑狼疮患者中较健康对照组降低但无统计学差异。Tfr细胞较健康对照组降低但无统计学差异(P = 0.527)。SLE组外周血中IL-21水平较健康对照组显著升高(P < 0.01)。SLE组Tfh/Tfr高于健康对照组(P = 0.020)。图1示流式细胞术检测SLE患者外周⾎中Tfh及其亚型细胞的代表性流式图。
Table 1. Cell percentage of Tfh, its isoforms and Tfr in peripheral blood [M (IQR)] and expression of IL-21 (M ± SD)
表1. 外周血中Tfh及其亚型和Tfr的细胞百分率[M(IQR)]及IL-21 (M ± SD)的表达
注:*为P < 0.05。
Figure 1. (a) Representative diagram of CD4+T cells in SLE group; (b) Representative diagram of CD4+CXCR5+ICOS+ PD-1+Tfh-EM cells in healthy control group; (c) Representative diagram of CD4+T cells in healthy control group; (d) Representative diagram of CD4+CXCR5+ICOS+PD-1+Tfh-EM cells in healthy control group
图1. (a) SLE组CD4+T细胞代表性图示;(b) 健康对照组CD4+CXCR5+ICOS+PD-1+Tfh-EM细胞代表性图示;(c) 健康对照组CD4+T细胞代表性图示;(d) 健康对照组CD4+CXCR5+ICOS+PD-1+Tfh-EM细胞代表性图示
3.2. SLE组外周血Tfh细胞及其亚群的表达与实验室指标的相关性分析
1) SLE组外周血Tfh-EM细胞的表达在不同SLE病情活动度(SLEDAI-2K评分)患者中的比较:如图2所示,病情活动度根据SLEDA-2K评分,将SLE患者分为2组:无活动和(或)轻度活动(分数为0~9)、中和(或)高度活动(分数 > 9),外周血Tfh-EM细胞的表达SLE中高病情活动度组的患者高于低疾病活动度组的患者(P = 0.024)。
Figure 2. Correlation of Tth-EM cells with disease activity in SLE
图2. Tth-EM细胞与SLE疾病活动度的相关性
2) SLE组外周血Tfh1、Tfh2、Tfh17及亚群细胞百分比与血清免疫球蛋白G、血沉、抗ds-DNA抗体均无明显相关性(P均 > 0.05),SLE组Tfh-EM细胞与抗ds-DNA抗体存在正相关(ρ = 0.444, P = 0.018),Tfr细胞的比率与疾病活动度SLEDAI-2K评分呈负相关(ρ = −0.392, P = 0.039) (见表2)。
Table 2. Correlation analysis of the expression of peripheral blood Tfh cells and their subpopulations and Tfr cells with laboratory indices in the SLE group
表2. SLE组外周血Tfh细胞及其亚群和Tfr细胞的表达与实验室指标的相关性分析
注:*为P < 0.05。
4. 讨论
SLE患者在遗传、环境等多种因素作用下免疫功能紊乱,T细胞减少、B细胞过度增殖,产生大量自身抗体,沉积在皮肤、血管、关节、肾小球等部位导致组织器官损伤 [14] 。Tfh细胞是重要的免疫调节细胞,对小鼠模型和人体样本的研究表明,GC反应增强和狼疮的内脏器官损伤有关,Tfh细胞在系统性红斑狼疮的自身抗体反应中起着重要作用 [15] 。
近年来,在自身免疫病中众多研究显示自身抗体的产生主要发生在生发中心。研究发现一种细胞膜表面稳定表达CXCR5的CD4+T细胞亚型存在于生发中心及外周血中,称为Tfh细胞。Tfh细胞无论是在生发中心还是外周血中都能够促进B细胞成熟分化为浆细胞产生抗体。Tfh细胞已经在多项研究中证明了其临床意义:SLE患者外周血CD4+CXCR5+PD-1+和CD4+CXCR5+ICOS+比例升高,这些细胞比例的升高与抗ds-DNA抗体等自身抗体的产生﹑肾脏损伤相关;类风湿性关节炎患者、多发性硬化症患者、自身免疫性甲状腺病患者外周血中CD4+CXCR5+ICOS+细胞比例升高且与病情进展有关;这些研究都提示,外周血Tfh细胞在自身免疫性疾病病程进展中发挥着重要的作用 [16] [17] [18] [19] 。外周血中Tfh可以分为中央记忆Tfh (Tfh-CM)和效应记忆Tfh (Tfh-EM)之分,ICOS及PD-1均是Tfh重要的功能分子,目前有对Tfh根据ICOS和PD-1的分型进行的相关研究 [3] [20] ,将效应记忆Tfh细胞(Tfh-EM)表型定义为CD4+CXCR5+ICOS+PD-1+,根据国内外研究,将Tfh分为Tfh1、Tfh2及Tfh17三种亚型,能够分别分泌多种细胞因子,如白细胞介素(IL) 4、17、21 [21] 等。但是直到现在,这些Tfh细胞亚型在自身免疫性疾病中的作用及作用机制尚不清楚。
多项研究集中于Tfh细胞在系统性红斑狼疮发病机制中的作用 [22] ,近年来发现的Tfr细胞在调节体液免疫中与Tfh细胞具有相反的作用 [23] 。Tfr细胞是近十年新发现的一种特殊的调节性T细胞(Treg)亚群,作用于生发中心 [10] [24] 。Tfr细胞起源于Treg细胞,与传统的Treg细胞相比,Tfr细胞呈现不同的转录特征,使其成为Treg细胞的一个独特子集,CXCR5的高表达通过CXC趋化因子受体13 (CXCR13)将Tfr细胞导向B细胞滤泡,然后对生发中心(GC)反应进行调控。Tfr细胞具有Tfh细胞和传统Treg细胞的双重特征。由于Tfr细胞的研究相对较新,其生理作用和机制知之甚少,可能在许多自身免疫性疾病中发挥重要作用 [25] 。本研究结果提示可能存在Tfr表达降低,Tfh表达升高致系统性红斑狼疮患者的Tfh/Tfr比率降低,SLE组存在Tfh/Tfr比值失衡的现象,Tfr细胞的比率与疾病活动度SLEDAI-2K评分呈负相关。Tfh-EM细胞的比率与疾病活动度和抗dsDNA抗体滴度呈正相关。
在这项研究中,观察到系统性红斑狼疮患者的CD4+CXCR5+Tfh细胞总数增加,这一观察结果与之前的几项研究一致 [22] [26] 。Tfh细胞及其前体分泌的细胞因子IL-21在系统性红斑狼疮患者中明显升高,这一发现支持了上述结果。研究发现系统性红斑狼疮患者的Tfh-EM细胞水平显著上升,提示PD-1+Tfh在循环中的高表达,提示着其可能是SLE疾病发展的一个原因。在Pd-1缺乏的小鼠中,免疫球蛋白A (IgAs)结合细菌的能力受损,PD-1通过与程序性细胞死亡蛋白配体1 (PD-L1)结合,抑制ICOS信号,从而抑制Tfh细胞的增殖。Pd-1缺乏会导致Tfh细胞数量异常增加,从而导致B细胞过度增殖并产生抗体 [27] 。Tfh-EM在SLE患者中的升高与疾病活动度SLEDAI-2K评分呈正相关性,Tfh-EM可能成为SLE病情活动的评价指标。研究中显示,SLE组外周血Tfh-EM与抗dsDNA抗体有中等相关性,已有证据表明抗dsDNA抗体参与SLE的病理过程 [6] [28] ,提示Tfh-EM细胞可能参与在促进B细胞成熟分化为浆细胞产生抗体的过程中。Tfh17细胞的表达高于健康对照组,这与Mao等人的研究结果一致 [29] ,提示Tfh细胞亚型Tfh17也可能与SLE患者发病机制有关。
5. 研究局限及展望
本研究纳入的SLE患者并非全是初发的,病程长会导致多个器官和组织发生复杂的改变,甚至诱发继发性疾病,继发性疾病引起的变化可能会掩盖系统性红斑狼疮的原发表型,也存在可能DMRADs药物等治疗以后导致的结果,SLE是一种高度异质性的疾病,存在不同的临床表型,导致不同的疾病结局,SLE患者可以根据不同的临床表型进行更加细致的分组,如疾病主要侵犯的器官,病程的长短,将更有助于研究SLE的发病机制,同时这种根据临床表型的分组能够帮助了解SLE的致病途径,研究和这些致病途径相关的靶向治疗。本研究显示,SLE组Tfr细胞较健康对照组降低但无统计学差异,这可能和例数较少有关,需要扩大样本量验证。
综上,目前关于SLE患者外周血中Tfh及Tfr的研究较少,特别是相关亚型的研究,本研究提示外周血中Tfh/Tfr的失衡及效应记忆Tfh可能参与SLE的发病,Tfh的不同亚型与SLE的发病密切相关,关注深入研究Tfh、Tfr及亚型细胞的表达和功能可能为开发SLE新的靶向治疗方案提供思路。
文章引用
安 平,邢 倩. 系统性红斑狼疮患者外周血滤泡辅助性T细胞和滤泡调节性T细胞表达变化及意义
Changes in Expression and Significance of Follicular Helper T Cells and Follicular Regulatory T Cells in Peripheral Blood of Patients with Systemic Lupus Erythematosus[J]. 临床医学进展, 2024, 14(04): 2469-2476. https://doi.org/10.12677/acm.2024.1441316
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NOTES
*通讯作者。