Th17和Th22细胞在吉兰—巴雷综合征发病机制中的作用
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摘要
吉兰-巴雷综合征(GBS)是一种自身免疫介导的炎症性脱髓鞘性多发性周围神经疾病，病变范围波及周围神经系统（PNS）的髓鞘和轴索。GBS的病因尚不清楚，多数患者发病前有感染、手术或疫苗接种史。临床上以快速进展的四肢对称性无力伴有腱反射减弱或消失为特点，脑脊液在发病两周后可表现为典型的“蛋白－细胞分离”现象。部分患者经过静脉注射丙种球蛋白（IVIg）或血浆置换（PE）治疗可缩短病程。GBS常见的类型主要有急性炎症性脱髓鞘性多发性周围神经根病（AIDP），急性运动轴索型神经病（AMAN），急性运动感觉轴索型神经病（AMSAN），Miller-Fisher综合征，急性自主神经病和急性感觉神经病。
既往研究表明，GBS以及其动物模型实验性自身免疫性神经炎（EAN）的免疫炎症反应主要由Th1细胞介导。GBS病人血清中IFN-γ的表达水平明显偏高，而且应用免疫组织化学方法发现GBS病人腓神经活检中IFN-γ表达阳性。近来发现了一种新的辅助性T细胞亚群，Th17细胞，已证实在动物模型和病人中可以介导多种组织炎症和自身免疫反应。阿托伐他汀（atorvastatin）是一种降脂药，具有抗炎症反应的作用，在治疗EAN动物后，Th1和Th17细胞水平明显下降，也证明了Th17细胞在EAN中的致病作用。化合物FTY720通过减少PNS中Th17细胞而减轻EAN的症状。以上结果显示除了Th1和IFN-γ以外，Th17和IL-17在EAN中也介导炎症过程。既往研究证实Th17，Th22细胞和IL-17、IL-22在多种炎症性和自身免疫性疾病的发病机制中起到重要作用，如炎症性肠病（IBD）、类风湿性关节炎（RA）、银屑病和多发性硬化（MS）。
迄今为止，尚未发现有关Th17和Th22细胞在GBS病人的实验研究，因此它们在GBS致病过程中作用不清。在本实验中，我们检测GBS急性期和恢复期病人末稍血Th1、Th17和Th22细胞及其亚群细胞比率和血浆IL-17和IL-22水平，GBS急性期配对脑脊液和血浆样本的IL-17和IL-22水平，同时分别评估这些细胞和细胞因子与GBS残疾程度评分（GDSs）的相关性，从而探索Th17和Th22细胞以及IL-17和IL-22在GBS发病机制中的作用。
材料和方法：自2010年6月至2011年8月期间，我们收集了吉林大学第一临床医院神经内科住院GBS患者29例，其他神经系统免疫炎症性疾病（ONIDs）对照患者32例［包括MS患者15例，病毒性脑炎或脑膜炎（VEM）患者17例］，健康对照20例。依据Hadden RD电生理诊断标准，分为AIDP（以髓鞘改变为主，n=13）和AMAN（以轴索改变为主，n=16）。GBS患者血样本采集两次，包括急性期（初始症状后1-14天，GBS-A）和平台期（初始症状后15-32天，GBS-P）。入院后在GBS-A病人应用静脉注射大剂量丙种球蛋白（IVIg）治疗0.4g/公斤体重/天，连续5天。并且自2010年6月至2011年12月期间，我们还收集了配对脑脊液和血浆样本的GBS急性期患者22例，健康对照者18例，均为在吉林大学第一临床医院和青岛医学院附属医院神经内科住院的患者。GBS患者均符合国际公认的GSB诊断标准。患者的神经系统功能缺失程度按GDSs评估。
采用Ficoll密度梯度离心法分离单个核细胞（PBMCs）。分离出的PBMCs用台盼兰染色计数，将细胞密度调整为1×10~7/ml。加入佛波酯（PMA），钙离子载体（Ionomyein）和BrefeldinA（BFA）共同刺激,放置于37℃，5%CO_2孵育培养箱孵育4小时后，应用PerCP标记的鼠抗人CD4单克隆抗体进行细胞外表面标志的标记，FITC标记的鼠抗人IFN-γ单克隆抗体、Alexa Fluor○R-647标记的鼠抗人IL-17A单克隆抗体、PE标记的鼠抗人IL-22单克隆抗体进行细胞内标志的标记。全血离心后的血浆样本和采集后的脑脊液样本分装，于-80℃超低温冰箱保存，应用酶联免疫吸附反应（ELISA）检测脑脊液和血浆IL-17、IL-22水平，步骤按照操作指南进行。全部数据均采用均数±标准差显示，应用单因素方差分析进行统计学处理，组间比较采用t检验。应用Pearson或Spearman相关系数分析两组数据相关性。P＜0.05认为有统计学意义。
结果：29例GBS病人（平均年龄41岁，包括20例男性，9例女性）均表现出急性进展的肢体无力。62.1%的病人有前驱感染史，其中上呼吸道感染者占20.7%，胃肠道感染者占34.5%,上呼吸道感染合并胃肠道感染者占6.9%。
流式细胞仪检测结果显示Th1（CD4+IFN-γ+）细胞、Th17细胞（CD4+IL-17A+）和Th22（CD4+IL-22+）细胞及其亚群细胞Th1/Th17亚群（IFN-γ+IL-17A+）、 Th17亚群（IL-17A+IFN-γ-, IL-17A+IL-22-和IL-17A+IL-22+）、和Th22亚群（IL-22+IL-17A-和IL-22+IFN-γ-）细胞在GBS-A和ONIDs明显升高，与健康对照组相比，差异有统计学意义［Th1细胞(GBS-A: P <0.001; RR-MS/R: P=0.007; VEM: P=0.002)；Th17细胞、Th22细胞、Th1/Th17亚群、Th17亚群和Th22亚群均为P <0.001)］，Th1亚群（IFN-γ+IL-17A-）细胞比率与健康对照相比在GBS-A明显升高（P=0.014）。同时，这些细胞水平经IVIg治疗后明显下降，GBS-A与GBS-P相比，差异有显著性（Th1亚群：P=0.044，其他细胞均为P <0.001)。升高的Th1、Th17和Th22细胞在GBS亚型AIDP和AMAN中的比率，差异无显著性。在GBS-A中，Th1、Th17和Th22细胞比率的升高均未发现与GDSs有明显相关，但Th22细胞有随着GDSs评分增高而升高的趋势。分别检测Th1、Th17和Th22细胞及其亚群细胞在GBS-A，GBS-P有前驱感染和无前驱感染中比率，差异均无显著性。
ELISA检测结果显示血浆IL-17和IL-22水平在GBS-A和RR-MS/R中明显升高，与健康对照组相比，差异有显著性［IL-17（GBS-A：P <0.001，RR-MS/R：P=0.01）；IL-22（GBS-A：P=0.009，RR-MS/R：P=0.007）］。IVIg治疗后，这两种细胞因子在GBS-P中下降，与GBS-A相比，差异有显著性（IL-17：P <0.001； IL-22：P=0.025）。配对脑脊液和血浆样本IL-17、IL-22水平在GBS急性期患者中升高，脑脊液IL-22水平升高最为明显(P <0.001)，然后是脑脊液IL-17水平(P=0.023),血浆IL-17(P=0.011),血浆IL-22(P=0.019),与健康对照组相比，差异有显著性。脑脊液IL-17和IL-22水平分别与GDSs有正相关(脑脊液IL-17：P=0.040；脑脊液IL-22：P=0.012)。血浆IL-17和IL-22水平与GDSs无明显相关性，但是血浆IL-22有随着GDSs评分增高而升高的趋势。脑脊液IL-17和脑脊液IL-22水平有正相关(P=0.026)。同时，脑脊液IL-22和血浆IL-22水平有相关性(P=0.039)。
讨论：本实验检测末稍血中Th17、Th22和Th1细胞比率在GBS病人明显升高，脑脊液和血浆中IL-17、和IL-22水平在GBS病人明显增高。因此，Th17和Th22细胞以及IL-17/IL-22可能参与GBS的发生和发展过程。
IL-6与转化生长因子(TGF)-β1，或是IL-6、IL-23协同IL-1β是有效刺激Th17细胞分化和分泌IL-17的因素，这些细胞因子也可以加速IL-22的分泌。IL-6, IL-1β, IL-23和TNF-α都属于前炎症因子，并且在GBS的发病机制中起到重要作用。因此，IL-17和IL-22与这些炎性细胞因子的协同作用参与GBS的发病机制。除Th1细胞和其相关细胞因子以外，IL-17和IL-22可能是介导GBS自身免疫反应的另一重要因子。
脑脊液中IL-17和IL-22的升高可能与PNS的局部炎症有关，促进脱髓鞘和轴索变性。而且，它们分别与GDSs相关，说明它们与脊神经炎症的轻重程度相关，并可能成为评估疾病严重程度或愈后的指标。脑脊液IL-17与脑脊液IL-22水平、脑脊液IL-22和血浆IL-22水平存在着正相关关系，说明了脑脊液中IL-17和IL-22的升高具有同步性和一致性，它们可能协同作用参与疾病的发生。
大剂量IVIg是治疗GBS的有效手段，能够抑制Th17细胞分化和增殖，也可以抑制与它相关的细胞因子产生。我们的结果显示IVIg治疗可以减少平台期患者Th17和Th22细胞的比率，以及相关细胞因子IL-17和IL-22的表达，IVIg可以通过减少这些细胞和细胞因子的水平而有效减轻GBS临床症状。我们的资料显示拮抗Th17和Th22细胞和相关细胞因子对减轻GBS病情可能有治疗作用。
结论：Th17和Th22细胞以及效应细胞因子IL-17、IL-22参与GBS的发病过程，并且脑脊液中IL-17和IL-22分别与GDSs相关，脑脊液IL-17与脑脊液IL-22水平、脑脊液IL-22和血浆IL-22水平也存在着正相关关系。IVIg通过减少这些细胞和细胞因子的表达而产生治疗作用。
Guillain-Barré syndrome (GBS) is an autoimmune inflammatorydisease affecting both myelin sheath and axons of the peripheral nervoussystem (PNS). The pathogenesis of GBS remains still enigmatic, mostcases are reported to undergo previous infections, surgery andvaccination. It is clinically characterized by rapidly progressingsymmetrical weakness and hyporeflexia/areflexia followed mostly byrecovery. Meanwhile, the cerebrospinal fluid (CSF) of GBS patientsusually shows characteristic albumin-cytological dissociation. Some ofGBS patients’ recovery can be shortened by plasma exchange (PE) andintravenous immunoglobulin (IVIg) therapy. Acute inflammatorydemyelinating polyradiculoneuropathy (AIDP), acute motor axonalneuropathy (AMAN), acute motor sensory axonal neuropathy (AMSAN)and Miller-Fisher syndrome are the most common subtypes of GBS.
GBS and its animal model experimental autoimmune neuritis (EAN)have hitherto been attributed to Th1cells-mediated disorders. IncreasedIFN-γ was seen in the serum of GBS patients at acute phase, and higherimmunoreactivity for IFN-γ was showed in sural nerves biopsies of GBSpatients. IL-17-producing T helper (Th) cells or Th17cells have beenidentified subsequently as an obvious distinct Th population and a novelTh lineage mediating tissue inflammation and autoimmune response inboth animal models and human. EAN has been observed with decreasedTh1and Th17cytokines when administered atorvastatin which hasanti-inflammatory properties. Furthermore, a Germany’s group reported acompound, FTY720, attenuated EAN via reducing Th17cells in PNS. These findings suggest that Th17and IL-17paticipate in the inflammationof EAN in addition to Th1and IFN-γ. Recent studies testified thatIL-17/Th17and IL-22/Th22cells play important roles in the pathogenesisof various inflammatory and autoimmune diseases, such as inflammatorybowel disease (IBD), rheumatoid arthritis (RA), psoriasis, and multiplesclerosis (MS).
The study on the role of Th17and Th22cells in GBS has not yetestablished so far. In the present study, we detected the frequency of Th1,Th17and Th22cells and their subgroup cells in the peripheral blood andlevels of IL-17and IL-22in plasma of GBS patients at the acute/plateauphase, IL-17and IL-22levels in paired CSF and plasma of GBS patientsat the acute phase, and evaluated the correlations between these twocytokines and GBS functional disability scales (GDSs) as well as variousCSF parameters. These human studies will allow us to understand the roleof Th17and Th22cells as well as IL-17and IL-22in the development ofthe autoimmune response in GBS.
Materials and methods
During June2010to August2011, we recruited29GBS patients,32other neurological inflammatory disease controls (ONIDs), including15MS,17encephalitis or meningitis infected by virus (VEM) and20healthy controls (HC). All subjects are from the Department ofNeurology, the First Hospital, Jilin University, Changchun, China. AllGBS patients were classified electrophysiologically as AIDP (n=13)and AMAN (n=16), using motor nerve conduction criteria. Blood wassampled two times at acute (1-14days from onset day, GBS-A) andplateau phases (15-32days from onset day, GBS-P) of GBS. The pre-treatment GBS patients were defined as absence of anyimmune-modulating drugs and other treatments within3months, and thepost-treatment patients as treatments with IVIg at a dose of0.4g/kgbody weight per day for5days consecutively in acute phase. In thisstudy, paired samples of CSF and plasma were collected from22GBSpatients and18HC at the Neurological Laboratory of the First Hospital,Jilin University, Changchun, and the Department of Neurology, theAffiliated Hospital of Medical College, Qingdao University, Qingdao,China during June2010to December2011. GBS patients fulfilledinternational diagnostic criteria for GBS or its variants. Severity of GBSwas scored by the use of GDSs.
Ficoll-PaqueTMdensity gradient centrifugation was used to separateperipheral blood mononuclear cells (PBMCs). PBMCs were resuspendedat1×10~7cells/ml by Trypan blue stain and stimulated with phorbol12-myristate13-acetate (PMA) and ionomycin in the presence ofBrefeldin A in37℃，5%CO_2cell incubation box for4h. We used mouseanti-human monoclonal antibodies (mAbs) of PerCP-conjugated CD4for extra-cellular marker stain and phycoerythrin (PE)-conjugated IL-22,FITC-conjugated IFN-γ, Alexa Fluor○R647-conjugated IL-17A forintra-cellular marker stain. Plasma and CSF samples were also collectedand cryopreserved at-80℃. Then we used ELISA performance to detectthe level of IL-17and IL-22according to the manufacturer’s instructions.Data were expressed as the mean±standard deviation (SD). Forstatistical analysis, differences of mean values were tested with one wayanalysis of variance (ANOVA) for multiple comparisons and thestudent-t test for two groups. The Pearson or Spearman correlation coefficient was used to analyze correlations depending on datadistribution. Reported P-values are two-tailed and considered statisticallysignificant at P <0.05.
Results
Twenty-nine GBS patients [mean age,41years (20men and9women)] had manifested acutely progressive weakness of limbs. Ahistory of antecedent illness was present in62.1%of the patients (upperrespiratory tract infectious symptoms in20.7%, gastrointestinal tractsymptoms in34.5%, and both symptoms in6.9%).
By flow cytometry, our data showed that Th1(CD4+IFN-γ+), Th17(CD4+IL-17A+), Th22(CD4+IL-22+) cells and Th1/Th17subgroup(IFN-γ+IL-17A+), Th17subgroup (IL-17A+IFN-γ-, IL-17A+IL-22-andIL-17A+IL-22+) as well as Th22subgroup (IL-22+IL-17A-and IL-22+IFN-γ-) cells were significantly increased in GBS-A and ONIDscompared with HC［Th1cells (GBS-A: P <0.001; RR-MS/R: P=0.007;VEM: P=0.002)；Th17, Th22cells, and Th1/Th17subgroup, Th17subgroup, Th22subgroup cells P <0.001)］. The frequency of Th1subgroup (IFN-γ+IL-17A-) was elevated in GBS-A (P=0.014) comparedwith HC. Interestingly, the intravenous immunoglobulin (IVIg) therapydown-regulated these cells in GBS-P compared with GBS-A (Th1subgroup：P=0.044，others: P <0.001). There was no significantdifference of elevated Th1, Th17and Th22cells between AIDP andAMAN. Though there was no quantitative uniqueness for the frequencyof Th1, Th17and Th22cells between GBS subtypes or no correlationwith GBS-A severity, the elevated Th22cells had a tendency withdisease severity status in GBS-A. There was no significant difference with regard to circulating Th1, Th17and Th22cells as well as Th17andTh22subgroup cells between GBS patients (both GBS-A and GBS-P)with and without prodromal infections (P>0.05).
Plasma levels of IL-17and IL-22in all groups were also measuredby ELISA. Our data demonstrated that plasma levels of IL-17and IL-22were significantly elevated in GBS-A and RR-MS/R compared with HC［IL-17(GBS-A：P <0.001，RR-MS/R：P=0.01)；IL-22(GBS-A：P=0.009，RR-MS/R：P=0.007)］. Clearly, IVIg treatments declined thelevels of these two cytokines in GBS-P compared with GBS-A (IL-17：P<0.001；IL-22：P=0.025). The levels of IL-17and IL-22in paired CSFand plasma were elevated in all GBS patients. The elevation was mostobvious for IL-22in CSF (P <0.001), followed by IL-17in CSF (P=0.023), IL-17in plasma (P=0.011), and IL-22in plasma (P=0.019),when compared with HC. IL-17and IL-22levels in CSF had positivecorrelation with GDSs (P=0.040; P=0.012, respectively). Althoughthere was no statistical significance, the elevated level of IL-22in plasmahad a tendency toward positive correlation with GBS severity. Thesignificant positive relationships were found between the levels of IL-17in CSF and IL-22in CSF (P=0.026), as well as the levels of IL-22inCSF and IL-22in plasma (P=0.039).
Discussion
In the present study, our results show that circulating Th1, Th17andTh22cells as well as their subgroups and IL-17, IL-22in CSF andplasma levels were obviously elevated in GBS at the acute phase. Thus itis speculated that Th17and Th22cells as well as IL-17/IL-22areinvolved in the initiation and development of GBS.
IL-6in the presence of TGF-β1, and IL-6, IL-23in combinationwith IL-1β had been proved to be the effective factors responsible for thedifferentiation of Th17cells and the production of IL-17. Thesecytokines milieux may also facilitate the expression of IL-22. IL-6, IL-1β,IL-23and TNF-α are all pro-inflammatory cytokines and play animportant role in the pathogenesis of GBS. Therefore, it is safe toconclude in our study that the extensive network of IL-17and IL-22incoordination with these inflammatory cytokines is associated with thepathogenesis of GBS. IL-17and IL-22might be important effectors inaddition to Th1cells and Th1cytokines in autoimmune-mediatedresponses of GBS.
Our data suggest that the elevation CSF levels of IL-17and IL-22inGBS might be related to PNS local inflammation that causesdemyelination and axon degeneration. The levels of them, respectively,were correlated with GDSs at the acute phase of GBS, and there was apositive correlation between them. Nevertheless, the levels of IL-22inCSF and IL-22in plasma also had a positive correlation. This indicatesthat the elevation of IL-17and IL-22in CSF is related to the severity ofinflammation in the spinal roots. Since their elevations in CSF aresynchronous, IL-17and IL-22may coordinate in the pathogenesis of thedisease and may be a biomarker for indicating disease severity orprognosis.
High-dose IVIg therapy is a fundamental effective treatment in GBS.Recent studies showed that IVIg inhibited the differentiation andamplification of Th17cells, as well as the production of their effectorcytokines IL-17and IL-22. In this study, our data showed that IVIg treatments could down-regulate these cells and their cytokines at theplateau phase and attenuates clinical signs of GBS. Our data suggest thatantagonists of Th17, Th22cells and their cytokines may have therapeuticpotentials for alleviating GBS.
Conclusions
In summary, increasing circulating Th17, Th22cells and theireffector cytokines may be involved in the pathogenesis of GBS. IL-17and IL-22levels in CSF are correlated with GDSs of GBS patients,respectively. The significant positive relationships could be foundbetween the levels of IL-17and IL-22in CSF, as well as IL-22in CSFand plasma of GBS patients, IVIg mediates its therapeutic effects bydown-regulating these cells and their cytokines in GBS patients.
既往研究表明，GBS以及其动物模型实验性自身免疫性神经炎（EAN）的免疫炎症反应主要由Th1细胞介导。GBS病人血清中IFN-γ的表达水平明显偏高，而且应用免疫组织化学方法发现GBS病人腓神经活检中IFN-γ表达阳性。近来发现了一种新的辅助性T细胞亚群，Th17细胞，已证实在动物模型和病人中可以介导多种组织炎症和自身免疫反应。阿托伐他汀（atorvastatin）是一种降脂药，具有抗炎症反应的作用，在治疗EAN动物后，Th1和Th17细胞水平明显下降，也证明了Th17细胞在EAN中的致病作用。化合物FTY720通过减少PNS中Th17细胞而减轻EAN的症状。以上结果显示除了Th1和IFN-γ以外，Th17和IL-17在EAN中也介导炎症过程。既往研究证实Th17，Th22细胞和IL-17、IL-22在多种炎症性和自身免疫性疾病的发病机制中起到重要作用，如炎症性肠病（IBD）、类风湿性关节炎（RA）、银屑病和多发性硬化（MS）。
迄今为止，尚未发现有关Th17和Th22细胞在GBS病人的实验研究，因此它们在GBS致病过程中作用不清。在本实验中，我们检测GBS急性期和恢复期病人末稍血Th1、Th17和Th22细胞及其亚群细胞比率和血浆IL-17和IL-22水平，GBS急性期配对脑脊液和血浆样本的IL-17和IL-22水平，同时分别评估这些细胞和细胞因子与GBS残疾程度评分（GDSs）的相关性，从而探索Th17和Th22细胞以及IL-17和IL-22在GBS发病机制中的作用。
材料和方法：自2010年6月至2011年8月期间，我们收集了吉林大学第一临床医院神经内科住院GBS患者29例，其他神经系统免疫炎症性疾病（ONIDs）对照患者32例［包括MS患者15例，病毒性脑炎或脑膜炎（VEM）患者17例］，健康对照20例。依据Hadden RD电生理诊断标准，分为AIDP（以髓鞘改变为主，n=13）和AMAN（以轴索改变为主，n=16）。GBS患者血样本采集两次，包括急性期（初始症状后1-14天，GBS-A）和平台期（初始症状后15-32天，GBS-P）。入院后在GBS-A病人应用静脉注射大剂量丙种球蛋白（IVIg）治疗0.4g/公斤体重/天，连续5天。并且自2010年6月至2011年12月期间，我们还收集了配对脑脊液和血浆样本的GBS急性期患者22例，健康对照者18例，均为在吉林大学第一临床医院和青岛医学院附属医院神经内科住院的患者。GBS患者均符合国际公认的GSB诊断标准。患者的神经系统功能缺失程度按GDSs评估。
采用Ficoll密度梯度离心法分离单个核细胞（PBMCs）。分离出的PBMCs用台盼兰染色计数，将细胞密度调整为1×10~7/ml。加入佛波酯（PMA），钙离子载体（Ionomyein）和BrefeldinA（BFA）共同刺激,放置于37℃，5%CO_2孵育培养箱孵育4小时后，应用PerCP标记的鼠抗人CD4单克隆抗体进行细胞外表面标志的标记，FITC标记的鼠抗人IFN-γ单克隆抗体、Alexa Fluor○R-647标记的鼠抗人IL-17A单克隆抗体、PE标记的鼠抗人IL-22单克隆抗体进行细胞内标志的标记。全血离心后的血浆样本和采集后的脑脊液样本分装，于-80℃超低温冰箱保存，应用酶联免疫吸附反应（ELISA）检测脑脊液和血浆IL-17、IL-22水平，步骤按照操作指南进行。全部数据均采用均数±标准差显示，应用单因素方差分析进行统计学处理，组间比较采用t检验。应用Pearson或Spearman相关系数分析两组数据相关性。P＜0.05认为有统计学意义。
结果：29例GBS病人（平均年龄41岁，包括20例男性，9例女性）均表现出急性进展的肢体无力。62.1%的病人有前驱感染史，其中上呼吸道感染者占20.7%，胃肠道感染者占34.5%,上呼吸道感染合并胃肠道感染者占6.9%。
流式细胞仪检测结果显示Th1（CD4+IFN-γ+）细胞、Th17细胞（CD4+IL-17A+）和Th22（CD4+IL-22+）细胞及其亚群细胞Th1/Th17亚群（IFN-γ+IL-17A+）、 Th17亚群（IL-17A+IFN-γ-, IL-17A+IL-22-和IL-17A+IL-22+）、和Th22亚群（IL-22+IL-17A-和IL-22+IFN-γ-）细胞在GBS-A和ONIDs明显升高，与健康对照组相比，差异有统计学意义［Th1细胞(GBS-A: P <0.001; RR-MS/R: P=0.007; VEM: P=0.002)；Th17细胞、Th22细胞、Th1/Th17亚群、Th17亚群和Th22亚群均为P <0.001)］，Th1亚群（IFN-γ+IL-17A-）细胞比率与健康对照相比在GBS-A明显升高（P=0.014）。同时，这些细胞水平经IVIg治疗后明显下降，GBS-A与GBS-P相比，差异有显著性（Th1亚群：P=0.044，其他细胞均为P <0.001)。升高的Th1、Th17和Th22细胞在GBS亚型AIDP和AMAN中的比率，差异无显著性。在GBS-A中，Th1、Th17和Th22细胞比率的升高均未发现与GDSs有明显相关，但Th22细胞有随着GDSs评分增高而升高的趋势。分别检测Th1、Th17和Th22细胞及其亚群细胞在GBS-A，GBS-P有前驱感染和无前驱感染中比率，差异均无显著性。
ELISA检测结果显示血浆IL-17和IL-22水平在GBS-A和RR-MS/R中明显升高，与健康对照组相比，差异有显著性［IL-17（GBS-A：P <0.001，RR-MS/R：P=0.01）；IL-22（GBS-A：P=0.009，RR-MS/R：P=0.007）］。IVIg治疗后，这两种细胞因子在GBS-P中下降，与GBS-A相比，差异有显著性（IL-17：P <0.001； IL-22：P=0.025）。配对脑脊液和血浆样本IL-17、IL-22水平在GBS急性期患者中升高，脑脊液IL-22水平升高最为明显(P <0.001)，然后是脑脊液IL-17水平(P=0.023),血浆IL-17(P=0.011),血浆IL-22(P=0.019),与健康对照组相比，差异有显著性。脑脊液IL-17和IL-22水平分别与GDSs有正相关(脑脊液IL-17：P=0.040；脑脊液IL-22：P=0.012)。血浆IL-17和IL-22水平与GDSs无明显相关性，但是血浆IL-22有随着GDSs评分增高而升高的趋势。脑脊液IL-17和脑脊液IL-22水平有正相关(P=0.026)。同时，脑脊液IL-22和血浆IL-22水平有相关性(P=0.039)。
讨论：本实验检测末稍血中Th17、Th22和Th1细胞比率在GBS病人明显升高，脑脊液和血浆中IL-17、和IL-22水平在GBS病人明显增高。因此，Th17和Th22细胞以及IL-17/IL-22可能参与GBS的发生和发展过程。
IL-6与转化生长因子(TGF)-β1，或是IL-6、IL-23协同IL-1β是有效刺激Th17细胞分化和分泌IL-17的因素，这些细胞因子也可以加速IL-22的分泌。IL-6, IL-1β, IL-23和TNF-α都属于前炎症因子，并且在GBS的发病机制中起到重要作用。因此，IL-17和IL-22与这些炎性细胞因子的协同作用参与GBS的发病机制。除Th1细胞和其相关细胞因子以外，IL-17和IL-22可能是介导GBS自身免疫反应的另一重要因子。
脑脊液中IL-17和IL-22的升高可能与PNS的局部炎症有关，促进脱髓鞘和轴索变性。而且，它们分别与GDSs相关，说明它们与脊神经炎症的轻重程度相关，并可能成为评估疾病严重程度或愈后的指标。脑脊液IL-17与脑脊液IL-22水平、脑脊液IL-22和血浆IL-22水平存在着正相关关系，说明了脑脊液中IL-17和IL-22的升高具有同步性和一致性，它们可能协同作用参与疾病的发生。
大剂量IVIg是治疗GBS的有效手段，能够抑制Th17细胞分化和增殖，也可以抑制与它相关的细胞因子产生。我们的结果显示IVIg治疗可以减少平台期患者Th17和Th22细胞的比率，以及相关细胞因子IL-17和IL-22的表达，IVIg可以通过减少这些细胞和细胞因子的水平而有效减轻GBS临床症状。我们的资料显示拮抗Th17和Th22细胞和相关细胞因子对减轻GBS病情可能有治疗作用。
结论：Th17和Th22细胞以及效应细胞因子IL-17、IL-22参与GBS的发病过程，并且脑脊液中IL-17和IL-22分别与GDSs相关，脑脊液IL-17与脑脊液IL-22水平、脑脊液IL-22和血浆IL-22水平也存在着正相关关系。IVIg通过减少这些细胞和细胞因子的表达而产生治疗作用。
Guillain-Barré syndrome (GBS) is an autoimmune inflammatorydisease affecting both myelin sheath and axons of the peripheral nervoussystem (PNS). The pathogenesis of GBS remains still enigmatic, mostcases are reported to undergo previous infections, surgery andvaccination. It is clinically characterized by rapidly progressingsymmetrical weakness and hyporeflexia/areflexia followed mostly byrecovery. Meanwhile, the cerebrospinal fluid (CSF) of GBS patientsusually shows characteristic albumin-cytological dissociation. Some ofGBS patients’ recovery can be shortened by plasma exchange (PE) andintravenous immunoglobulin (IVIg) therapy. Acute inflammatorydemyelinating polyradiculoneuropathy (AIDP), acute motor axonalneuropathy (AMAN), acute motor sensory axonal neuropathy (AMSAN)and Miller-Fisher syndrome are the most common subtypes of GBS.
GBS and its animal model experimental autoimmune neuritis (EAN)have hitherto been attributed to Th1cells-mediated disorders. IncreasedIFN-γ was seen in the serum of GBS patients at acute phase, and higherimmunoreactivity for IFN-γ was showed in sural nerves biopsies of GBSpatients. IL-17-producing T helper (Th) cells or Th17cells have beenidentified subsequently as an obvious distinct Th population and a novelTh lineage mediating tissue inflammation and autoimmune response inboth animal models and human. EAN has been observed with decreasedTh1and Th17cytokines when administered atorvastatin which hasanti-inflammatory properties. Furthermore, a Germany’s group reported acompound, FTY720, attenuated EAN via reducing Th17cells in PNS. These findings suggest that Th17and IL-17paticipate in the inflammationof EAN in addition to Th1and IFN-γ. Recent studies testified thatIL-17/Th17and IL-22/Th22cells play important roles in the pathogenesisof various inflammatory and autoimmune diseases, such as inflammatorybowel disease (IBD), rheumatoid arthritis (RA), psoriasis, and multiplesclerosis (MS).
The study on the role of Th17and Th22cells in GBS has not yetestablished so far. In the present study, we detected the frequency of Th1,Th17and Th22cells and their subgroup cells in the peripheral blood andlevels of IL-17and IL-22in plasma of GBS patients at the acute/plateauphase, IL-17and IL-22levels in paired CSF and plasma of GBS patientsat the acute phase, and evaluated the correlations between these twocytokines and GBS functional disability scales (GDSs) as well as variousCSF parameters. These human studies will allow us to understand the roleof Th17and Th22cells as well as IL-17and IL-22in the development ofthe autoimmune response in GBS.
Materials and methods
During June2010to August2011, we recruited29GBS patients,32other neurological inflammatory disease controls (ONIDs), including15MS,17encephalitis or meningitis infected by virus (VEM) and20healthy controls (HC). All subjects are from the Department ofNeurology, the First Hospital, Jilin University, Changchun, China. AllGBS patients were classified electrophysiologically as AIDP (n=13)and AMAN (n=16), using motor nerve conduction criteria. Blood wassampled two times at acute (1-14days from onset day, GBS-A) andplateau phases (15-32days from onset day, GBS-P) of GBS. The pre-treatment GBS patients were defined as absence of anyimmune-modulating drugs and other treatments within3months, and thepost-treatment patients as treatments with IVIg at a dose of0.4g/kgbody weight per day for5days consecutively in acute phase. In thisstudy, paired samples of CSF and plasma were collected from22GBSpatients and18HC at the Neurological Laboratory of the First Hospital,Jilin University, Changchun, and the Department of Neurology, theAffiliated Hospital of Medical College, Qingdao University, Qingdao,China during June2010to December2011. GBS patients fulfilledinternational diagnostic criteria for GBS or its variants. Severity of GBSwas scored by the use of GDSs.
Ficoll-PaqueTMdensity gradient centrifugation was used to separateperipheral blood mononuclear cells (PBMCs). PBMCs were resuspendedat1×10~7cells/ml by Trypan blue stain and stimulated with phorbol12-myristate13-acetate (PMA) and ionomycin in the presence ofBrefeldin A in37℃，5%CO_2cell incubation box for4h. We used mouseanti-human monoclonal antibodies (mAbs) of PerCP-conjugated CD4for extra-cellular marker stain and phycoerythrin (PE)-conjugated IL-22,FITC-conjugated IFN-γ, Alexa Fluor○R647-conjugated IL-17A forintra-cellular marker stain. Plasma and CSF samples were also collectedand cryopreserved at-80℃. Then we used ELISA performance to detectthe level of IL-17and IL-22according to the manufacturer’s instructions.Data were expressed as the mean±standard deviation (SD). Forstatistical analysis, differences of mean values were tested with one wayanalysis of variance (ANOVA) for multiple comparisons and thestudent-t test for two groups. The Pearson or Spearman correlation coefficient was used to analyze correlations depending on datadistribution. Reported P-values are two-tailed and considered statisticallysignificant at P <0.05.
Results
Twenty-nine GBS patients [mean age,41years (20men and9women)] had manifested acutely progressive weakness of limbs. Ahistory of antecedent illness was present in62.1%of the patients (upperrespiratory tract infectious symptoms in20.7%, gastrointestinal tractsymptoms in34.5%, and both symptoms in6.9%).
By flow cytometry, our data showed that Th1(CD4+IFN-γ+), Th17(CD4+IL-17A+), Th22(CD4+IL-22+) cells and Th1/Th17subgroup(IFN-γ+IL-17A+), Th17subgroup (IL-17A+IFN-γ-, IL-17A+IL-22-andIL-17A+IL-22+) as well as Th22subgroup (IL-22+IL-17A-and IL-22+IFN-γ-) cells were significantly increased in GBS-A and ONIDscompared with HC［Th1cells (GBS-A: P <0.001; RR-MS/R: P=0.007;VEM: P=0.002)；Th17, Th22cells, and Th1/Th17subgroup, Th17subgroup, Th22subgroup cells P <0.001)］. The frequency of Th1subgroup (IFN-γ+IL-17A-) was elevated in GBS-A (P=0.014) comparedwith HC. Interestingly, the intravenous immunoglobulin (IVIg) therapydown-regulated these cells in GBS-P compared with GBS-A (Th1subgroup：P=0.044，others: P <0.001). There was no significantdifference of elevated Th1, Th17and Th22cells between AIDP andAMAN. Though there was no quantitative uniqueness for the frequencyof Th1, Th17and Th22cells between GBS subtypes or no correlationwith GBS-A severity, the elevated Th22cells had a tendency withdisease severity status in GBS-A. There was no significant difference with regard to circulating Th1, Th17and Th22cells as well as Th17andTh22subgroup cells between GBS patients (both GBS-A and GBS-P)with and without prodromal infections (P>0.05).
Plasma levels of IL-17and IL-22in all groups were also measuredby ELISA. Our data demonstrated that plasma levels of IL-17and IL-22were significantly elevated in GBS-A and RR-MS/R compared with HC［IL-17(GBS-A：P <0.001，RR-MS/R：P=0.01)；IL-22(GBS-A：P=0.009，RR-MS/R：P=0.007)］. Clearly, IVIg treatments declined thelevels of these two cytokines in GBS-P compared with GBS-A (IL-17：P<0.001；IL-22：P=0.025). The levels of IL-17and IL-22in paired CSFand plasma were elevated in all GBS patients. The elevation was mostobvious for IL-22in CSF (P <0.001), followed by IL-17in CSF (P=0.023), IL-17in plasma (P=0.011), and IL-22in plasma (P=0.019),when compared with HC. IL-17and IL-22levels in CSF had positivecorrelation with GDSs (P=0.040; P=0.012, respectively). Althoughthere was no statistical significance, the elevated level of IL-22in plasmahad a tendency toward positive correlation with GBS severity. Thesignificant positive relationships were found between the levels of IL-17in CSF and IL-22in CSF (P=0.026), as well as the levels of IL-22inCSF and IL-22in plasma (P=0.039).
Discussion
In the present study, our results show that circulating Th1, Th17andTh22cells as well as their subgroups and IL-17, IL-22in CSF andplasma levels were obviously elevated in GBS at the acute phase. Thus itis speculated that Th17and Th22cells as well as IL-17/IL-22areinvolved in the initiation and development of GBS.
IL-6in the presence of TGF-β1, and IL-6, IL-23in combinationwith IL-1β had been proved to be the effective factors responsible for thedifferentiation of Th17cells and the production of IL-17. Thesecytokines milieux may also facilitate the expression of IL-22. IL-6, IL-1β,IL-23and TNF-α are all pro-inflammatory cytokines and play animportant role in the pathogenesis of GBS. Therefore, it is safe toconclude in our study that the extensive network of IL-17and IL-22incoordination with these inflammatory cytokines is associated with thepathogenesis of GBS. IL-17and IL-22might be important effectors inaddition to Th1cells and Th1cytokines in autoimmune-mediatedresponses of GBS.
Our data suggest that the elevation CSF levels of IL-17and IL-22inGBS might be related to PNS local inflammation that causesdemyelination and axon degeneration. The levels of them, respectively,were correlated with GDSs at the acute phase of GBS, and there was apositive correlation between them. Nevertheless, the levels of IL-22inCSF and IL-22in plasma also had a positive correlation. This indicatesthat the elevation of IL-17and IL-22in CSF is related to the severity ofinflammation in the spinal roots. Since their elevations in CSF aresynchronous, IL-17and IL-22may coordinate in the pathogenesis of thedisease and may be a biomarker for indicating disease severity orprognosis.
High-dose IVIg therapy is a fundamental effective treatment in GBS.Recent studies showed that IVIg inhibited the differentiation andamplification of Th17cells, as well as the production of their effectorcytokines IL-17and IL-22. In this study, our data showed that IVIg treatments could down-regulate these cells and their cytokines at theplateau phase and attenuates clinical signs of GBS. Our data suggest thatantagonists of Th17, Th22cells and their cytokines may have therapeuticpotentials for alleviating GBS.
Conclusions
In summary, increasing circulating Th17, Th22cells and theireffector cytokines may be involved in the pathogenesis of GBS. IL-17and IL-22levels in CSF are correlated with GDSs of GBS patients,respectively. The significant positive relationships could be foundbetween the levels of IL-17and IL-22in CSF, as well as IL-22in CSFand plasma of GBS patients, IVIg mediates its therapeutic effects bydown-regulating these cells and their cytokines in GBS patients.
引文
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