IL-9~+CD4~+T细/IL-9与幽门杆菌感染的相关性研究和γδT细胞在金黄色葡萄球菌肺炎的宿主应答中的作用
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摘要
幽门螺杆菌(Helicobacter pylori, H. pylori)是弯曲、棒状的革兰阴性杆菌，主要定植在胃部和十二指肠部位(1)。近年来的大量研究证明，幽门螺杆菌可引发人群中不同程度的急性或慢性胃炎，少数发展为消化性溃疡和胃癌(2)。其中按是否含有细胞毒素相关蛋白(cytotoxin associated protein,CagA)将幽门螺杆菌分为Ⅰ型和Ⅱ型。在临床大多数胃炎病例中，胃体萎缩性胃炎是由Ⅰ型H. pylori感染引起的主要临床胃炎类型，并与胃癌的发生高度相关。CagA依赖于Ⅳ型分泌系统(type Ⅳ secretion system,T4SS)，转运至胃粘膜上皮细胞并发生磷酸化，从而激活下游细胞信号通路，发挥细胞免疫学功能，引起胃上皮细胞“蜂巢”型形态学改变和更严重的感染症状(3,4)。受到刺激的上皮细胞释放大量炎症趋化因子和细胞因子等诱导宿主产生相应的细胞免疫应答。已有文献报道，H. pylori作为胞外菌可诱导宿主产生以CD4~+T细胞为主的免疫应答反应，CD4~+T细胞应答在H.pylori感染的机体免疫炎性损伤和抗感染免疫保护中发挥重要作用(5)。细胞因子IL-9是Uyttenhove等(6)人于1988年在Th2细胞株中发现的T细胞生长因子，它具有多效性的免疫功能。2011年Stephens等人在自身免疫性胃炎疾病中发现Th17分泌的IL9通过刺激粘膜肥大细胞增殖间接抑制Th17的免疫活性，起到一定的抗炎的作用，且提出IL-9最终发挥促炎还是抗炎功能的重要因素是由疾病造成的微环境所决定(7)。近年来，已有多篇文献报导IL-9功能具有双重性，一方面IL-9激活巨噬细胞，肥大细胞和嗜酸细胞起到促进炎症和过敏反应；另一方面IL-9负向调节病毒介导的炎症和增强天然Treg细胞免疫抑制活性。在哮喘小鼠模型中，Arnold等通过诱导iTreg细胞揭示幽门螺旋杆菌感染能够降低哮喘严重程度，提示幽门螺旋杆菌感染可能与哮喘程度存在负相关(8)。综上，CD4~+T细胞参与宿主的免疫应答反应，其中细胞因子IL-9是否也参与机体免疫应答以及发挥怎样的免疫调节功能尚不清楚。
本课题将以IL-9~+CD4~+T细胞为主要研究对象，在H.pylori/B0菌株感染野生型(widetype, WT)BALB/c小鼠和IL-9基因敲除(IL-9ko)小鼠的模型下，初步研究IL-9~+CD4~+T细胞/IL-9与幽门螺杆菌感染的相关性研究，将为深入探讨IL-9~+CD4~+T细胞在H.pylori自然感染条件下发挥复杂的免疫学功能提供新的参考和指导。
方法
1. H.pylori菌株感染受检者血标本中细胞因子检测
收集了临床受检者的血清，通过检测血清中抗H.pylori特异性抗体把标本分为H.pylori感染阳性和阴性2组，通过ELISA方法检测人外周血清中IL-9蛋白水平的表达。
2. IL-9在幽门螺杆菌感染小鼠模型中的表达检测
(1) H.pylori/B0菌株感染BALB/c、IL-9ko小鼠模型建立方法
(2) IL-9在幽门螺杆菌感染小鼠模型中动态表达检测
3. IL-9在幽门螺杆菌感染小鼠模型中功能的初步研究
(1) H. pylori/B0在小鼠胃内定植量水平检测
(2)胃组织炎症评分及病理HE染色结果分析
4. IL-9在幽门螺杆菌感染中的细胞来源研究
(1)幽门螺杆菌患者外周血产IL-9的T细胞的诱导分化研究
(2)幽门螺杆菌感染小鼠脾脏产IL-9的T细胞的诱导分化研究
结果
1.临床血清标本中细胞因子IL-9在H.pylori感染阴性受检者中表达明显高于H.pylori感染阳性受检者。
2.相对于H.pylori/B0未感染组，野生型小鼠背景的H.pylori感染组的胃部H.pylori/B0定植在在感染后各个时间点明显增高。结果证明H.pylori感染小鼠的动态评价模型建立成功。28天时，H. pylori/B0菌株感染BALB/c与未感染对照组相比，细胞因子IL-17、IFN-γ和IL-10的mRNA水平都有显著提高，相比之下IL-10和IFN-γ增加更明显。而感染组IL-9的mRNA水平较未感染组显著下降。
3. BALB/c小鼠在H. pylori/B0菌株感染后的第28天胃内定植量达到最高值，其前后一周内维持在较高水平，但35d后定植量开始逐渐下降。IL-9ko感染组小鼠胃组织内定植量水平高于BALB/c小鼠感染组，在感染后第28天检测胃内定植量也达到峰值。IL-9ko小鼠在敲除细胞因子IL-9后，H. pylori/B0菌株感染小鼠胃粘膜组织的定植量比WT感染组小鼠高。在相同实验条件下，观察HE染色病理切片，IL-9ko感染组胃固有层部位炎症细胞侵润比WT感染组更多且胃粘膜表面局部有少量壁细胞破损。
4. H.pylori菌株感染阴性受检者和阳性受检者PBMC中的IL-9~+CD4~+T细胞占CD4T淋巴细胞的比例分别为1.9％和0.914％，统计结果也显示阴性受检者组IL-9~+CD4~+T细胞比阳性受检者组多。在小鼠体内再次验证以上结果，H.pylori.B0菌株感染阴性小鼠和阳性小鼠脾单个核细胞中的IL-9~+CD4~+T细胞占CD4T淋巴细胞的比例分别为0.7％和0.31％，统计结果也显示阴性受检者组IL-9~+CD4~+T细胞比阳性受检者组多。且加入适当细胞因子可诱导IL-9~+CD4~+T细胞的分泌IL-9。
结论
1. H.pylori感染人和动物体后，细胞因子IL-9在转录水平和细胞水平都下降。在WT和IL-9ko小鼠感染模型中，验证IL-9与H.pylori/B0引起的免疫应答反应相关。
2.在H.pylori感染后引起的宿主免疫应答反应中，T细胞经体外诱导分化后，IL-9可以来自于细胞因子诱导分化下的Th9细胞。
金黄色葡萄球菌(Staphyloccocus aureus，S. aureus)是一种有鞭毛、无芽胞、多数无荚膜的革兰阳性胞外细菌，显微镜下形态为圆球型，直径约0.8μm，葡萄串状(1)。金黄色葡萄球菌是人类重要的致病菌，可引发从皮肤和软组织感染到侵袭性感染疾病，包括肺炎、骨髓炎、脓毒性关节炎、菌血症、心内膜炎和蜂窝织炎等。由金黄色葡萄球菌引起的肺炎占医源性肺炎和社区性肺炎的比例分别为20-50%和25.5%，导致严重的肺内感染，具有高发病率及高死亡率(2,3)。金黄色葡萄球菌的致病力强弱主要取决于其产生的多种毒素和侵袭性酶,包括：血浆凝固酶、葡萄球菌溶血素、杀白细胞素、肠毒素、表皮溶解毒素、毒性休克综合毒素Ⅰ和葡激酶。近年来，金黄色葡萄球菌和甲氧西林易感金黄色葡萄球菌感染引起后天免疫性群体耐甲氧西林金黄色葡萄球(community-acquired methicillin-resistant S. aureus, CA-MRSA)，它能抵抗人类目前所有β-内酰胺类抗菌药物，给临床治疗带来很大困难，引起人们的高度重视。
在固有性免疫应答中，根据TCR双肽链结构的不同，可将T细胞分为αβ T细胞和γδ T细胞两类。其中γδ T细胞在人和动物体内表达量较少，主要分布在皮肤和呼吸道、消化道、生殖系统等黏膜组织部位。多数γδ T细胞表面不表达MHC I和MHCII类分子自身识别的CD8和CD4共受体分子。Γδ T细胞是固有免疫和获得性免疫联系的桥梁，具有免疫监视、免疫调节、肿瘤细胞识别等功能。在细菌感染的宿主免疫应答反应中，γδ T细胞发挥重要功能，是固有免疫的第一道防线。根据细胞因子分泌的不同可分为两种的Vγ1~+和Vγ4~+细胞亚群。
金黄色葡萄球菌感染可引起宿主体内的固有性免疫应答反应，入侵的病原微生物入可诱导宿主大量的中性粒细胞被募集到感染部位清除病原菌(4)。尽管肺部的γδ T细胞只占据固有性免疫细胞中的一小部分，但他们在病原微生物入侵中是抵御病原微生物的第一道防线。根据文献报道，在肺炎克雷伯氏菌、结核分枝杆菌、肺炎链球菌引起的肺部感染，去除γδ T细胞可降低宿主免疫保护功能，导致更严重的肺组织炎症损伤。而γδ T细胞在金黄色葡萄球菌诱导的皮肤病中具有重要作用。近年来，γδ T细胞在金黄色葡萄球菌感染的肺组织炎症中的免疫应答作用和机制还未见报道。
为了研究γδ T细胞在急性金黄色葡萄球菌肺炎中的作用，本课题建立金黄色葡萄球菌株感染的野生型(WT) C57BL/6小鼠和TCR-δ~(-/-)小鼠的肺炎模型，以γδ T细胞为研究对象，初步探讨了在金黄色葡萄球菌的肺炎中γδ T细胞对宿主机体的免疫应答作用和机制研究。
方法
1. S.aures/75菌株感染C57BL/6、B6TCR-δ~(-/-)小鼠模型建立方法
2.肺组织中指标检测
2.1细菌定植总数评价
2.2肺组织病理切片的苏木精-伊红(hematoxylin-eosin, HE)染色
2.3Real-time PCR法检测小鼠肺组织细胞因子的mRNA表达
2.4.流式细胞技术检测细胞内因子
结果
1.在S.aures/75菌株感染小鼠肺炎中小鼠肺组织γδ T细胞明显增加，Vγ4~+细胞亚型数量多于Vγ1~+亚型。
2. TCR-δ~(-/-)小鼠可导致宿主对细菌清除减弱和急性肺损伤的严重程度减弱。
3.感染S.aures/75菌株后，在TCR-δ~(-/-)小鼠感染部位，表现出中性粒细胞的募集被抑制及细胞因子产生减少的现象。
4. S.aures/75菌株感染可早期诱导WT小鼠在肺组织局部引起γδ T细胞免疫应答反应，产细胞因子IL-17。但在TCR-δ~(-/-)小鼠感染组中，γδ T细胞的缺失导致IL-17的产生的缺失。
5. γδ T细胞的缺失导致中性粒细胞募集受到抑制。
结论
1.在S.aures/75菌株感染的肺组织中，γδ T细胞的增加有助于宿主体内细菌的清除和肺组织炎症损伤。
2. γδ T细胞是细胞因子IL-17的主要来源，在S.aures/75菌株感染早期可能影响中性粒细胞的募集。
Helicobacter pylori (H. pylori) is a helix-shaped, Gram-negative bacterium found inthe stomach and duodenum. Recently, it has been well identified that H. pylori can causeacute or chronic gastritis, even peptic ulcers and gastric cancer in human. It is subdividedinto cagA-positive (type Ⅰ) and cagA-negative strains (typeⅡ). In most clinical cases,atrophic gastritis is caused by typeⅠH. pylori and is highly associated with gastric cancer.The cytotoxin associated protein (CagA) is delivered into host gastric epithelial cellsthrough type IV secretion system, and phosphorylated, and then it activates downstreamcell signal pathways and causes the gastric epithelial cells shaped into hummingbird cellsand more severe infectious symptoms. The infected epithelial cells release large amounts ofcytokines and chemokines and induce the the host’s cell immune responses. It’s proved thatCD4~~+T cells play important roles in H. pylori infection. IL-9is a T cell growth factor found inTh2cell lines by Uyttenhove in1988. IL-9can function as either a positive or a negativeregulator of immune responses. In2011, Stephens et al found that IL-9secreted by Th17cells can indirectly inhibit Th17cells’ immune activities through stimulating proliferationof mucosa mast cells. They propose that whether IL-9functioning as a proinflammatory orantiinflammatory cytokine is depended on the microenviroment caused by the diseases.Recently, a lot pf papers have reported the dual functions of IL-9. On the one hand, IL-9promotes inflammatory and allergy through activating macrophage, mast cell andeosinophilic granulocyte; on the other hand, IL-9negatively reguates inflammatory inducedby viruses and inhances nTreg cells’ immune inhibition activity. In a mouse model ofasthma, Arnold reveled that H. pylori infection can reduce the severity of asthma byinducing iTreg cells. It showed that H. pylori infection may have a negative correlation withasthma. In summary, CD4~+T cells are involved in the host’s immune response, but itremains unclear whether IL-9is involved in the immune response and what regulateryfunction it plays.
In this study, we use H. pylori/B0strain to infect wide type (WT) BALB/c mice and IL-9knock-out (IL-9ko) mice, in order to investigate the relationship between IL-9~+CD4~+Tcells/IL-9and H. pylori infection. It will provide new guides and thoughts for the study ofIL-9~+CD4~+T cells’ roles in the natural process of H. pylori infection.
Methods
1.Cytokine test in blood samples of H.pylori infected persons
Serum samples of clinical donors were collected and divided into H.pylori infectionpositive and negative groups based on the results of H.pylori-specific antibody test. Thenthe IL-9protein levels in the serum samples were tested by ELISA.
IL-9detection in H.pylori infected mouse model
(1) Establishment of H.pylori/B0infected BALB/c and IL9ko mouse model.
(2) IL-9detection in H.pylori/B0infected mouse model.
3. Preliminary function study of IL-9in H.pylori infected mouse model
(1) Bacteria loads detection in stomach of mouse model.
(2)Inflammation scoring and analysis of histopathological changes (H.E staining) ofgastric tissue.
4.Cell resources of IL-9in H.pylori/B0infected mouse model
(1) Inducing differentiation of IL-9-producing T cells in peripheral blood of H.pyloriinfected persons.
(2)Inducing differentiation of IL-9-producing T cells in mouse spleen.
Results
1.Serum IL-9levels were significantly higher in H.pylori-negative group than inH.pylori-positive group.
2.Compared to uninfected control group, bacteria loads in stomachs of H.pyloriinfected WT mice were increased at any time points after infection.It indicated thesuccessful establishment of H.pylori/B0strain infected mouse model. On day28, mRNAexpression levels of IL-17, especially of IFN-γ and IL-10,were significantly increased inH.pylori infected group than control group.While the mRNA expression level of IL-9issignificantly lower in infected group.
3.Bacteria loads in stomachs of H.pylori infected BALB/c mice reached maximum onday28after infection, and maintained high a week before and after this day, and then began to decrease on day35. Bacteria loads in stomachs of H.pylori infected IL-9ko mice thaninfected BALB/c mice and also reached peak on day28. Pathological changes of stomachsections under the same experiment condition were analyzed and it shows thatinflammatory cell infiltration in laminae propria was higher in IL-9ko group than WTgroup.
4.IL-9~+CD4~+T cells’percentage in PBMC of H.pylori infection negative and positivepersons was1.9％and0.914％, respectively. The result was validated in mice, too.IL-9~+CD4~+T cells’percentage in mononuclear cells of mice splenocytes was0.7％and0.31％, respectively. When adding the cytokines into the PBMC or mononuclear cells ofH.pylori infection for unspecific activation, IL-9~+CD4~+T cells’percentage were notablelyincreased.
Conclusions
Both mRNA expression and cellular production of IL-9were decreased in H.pyloriinfected persons and mice. In H.pylori/B0infected WT and IL9ko mouse model, bacterialoads of H.pylori/B0were negatively related to inflammatory injury.
In host immune to H.pylori/B0strain, CD4~+T cells decreased IL-9secretion indicatedthat IL-9~+CD4~+T cells could inhibition of host Th9cell immune response.
Staphylococcus aureus (S.aureus) is a flagellum, non-endospore, non-capsulated,Gram-positive, extracellular bacterium. The shape under the microscope is spheroidal, thediameter is0.8μm, and thyrsiform. Staphylococcus aureus is important pathogenicbacterium causing that a lot of infections ranging from skin and soft tissue infections,including pneumonia, osteomyelitis, septic arthritis, bacteremia, endocarditic and cellulitis.S.aureus-induced pneumonia accounts for25.5%of community-acquired pneumonia and20-50%nosocomial pneumonia, which could cause especially severe pulmonary infectionand is associated with high morbidity and mortality. Pathogenicity of S.aureus isprincipally depended on multiple toxin and invasive enzyme, such as plasma-coagulase,Staphyolysin, Leukocidin, Enterotoxin, Epidermolytic toxin, Toxic shock syndrome toxin1,Staphylokinase. In recent years, S. aureus infections and methicillin susceptible S. aureus(MSSA) caused community-acquired methicillin-resistant S. aureus (CA-MRSA). It couldresist all kinds of human Beta-lactam antibiotics and clinical treatment was became toodifficult.
In innate immune responses, according to the different structure of TCR’s doublechain, Tcells are divided into αβ T cells and γδ T cells. γδ T cells are Lower expression inhuman and animal,and are distributed mainly over skin, respiratory passages, alimentarytract, genital system. Majority γδ T cells surface do not express adaptor molecule of CD8and CD4through MHC I and MHC II molecule self recognition. γδ Tcell is worked as abridge between inherent immunity and acquired immunity, which have function such asimmune surveillance, immunoloregulation, Tumor cell recognition. In host immune, γδTcell play an important role as the first protector against the entry of microorganisms.According to the different cytokine secretory, γδ Tcell are divided into Vγ1~+cell andVγ4~+cell subsets.
Staphylococcus aureus can revoke innate immune responses in host, the entry ofmicroorganisms induce abundant neutrophil to the site of infection for removal of pathogenic bacteria. In spite of γδ Tcells in lung tissue were occupied a small part of innateimmune cell, γδ Tcell worked as the first protector against the entry of microorganisms.According to the study, k.pneumoniae, Mycobacterium tuberculosis, streptococcuspneumoniae induced pulmonary infection, γδ Tcell can decrease the host immuneprotection function and lead to more serious inflammatory lung injury. γδ Tcell play animportant role in Staphylococcus aureus-induced skin disease. In recent years, the role ofimmune response and mechanism of γδ Tcell has not been reported in the lung tissueinflammation of Staphylococcus aureus infection.
In order to study the effect of γδ Tcells in acute Staphylococcus aureus pneumonia, inthis work, we establish the Staphylococcus aureus strains infection model of pneumonia inC57BL/6mice and TCR-δ~(-/-)mice. In order to γδ Tcells as the research object, we havepreliminary study on Staphylococcus aureus pneumonia gamma delta T cells of the hostimmune response and mechanism research.
Methods:
1.Establishment of Staphylococcus aureus infected C57BL/6and TCR-δ~(-/-)micemodel.
2. Detection index in lung tissue
2.1The total number of bacterial load evaluation.
2.2Lung tissue pathological section hematoxylin-eosin staining (hematoxylin-eosin,HE).
2.3To detect the expression of cytokines in lung tissue of mice Real-time by PCRmRNA.
2.4Flow cytometry were used to study the cytokine.
Results:
1. In S.aures/75strain infection pneumonia of mice lung tissue, γδ Tcells are increaseand the number of V γ4~+cell subsets aremore than V γ1~+subsets.
2. TCR-δ~(-/-)mice can lead to host the bacterial clearance severity weaken and acutelung injury.
3. Infection of S.aures/75, in the TCR-δ~(-/-)mice infected site, showed neutrophilrecruitment was inhibited and cytokine production to reduce the phenomenon.
4. S.aures/75strain infection can be localized by γδ Tcell immune response in the lungtissue of mice induced by early WT, production of cytokines IL-17. But in the TCR-δ~(-/-)mice infected group, lack of γδ Tcells leading to the generation of IL-17deletion.
5. Lack of γδ T cells caused by inhibition of neutrophil recruitment.
Conclusions:
1. In the lung tissue infected with S.aures/75strain, γδ Tcells increased inflammatoryinjury of lung tissue and helped the bacterial clearance in the host.
2. γδ Tcells are a major source of cytokines IL-17, and S.aures/75strain infection inearly may influence neutrophil recruitment.
本课题将以IL-9~+CD4~+T细胞为主要研究对象，在H.pylori/B0菌株感染野生型(widetype, WT)BALB/c小鼠和IL-9基因敲除(IL-9ko)小鼠的模型下，初步研究IL-9~+CD4~+T细胞/IL-9与幽门螺杆菌感染的相关性研究，将为深入探讨IL-9~+CD4~+T细胞在H.pylori自然感染条件下发挥复杂的免疫学功能提供新的参考和指导。
方法
1. H.pylori菌株感染受检者血标本中细胞因子检测
收集了临床受检者的血清，通过检测血清中抗H.pylori特异性抗体把标本分为H.pylori感染阳性和阴性2组，通过ELISA方法检测人外周血清中IL-9蛋白水平的表达。
2. IL-9在幽门螺杆菌感染小鼠模型中的表达检测
(1) H.pylori/B0菌株感染BALB/c、IL-9ko小鼠模型建立方法
(2) IL-9在幽门螺杆菌感染小鼠模型中动态表达检测
3. IL-9在幽门螺杆菌感染小鼠模型中功能的初步研究
(1) H. pylori/B0在小鼠胃内定植量水平检测
(2)胃组织炎症评分及病理HE染色结果分析
4. IL-9在幽门螺杆菌感染中的细胞来源研究
(1)幽门螺杆菌患者外周血产IL-9的T细胞的诱导分化研究
(2)幽门螺杆菌感染小鼠脾脏产IL-9的T细胞的诱导分化研究
结果
1.临床血清标本中细胞因子IL-9在H.pylori感染阴性受检者中表达明显高于H.pylori感染阳性受检者。
2.相对于H.pylori/B0未感染组，野生型小鼠背景的H.pylori感染组的胃部H.pylori/B0定植在在感染后各个时间点明显增高。结果证明H.pylori感染小鼠的动态评价模型建立成功。28天时，H. pylori/B0菌株感染BALB/c与未感染对照组相比，细胞因子IL-17、IFN-γ和IL-10的mRNA水平都有显著提高，相比之下IL-10和IFN-γ增加更明显。而感染组IL-9的mRNA水平较未感染组显著下降。
3. BALB/c小鼠在H. pylori/B0菌株感染后的第28天胃内定植量达到最高值，其前后一周内维持在较高水平，但35d后定植量开始逐渐下降。IL-9ko感染组小鼠胃组织内定植量水平高于BALB/c小鼠感染组，在感染后第28天检测胃内定植量也达到峰值。IL-9ko小鼠在敲除细胞因子IL-9后，H. pylori/B0菌株感染小鼠胃粘膜组织的定植量比WT感染组小鼠高。在相同实验条件下，观察HE染色病理切片，IL-9ko感染组胃固有层部位炎症细胞侵润比WT感染组更多且胃粘膜表面局部有少量壁细胞破损。
4. H.pylori菌株感染阴性受检者和阳性受检者PBMC中的IL-9~+CD4~+T细胞占CD4T淋巴细胞的比例分别为1.9％和0.914％，统计结果也显示阴性受检者组IL-9~+CD4~+T细胞比阳性受检者组多。在小鼠体内再次验证以上结果，H.pylori.B0菌株感染阴性小鼠和阳性小鼠脾单个核细胞中的IL-9~+CD4~+T细胞占CD4T淋巴细胞的比例分别为0.7％和0.31％，统计结果也显示阴性受检者组IL-9~+CD4~+T细胞比阳性受检者组多。且加入适当细胞因子可诱导IL-9~+CD4~+T细胞的分泌IL-9。
结论
1. H.pylori感染人和动物体后，细胞因子IL-9在转录水平和细胞水平都下降。在WT和IL-9ko小鼠感染模型中，验证IL-9与H.pylori/B0引起的免疫应答反应相关。
2.在H.pylori感染后引起的宿主免疫应答反应中，T细胞经体外诱导分化后，IL-9可以来自于细胞因子诱导分化下的Th9细胞。
金黄色葡萄球菌(Staphyloccocus aureus，S. aureus)是一种有鞭毛、无芽胞、多数无荚膜的革兰阳性胞外细菌，显微镜下形态为圆球型，直径约0.8μm，葡萄串状(1)。金黄色葡萄球菌是人类重要的致病菌，可引发从皮肤和软组织感染到侵袭性感染疾病，包括肺炎、骨髓炎、脓毒性关节炎、菌血症、心内膜炎和蜂窝织炎等。由金黄色葡萄球菌引起的肺炎占医源性肺炎和社区性肺炎的比例分别为20-50%和25.5%，导致严重的肺内感染，具有高发病率及高死亡率(2,3)。金黄色葡萄球菌的致病力强弱主要取决于其产生的多种毒素和侵袭性酶,包括：血浆凝固酶、葡萄球菌溶血素、杀白细胞素、肠毒素、表皮溶解毒素、毒性休克综合毒素Ⅰ和葡激酶。近年来，金黄色葡萄球菌和甲氧西林易感金黄色葡萄球菌感染引起后天免疫性群体耐甲氧西林金黄色葡萄球(community-acquired methicillin-resistant S. aureus, CA-MRSA)，它能抵抗人类目前所有β-内酰胺类抗菌药物，给临床治疗带来很大困难，引起人们的高度重视。
在固有性免疫应答中，根据TCR双肽链结构的不同，可将T细胞分为αβ T细胞和γδ T细胞两类。其中γδ T细胞在人和动物体内表达量较少，主要分布在皮肤和呼吸道、消化道、生殖系统等黏膜组织部位。多数γδ T细胞表面不表达MHC I和MHCII类分子自身识别的CD8和CD4共受体分子。Γδ T细胞是固有免疫和获得性免疫联系的桥梁，具有免疫监视、免疫调节、肿瘤细胞识别等功能。在细菌感染的宿主免疫应答反应中，γδ T细胞发挥重要功能，是固有免疫的第一道防线。根据细胞因子分泌的不同可分为两种的Vγ1~+和Vγ4~+细胞亚群。
金黄色葡萄球菌感染可引起宿主体内的固有性免疫应答反应，入侵的病原微生物入可诱导宿主大量的中性粒细胞被募集到感染部位清除病原菌(4)。尽管肺部的γδ T细胞只占据固有性免疫细胞中的一小部分，但他们在病原微生物入侵中是抵御病原微生物的第一道防线。根据文献报道，在肺炎克雷伯氏菌、结核分枝杆菌、肺炎链球菌引起的肺部感染，去除γδ T细胞可降低宿主免疫保护功能，导致更严重的肺组织炎症损伤。而γδ T细胞在金黄色葡萄球菌诱导的皮肤病中具有重要作用。近年来，γδ T细胞在金黄色葡萄球菌感染的肺组织炎症中的免疫应答作用和机制还未见报道。
为了研究γδ T细胞在急性金黄色葡萄球菌肺炎中的作用，本课题建立金黄色葡萄球菌株感染的野生型(WT) C57BL/6小鼠和TCR-δ~(-/-)小鼠的肺炎模型，以γδ T细胞为研究对象，初步探讨了在金黄色葡萄球菌的肺炎中γδ T细胞对宿主机体的免疫应答作用和机制研究。
方法
1. S.aures/75菌株感染C57BL/6、B6TCR-δ~(-/-)小鼠模型建立方法
2.肺组织中指标检测
2.1细菌定植总数评价
2.2肺组织病理切片的苏木精-伊红(hematoxylin-eosin, HE)染色
2.3Real-time PCR法检测小鼠肺组织细胞因子的mRNA表达
2.4.流式细胞技术检测细胞内因子
结果
1.在S.aures/75菌株感染小鼠肺炎中小鼠肺组织γδ T细胞明显增加，Vγ4~+细胞亚型数量多于Vγ1~+亚型。
2. TCR-δ~(-/-)小鼠可导致宿主对细菌清除减弱和急性肺损伤的严重程度减弱。
3.感染S.aures/75菌株后，在TCR-δ~(-/-)小鼠感染部位，表现出中性粒细胞的募集被抑制及细胞因子产生减少的现象。
4. S.aures/75菌株感染可早期诱导WT小鼠在肺组织局部引起γδ T细胞免疫应答反应，产细胞因子IL-17。但在TCR-δ~(-/-)小鼠感染组中，γδ T细胞的缺失导致IL-17的产生的缺失。
5. γδ T细胞的缺失导致中性粒细胞募集受到抑制。
结论
1.在S.aures/75菌株感染的肺组织中，γδ T细胞的增加有助于宿主体内细菌的清除和肺组织炎症损伤。
2. γδ T细胞是细胞因子IL-17的主要来源，在S.aures/75菌株感染早期可能影响中性粒细胞的募集。
Helicobacter pylori (H. pylori) is a helix-shaped, Gram-negative bacterium found inthe stomach and duodenum. Recently, it has been well identified that H. pylori can causeacute or chronic gastritis, even peptic ulcers and gastric cancer in human. It is subdividedinto cagA-positive (type Ⅰ) and cagA-negative strains (typeⅡ). In most clinical cases,atrophic gastritis is caused by typeⅠH. pylori and is highly associated with gastric cancer.The cytotoxin associated protein (CagA) is delivered into host gastric epithelial cellsthrough type IV secretion system, and phosphorylated, and then it activates downstreamcell signal pathways and causes the gastric epithelial cells shaped into hummingbird cellsand more severe infectious symptoms. The infected epithelial cells release large amounts ofcytokines and chemokines and induce the the host’s cell immune responses. It’s proved thatCD4~~+T cells play important roles in H. pylori infection. IL-9is a T cell growth factor found inTh2cell lines by Uyttenhove in1988. IL-9can function as either a positive or a negativeregulator of immune responses. In2011, Stephens et al found that IL-9secreted by Th17cells can indirectly inhibit Th17cells’ immune activities through stimulating proliferationof mucosa mast cells. They propose that whether IL-9functioning as a proinflammatory orantiinflammatory cytokine is depended on the microenviroment caused by the diseases.Recently, a lot pf papers have reported the dual functions of IL-9. On the one hand, IL-9promotes inflammatory and allergy through activating macrophage, mast cell andeosinophilic granulocyte; on the other hand, IL-9negatively reguates inflammatory inducedby viruses and inhances nTreg cells’ immune inhibition activity. In a mouse model ofasthma, Arnold reveled that H. pylori infection can reduce the severity of asthma byinducing iTreg cells. It showed that H. pylori infection may have a negative correlation withasthma. In summary, CD4~+T cells are involved in the host’s immune response, but itremains unclear whether IL-9is involved in the immune response and what regulateryfunction it plays.
In this study, we use H. pylori/B0strain to infect wide type (WT) BALB/c mice and IL-9knock-out (IL-9ko) mice, in order to investigate the relationship between IL-9~+CD4~+Tcells/IL-9and H. pylori infection. It will provide new guides and thoughts for the study ofIL-9~+CD4~+T cells’ roles in the natural process of H. pylori infection.
Methods
1.Cytokine test in blood samples of H.pylori infected persons
Serum samples of clinical donors were collected and divided into H.pylori infectionpositive and negative groups based on the results of H.pylori-specific antibody test. Thenthe IL-9protein levels in the serum samples were tested by ELISA.
IL-9detection in H.pylori infected mouse model
(1) Establishment of H.pylori/B0infected BALB/c and IL9ko mouse model.
(2) IL-9detection in H.pylori/B0infected mouse model.
3. Preliminary function study of IL-9in H.pylori infected mouse model
(1) Bacteria loads detection in stomach of mouse model.
(2)Inflammation scoring and analysis of histopathological changes (H.E staining) ofgastric tissue.
4.Cell resources of IL-9in H.pylori/B0infected mouse model
(1) Inducing differentiation of IL-9-producing T cells in peripheral blood of H.pyloriinfected persons.
(2)Inducing differentiation of IL-9-producing T cells in mouse spleen.
Results
1.Serum IL-9levels were significantly higher in H.pylori-negative group than inH.pylori-positive group.
2.Compared to uninfected control group, bacteria loads in stomachs of H.pyloriinfected WT mice were increased at any time points after infection.It indicated thesuccessful establishment of H.pylori/B0strain infected mouse model. On day28, mRNAexpression levels of IL-17, especially of IFN-γ and IL-10,were significantly increased inH.pylori infected group than control group.While the mRNA expression level of IL-9issignificantly lower in infected group.
3.Bacteria loads in stomachs of H.pylori infected BALB/c mice reached maximum onday28after infection, and maintained high a week before and after this day, and then began to decrease on day35. Bacteria loads in stomachs of H.pylori infected IL-9ko mice thaninfected BALB/c mice and also reached peak on day28. Pathological changes of stomachsections under the same experiment condition were analyzed and it shows thatinflammatory cell infiltration in laminae propria was higher in IL-9ko group than WTgroup.
4.IL-9~+CD4~+T cells’percentage in PBMC of H.pylori infection negative and positivepersons was1.9％and0.914％, respectively. The result was validated in mice, too.IL-9~+CD4~+T cells’percentage in mononuclear cells of mice splenocytes was0.7％and0.31％, respectively. When adding the cytokines into the PBMC or mononuclear cells ofH.pylori infection for unspecific activation, IL-9~+CD4~+T cells’percentage were notablelyincreased.
Conclusions
Both mRNA expression and cellular production of IL-9were decreased in H.pyloriinfected persons and mice. In H.pylori/B0infected WT and IL9ko mouse model, bacterialoads of H.pylori/B0were negatively related to inflammatory injury.
In host immune to H.pylori/B0strain, CD4~+T cells decreased IL-9secretion indicatedthat IL-9~+CD4~+T cells could inhibition of host Th9cell immune response.
Staphylococcus aureus (S.aureus) is a flagellum, non-endospore, non-capsulated,Gram-positive, extracellular bacterium. The shape under the microscope is spheroidal, thediameter is0.8μm, and thyrsiform. Staphylococcus aureus is important pathogenicbacterium causing that a lot of infections ranging from skin and soft tissue infections,including pneumonia, osteomyelitis, septic arthritis, bacteremia, endocarditic and cellulitis.S.aureus-induced pneumonia accounts for25.5%of community-acquired pneumonia and20-50%nosocomial pneumonia, which could cause especially severe pulmonary infectionand is associated with high morbidity and mortality. Pathogenicity of S.aureus isprincipally depended on multiple toxin and invasive enzyme, such as plasma-coagulase,Staphyolysin, Leukocidin, Enterotoxin, Epidermolytic toxin, Toxic shock syndrome toxin1,Staphylokinase. In recent years, S. aureus infections and methicillin susceptible S. aureus(MSSA) caused community-acquired methicillin-resistant S. aureus (CA-MRSA). It couldresist all kinds of human Beta-lactam antibiotics and clinical treatment was became toodifficult.
In innate immune responses, according to the different structure of TCR’s doublechain, Tcells are divided into αβ T cells and γδ T cells. γδ T cells are Lower expression inhuman and animal,and are distributed mainly over skin, respiratory passages, alimentarytract, genital system. Majority γδ T cells surface do not express adaptor molecule of CD8and CD4through MHC I and MHC II molecule self recognition. γδ Tcell is worked as abridge between inherent immunity and acquired immunity, which have function such asimmune surveillance, immunoloregulation, Tumor cell recognition. In host immune, γδTcell play an important role as the first protector against the entry of microorganisms.According to the different cytokine secretory, γδ Tcell are divided into Vγ1~+cell andVγ4~+cell subsets.
Staphylococcus aureus can revoke innate immune responses in host, the entry ofmicroorganisms induce abundant neutrophil to the site of infection for removal of pathogenic bacteria. In spite of γδ Tcells in lung tissue were occupied a small part of innateimmune cell, γδ Tcell worked as the first protector against the entry of microorganisms.According to the study, k.pneumoniae, Mycobacterium tuberculosis, streptococcuspneumoniae induced pulmonary infection, γδ Tcell can decrease the host immuneprotection function and lead to more serious inflammatory lung injury. γδ Tcell play animportant role in Staphylococcus aureus-induced skin disease. In recent years, the role ofimmune response and mechanism of γδ Tcell has not been reported in the lung tissueinflammation of Staphylococcus aureus infection.
In order to study the effect of γδ Tcells in acute Staphylococcus aureus pneumonia, inthis work, we establish the Staphylococcus aureus strains infection model of pneumonia inC57BL/6mice and TCR-δ~(-/-)mice. In order to γδ Tcells as the research object, we havepreliminary study on Staphylococcus aureus pneumonia gamma delta T cells of the hostimmune response and mechanism research.
Methods:
1.Establishment of Staphylococcus aureus infected C57BL/6and TCR-δ~(-/-)micemodel.
2. Detection index in lung tissue
2.1The total number of bacterial load evaluation.
2.2Lung tissue pathological section hematoxylin-eosin staining (hematoxylin-eosin,HE).
2.3To detect the expression of cytokines in lung tissue of mice Real-time by PCRmRNA.
2.4Flow cytometry were used to study the cytokine.
Results:
1. In S.aures/75strain infection pneumonia of mice lung tissue, γδ Tcells are increaseand the number of V γ4~+cell subsets aremore than V γ1~+subsets.
2. TCR-δ~(-/-)mice can lead to host the bacterial clearance severity weaken and acutelung injury.
3. Infection of S.aures/75, in the TCR-δ~(-/-)mice infected site, showed neutrophilrecruitment was inhibited and cytokine production to reduce the phenomenon.
4. S.aures/75strain infection can be localized by γδ Tcell immune response in the lungtissue of mice induced by early WT, production of cytokines IL-17. But in the TCR-δ~(-/-)mice infected group, lack of γδ Tcells leading to the generation of IL-17deletion.
5. Lack of γδ T cells caused by inhibition of neutrophil recruitment.
Conclusions:
1. In the lung tissue infected with S.aures/75strain, γδ Tcells increased inflammatoryinjury of lung tissue and helped the bacterial clearance in the host.
2. γδ Tcells are a major source of cytokines IL-17, and S.aures/75strain infection inearly may influence neutrophil recruitment.
引文
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