【摘要】：冠心病(coronary heart disease CHD)是20世紀(jì)以來威脅人類生命健康的最主要疾病之一,而且其發(fā)病率越來越高,其發(fā)病原因及防治方法一直是社會關(guān)注的焦點。冠心病的診治方法日漸完善,但其發(fā)病機(jī)制卻未十分明了。動脈粥樣硬化(atherosclerosis AS)是心腦血管疾病發(fā)病的主要病理基礎(chǔ)。AS的形成機(jī)制學(xué)說主要有脂質(zhì)沉淀、損傷修復(fù)、血栓形成等。眾所周知,心臟病家族史、性別、高齡、吸煙、高血壓病、糖尿病、高脂血癥等是AS的高危因素,近年研究表明感染因素如肺炎衣原體、幽門螺旋桿菌、巨細(xì)胞病毒等也與CHD有重要關(guān)系。急性冠脈綜合征是冠心病的一個重要進(jìn)展階段,而易損斑塊是急性冠脈綜合征的主要病理基礎(chǔ)。國內(nèi)外的研究發(fā)現(xiàn),炎癥反應(yīng)在易損斑塊的進(jìn)展中發(fā)揮著重要的作用,是斑塊不穩(wěn)定及容易破裂的主要原因,因而CHD可能是一種冠狀動脈慢性炎癥及全身免疫性疾病。 樹突狀細(xì)胞(Dendritic cell, DCs)在免疫過程中主要起抗原呈遞作用,是體內(nèi)功能最強的專職抗原呈遞細(xì)胞。極少量的DCs即可強烈激活T淋巴細(xì)胞啟動特異性細(xì)胞免疫反應(yīng)。國內(nèi)外研究發(fā)現(xiàn),正常動脈內(nèi)膜存在一種血管相關(guān)淋巴組織(VALT),散在分布著一些由免疫活性細(xì)胞和抗原呈遞細(xì)胞組成的細(xì)胞群,對血管組織中可能有害的內(nèi)源性或外源性抗原進(jìn)行監(jiān)視和篩查。研究發(fā)現(xiàn),DCs在AS病變中聚集明顯增加,DCs與T淋巴細(xì)胞共同出現(xiàn)于AS的病變薄弱位置。當(dāng)DC遇到內(nèi)源性或外源性抗原時,可將抗原呈遞給T細(xì)胞,使其活化增殖,分泌細(xì)胞因子,然后啟動一系列免疫反應(yīng),導(dǎo)致AS的發(fā)生發(fā)展。最近的研究顯示氧化修飾的低密度脂蛋白可通過激活DCs介導(dǎo)的獲得性免疫反應(yīng),促進(jìn)AS病變的進(jìn)展。 研究發(fā)現(xiàn),氧化型低密度脂蛋白(oxidized low density lipoprotein, ox-LDL)是一種內(nèi)源性免疫反應(yīng)激活劑,可引起血管內(nèi)皮功能失調(diào)、參與泡沫細(xì)胞形成、促進(jìn)血管平滑肌細(xì)胞增殖及誘導(dǎo)凋亡等。已有的研究表明,ox-LDL在動脈粥樣硬化局部沉積后,促進(jìn)DC與血管內(nèi)皮粘附,并且作為自身抗原刺激局部產(chǎn)生抗氧化型低密度脂蛋白抗體,促進(jìn)DC分化成熟,并激活T淋巴細(xì)胞,參與動脈粥樣硬化局部免疫炎癥病變。適度ox-LDL可促進(jìn)單核細(xì)胞來源的樹突狀細(xì)胞成熟,增強其激活T細(xì)胞的功能,增加DC分泌細(xì)胞因子IL-2、IL-12、IL-18、INF-γ(?)(?)TNFα等,并且這些作用隨ox-LDL濃度和氧化程度的增高而增強,但是過高的濃度卻會導(dǎo)致DCs凋亡 越來越多研究發(fā)現(xiàn),多種炎癥標(biāo)志物參與了CHD的發(fā)生、發(fā)展及預(yù)后,如IL-6、IL-10、IL-18、IL-12及超敏C反應(yīng)蛋白(high sensitive C-reactive protein, hs-CRP)等。IL-27 (Interleukin-27, IL-27)是新近發(fā)現(xiàn)的屬于IL-6/IL-12家族細(xì)胞因子,由p28和EBI3組成,具有促進(jìn)及抑制免疫反應(yīng)的雙重作用。由于IL-27在免疫反應(yīng)和免疫耐受的調(diào)節(jié)中扮演了不可或缺的角色,因此在炎癥性、自身免疫性、感染性、腫瘤性疾病中均發(fā)現(xiàn)IL-27的表達(dá)及功能變化。但是在冠心病的研究中卻十分稀少,本研究通過檢測不同類型冠心病患者的血漿IL-27水平,了解CHD患者血漿IL-27的變化,并探討它們之間的關(guān)系。 IL-27主要由活化的DC細(xì)胞產(chǎn)生,單核細(xì)胞、巨噬細(xì)胞、NK細(xì)胞等也可以分泌一定量的IL-27,當(dāng)DCs表面的Toll樣受體(TLRs)受到病原體相關(guān)分子模式(PAMP)刺激后會分泌IL-27。人外周血單核細(xì)胞來源的DC表達(dá)IL-27受體(EBI3和p28組成的異二聚體),提示IL-27能夠?qū)魏思?xì)胞來源的DC產(chǎn)生影響,它可以反饋作用于DCs,促進(jìn)DCs表面共刺激分子的表達(dá)以及提高其激活輔助性T細(xì)胞(Th)的能力。國外研究學(xué)者發(fā)現(xiàn)WSX-1敲除的小鼠中DC在體外受到LPS刺激后表面分子CD80/CD86表達(dá)上調(diào),誘導(dǎo)Thl細(xì)胞增殖和產(chǎn)生IFN-γ的能力也大大提高。 DCs是聯(lián)系天然防御功能和獲得性免疫的關(guān)鍵,與CHD發(fā)生發(fā)展密切相關(guān),那么在CHD發(fā)生發(fā)展的機(jī)制中,IL-27是否通過作用于DCs發(fā)揮免疫調(diào)節(jié)功能?IL-27處理后DCs的功能狀態(tài)如何,是否會影響其功能蛋白及免疫調(diào)節(jié)分子的分泌?本文旨在研究IL-27對體外擴(kuò)增DC免疫活性的影響,為IL-27結(jié)合DC用于CHD免疫機(jī)制研究提供依據(jù)。 本課題分為三個部分,第一部分：通過ELISA法及免疫比濁法分別檢測不同類型冠狀動脈粥樣硬化性心臟病(簡稱冠心病,CHD)患者血漿白介素27(IL-27)及超敏C反應(yīng)蛋白(hs-CRP)的水平,并進(jìn)行比較,以探討IL-27是否與冠心病的進(jìn)展以及粥樣斑塊的穩(wěn)定密切相關(guān)。第二部分：將人PBMC來源的DC作為實驗?zāi)Ｐ?以O(shè)X-LDL作為抗原誘導(dǎo)DC成熟,用RT—PCR的方法測定DC產(chǎn)生IL-27亞基的情況,探討人體內(nèi)IL-27的由來。第三部分：將人PBMC來源的DC作為實驗?zāi)Ｐ?以O(shè)X-LDL作為抗原誘導(dǎo)DC成熟,用流式細(xì)胞技術(shù)及ELISA方法,觀察DC的成熟程度和分泌細(xì)胞因子的能力,并進(jìn)一步應(yīng)用IL-27進(jìn)行干預(yù)研究。本課題通過研究IL-27對體外擴(kuò)增DC免疫活性的影響,為IL-27結(jié)合DC用于CHD免疫機(jī)制研究提供依據(jù),為AS發(fā)生發(fā)展的免疫學(xué)介導(dǎo)學(xué)說提供實驗依據(jù),具有深遠(yuǎn)的意義。結(jié)果分述如下： 1不同CHD患者血漿中IL-27及hs-CRP水平具有差異性 1.1入選各組病例一般臨床資料比較無顯著性差異 臨床入選病例共88例,其中對照組28例,SAP組10例,UAP組25例,AMI組 25例,以上各組一般臨床資料的比較無顯著性差異,具有可比性。 1.2不同CHD患者血漿中IL-27水平具有差異性 CHD組血漿IL-27水平明顯高于對照組；SAP組及UAP組血漿IL-27水平無差異；UAP組及SAP組血漿IL-27水平高于AMI組。 1.3不同CHD患者血漿中hs-CRP具有差異性 CHD組患者血漿hs-CRP水平高于對照組；UAP組血漿hs-CRP水平高于SAP組；AMI組均高于UAP及SAP組。 1.4 hs-CRP、IL-27在CHD中表達(dá)的關(guān)系 將88例患者血清中hs-CRP與IL-27進(jìn)行相關(guān)分析,結(jié)果顯示IL-27與hs-CRP呈正相關(guān),r=0.308,P0.01。 2 ox-LDL誘導(dǎo)人DC細(xì)胞成熟,用RT-PCR的方法測定DC的IL-27亞基mRNA表達(dá) 將加ox-LDL分為四組(n=3)：(1)對照組：DC+PBS；(2)DC+ox-LDL(100mg/L,作用8小時)組；(3)DC+0x-LDL(100mg/L,作用16小時)組；(4)DC+ox-LDL(100mg/L,作用24小時)組。 2.1 DC的鏡下鑒定： 倒置相差顯微鏡及掃描電鏡下,從健康人外周血中分離的PBMC經(jīng)ox-LDL誘導(dǎo)后成為細(xì)胞形態(tài)不規(guī)則、表面毛刺狀突起、細(xì)胞質(zhì)豐富的成熟DC。 2.2用RT-PCR的方法檢測DC的IL-27亞基(P28及EBI3)mRNA表達(dá) ox-LDL上調(diào)DC的IL-27亞基(P28及EBI3)mRNA的表達(dá),ox-LDL刺激組P28及EBI3mRNA表達(dá)均比對照組高,并有時間依賴性的特點。 3 IL-27對ox-LDL介導(dǎo)樹突狀細(xì)胞免疫成熟作用的研究 將加IL-27分為三組(n=5),均作用24小時：(1)對照組：DC+PBS；(2)DC+ox-LDL(100mg/L組；(3)DC+ox-LDL(100mg/L)+IL-27(100ng/mL)組。 3.1 DC的鏡下鑒定： 倒置相差顯微鏡及掃描電鏡下觀察,從外周血中分離的PBMC經(jīng)ox-LDL及IL-27誘導(dǎo)后成為細(xì)胞形態(tài)不規(guī)則、表面毛刺狀突起、細(xì)胞質(zhì)豐富的成熟DC。 3.2用流式細(xì)胞儀檢測對DC細(xì)胞表型的影響 3.2.1 ox-LDL上調(diào)DC細(xì)胞表型表達(dá) 流式細(xì)胞儀檢測人外周血PBMC來源的DC表型HLA-DR.CD83及CD86。ox-LDL組HLA-DR.CD83及CD86表型表達(dá)較對照組高,說明ox-LDL可刺激外周血PBMC來源的DC成熟,具有一定的抗原呈遞功能。 3.2.2 IL-27上調(diào)ox-LDL誘導(dǎo)成熟的DC表型的表達(dá) 加入IL-27后DC表面的HLA-DR、CD83及CD86表達(dá)高于ox-LDL組,說明IL-27可進(jìn)一步促進(jìn)ox-LDL刺激外周血PBMC來源的DC成熟。 3.3對DC培養(yǎng)上清液細(xì)胞因子IL-6、IL-10及IL-12p70的影響 3.3.1 ox-LDL上調(diào)DC培養(yǎng)上清液細(xì)胞因子IL-6及IL-10的表達(dá),下調(diào)IL-12p70的表達(dá)。 ox-LDL組DC培養(yǎng)上清液細(xì)胞因子IL-6及IL-10的表達(dá)均比對照組高,IL-12p70表達(dá)比對照組低。說明ox-LDL刺激DC免疫成熟后,促進(jìn)Thl型細(xì)胞因子IL-6分泌,具有Th1型免疫反應(yīng)的能力。 3.3.2 IL—27上調(diào)ox-LDL誘導(dǎo)成熟的DC表達(dá)IL-6,下調(diào)IL-10的表達(dá)。 用ox-LDL誘導(dǎo)DC成熟后,加入IL-27刺激,DC培養(yǎng)上清液細(xì)胞因子IL-6表達(dá)比ox-LDL高,IL-10的表達(dá)比ox-LDL低。說明IL-27具有一定促進(jìn)Thl型免疫反應(yīng)及抑制Th2型免疫反應(yīng)的能力。 通過上述三個部分的實驗,我們可以得出以下結(jié)論： 1、不同類型CHD患者血漿IL-27及hs-CRP均較對照組升高,說明與病情相關(guān),可作為CHD病情評估的參考指標(biāo)； 2、ox-LDL上調(diào)DC的IL-27亞基(P28及EBI3)mRNA的表達(dá),說明ox-LDL能夠使活化的人PBMC來源的DC分泌IL-27。 3、ox-LDL可促進(jìn)DC免疫分化成熟。 4、ox-LDL可促進(jìn)DC免疫成熟,并促進(jìn)DC分泌IL-6及IL-10。 5、IL—27上調(diào)ox-LDL所誘導(dǎo)的DC的免疫成熟,并進(jìn)一步促進(jìn)DC分泌IL-6及抑制DC分泌IL-10。
[Abstract]:Coronary heart disease (CHD) is one of the most important diseases threatening human life and health since the 20th century, and its incidence is increasing. The causes and prevention methods of CHD have been the focus of social attention. As is known to all, family history of heart disease, sex, old age, smoking, hypertension, diabetes, hyperlipidemia and so on are high risk factors for AS. Recent studies have shown that infectious factors such as Chlamydia pneumoniae, pylorus and so on. Spirulina, cytomegalovirus and so on also have the important relations with CHD. Acute coronary syndrome is an important progress stage of coronary heart disease, and vulnerable plaque is the main pathological basis of acute coronary syndrome. Therefore, CHD may be a chronic inflammatory disease of the coronary artery and systemic immune diseases.
Dendritic cells (DCs) are the most powerful professional antigen presenting cells in vivo and play a major role in antigen presenting during the immune process. Very few DCs can activate T lymphocytes to initiate specific cellular immune responses. Domestic and foreign studies have found that there is a vascularly associated lymphoid tissue (VALT) in the intima of normal arteries. A number of immunocompetent cells and antigen presenting cells are distributed to monitor and screen for potentially harmful endogenous or exogenous antigens in vascular tissues. Studies have shown that DCs aggregate significantly in AS lesions, and DCs and T lymphocytes co-occur in the weaker sites of AS lesions. Sex antigens present antigens to T cells to activate and proliferate, secrete cytokines, and then initiate a series of immune responses leading to the development of AS. Recent studies have shown that oxidized low density lipoproteins can promote the progression of AS by activating DCs-mediated acquired immune responses.
It has been found that oxidized low density lipoprotein (ox-LDL) is an endogenous immune activator, which can cause endothelial dysfunction, participate in foam cell formation, promote the proliferation and induce apoptosis of vascular smooth muscle cells. Previous studies have shown that ox-LDL is localized after atherosclerosis. Promote DC adhesion to vascular endothelium, and as an autoantigen stimulate local production of anti-oxidative LDL antibodies, promote DC differentiation and maturation, and activate T lymphocytes, participate in atherosclerotic local immune inflammation. Increasing the secretion of cytokines IL-2, IL-12, IL-18, INF-gamma (?) TNFa and so on, and these effects increased with the increase of ox-LDL concentration and oxidation degree, but too high concentration would lead to apoptosis of DCs.
More and more studies have found that a variety of inflammatory markers are involved in the occurrence, development and prognosis of CHD, such as IL-6, IL-10, IL-18, IL-12 and high sensitive C-reactive protein (hs-CRP), etc. IL-27 (Interleukin-27, IL-27) is a newly discovered cytokine belonging to the IL-6/IL-12 family, which is composed of p28 and EBI3, and has promotive and inhibitory effects. Because IL-27 plays an indispensable role in the regulation of immune response and immune tolerance, the expression and function of IL-27 are found in inflammatory, autoimmune, infectious, and tumor diseases. However, it is rare in the study of coronary heart disease. This study examined different types of coronary artery disease. The level of plasma IL-27 in patients with heart disease was investigated, and the changes of plasma IL-27 in CHD patients were investigated, and the relationship between them was also discussed.
IL-27 is mainly produced by activated DC cells. Monocytes, macrophages, NK cells and so on can also secrete a certain amount of IL-27. Toll-like receptors (TLRs) on the surface of DCs can secrete IL-27 when stimulated by pathogen-associated molecular model (PAMP). Human peripheral blood monocyte-derived DC expresses IL-27 receptors (heterodimer composed of EBI3 and p28), suggesting that IL-27 is expressed in peripheral blood monocytes. -27 can affect monocyte-derived DC, which can feedback DCs, promote the expression of costimulatory molecules on DCs surface and enhance their ability to activate helper T cells (Th). Foreign researchers have found that in WSX-1 knockout mice, the expression of CD80/CD86 on DCs surface is up-regulated after LPS stimulation, and induces Thl cell proliferation. And the ability to produce IFN- gamma is also greatly improved.
DCs are the key link between natural defense and acquired immunity, and are closely related to the occurrence and development of CHD. Does IL-27 play an immunoregulatory role in the pathogenesis of CHD? What is the functional status of DCs after IL-27 treatment, and whether it affects the secretion of functional proteins and immunoregulatory molecules? The effect of L-27 on the DC activity in vitro was amplified, which provided a basis for the study of IL-27 combined with DC for the immune mechanism of CHD.
This study is divided into three parts. The first part is to detect the levels of interleukin-27 (IL-27) and high-sensitivity C-reactive protein (hs-CRP) in different types of coronary atherosclerotic heart disease (CHD) patients by ELISA and immunoturbidimetry, and compare them to explore whether IL-27 and coronary heart disease progress and atherosclerotic plaque. Part two: DC derived from human PBMC was used as an experimental model, OX-LDL was used as an antigen to induce DC maturation, and RT-PCR was used to determine the production of IL-27 subunit in DC. Part three: DC derived from human PBMC was used as an experimental model, OX-LDL was used as an antigen to induce DC maturation, and flow was used as an antigen to induce DC maturation. The maturity of DC and the ability of secreting cytokines were observed by cell-based immunoassay and ELISA, and the effect of IL-27 on the immune activity of DC was further studied. This study provides a basis for the study of the immune mechanism of IL-27 combined with DC in CHD and provides a basis for the immunological mediation theory of AS development. The results are of far-reaching significance. The results are as follows:
1 the levels of IL-27 and hs-CRP in plasma of different CHD patients are different.
1.1 there was no significant difference in clinical data between the selected groups.
A total of 88 clinical cases were selected, including 28 cases in the control group, 10 cases in group SAP, 25 cases in group UAP, and AMI group.
In 25 cases, there was no significant difference in general clinical data between the above groups.
1.2 the level of IL-27 in plasma of different CHD patients is different.
The level of IL-27 in plasma of CHD group was significantly higher than that of control group, and there was no difference between SAP group and UAP group. The level of IL-27 in plasma of UAP group and SAP group was higher than that of AMI group.
1.3 hs-CRP in plasma of different CHD patients is different.
The level of hs-CRP in plasma of CHD group was higher than that of control group, UAP group was higher than that of SAP group, AMI group was higher than that of UAP and SAP group.
Relationship between 1.4 hs-CRP and IL-27 expression in CHD
Correlation analysis of serum hs-CRP and IL-27 in 88 patients showed that IL-27 was positively correlated with hs-CRP, r=0.308, P 0.01.
2 ox-LDL induced the maturation of human DC cells, and mRNA expression of DC IL-27 subunit was determined by RT-PCR.
Ox-LDL was divided into four groups (n=3): (1) control group: DC + PBS; (2) DC + ox-LDL (100mg / L, 8 hours) group; (3) DC + 0x-LDL (100mg / L, 16 hours) group; (4) DC + ox-LDL (100mg / L, 24 hours) group.
2.1 DC for microscopic identification:
Under inverted phase contrast microscopy and scanning electron microscopy, PBMCs isolated from healthy human peripheral blood were induced by ox-LDL to become mature DC with irregular cell morphology, burr-like process on the surface and abundant cytoplasm.
2.2 the expression of DC IL-27 subunit (P28 and EBI3) mRNA was detected by RT-PCR.
Ox-LDL up-regulated the expression of IL-27 subunit (P28 and EBI3) mRNA in DC, and the expression of P28 and EBI3 mRNA in ox-LDL-stimulated group was higher than that in control group, and the expression was time-dependent.
Effect of 3 IL-27 on ox-LDL mediated immune maturation of dendritic cells
IL-27 was divided into three groups (n=5) for 24 hours: (1) control group: DC + PBS; (2) DC + ox-LDL group (100mg / L); and (3) DC + ox-LDL (100mg / L) + IL-27 (100ng / mL).
3.1 DC for microscopic identification:
Under inverted phase contrast microscope and scanning electron microscope, PBMCs isolated from peripheral blood were induced by ox-LDL and IL-27 to form mature DC with irregular morphology, burr-like process on the surface and abundant cytoplasm.
3.2 the effect of flow cytometry on the phenotype of DC cells.
3.2.1 ox-LDL upregulated DC cell phenotypic expression
The expression of HLA-DR.CD83 and CD86.ox-LDL phenotypes in PBMC-derived DC from human peripheral blood was higher than that in control group by flow cytometry.
3.2.2 IL-27 upregulated ox-LDL induced expression of mature DC phenotype.
After adding IL-27, the expression of HLA-DR, CD83 and CD86 on DC surface was higher than that in ox-LDL group, indicating that IL-27 could further promote the maturation of PBMC-derived DC stimulated by ox-LDL.
Effect of 3.3 on cytokines IL-6, IL-10 and IL-12p70 in supernatant of DC culture
3.3.1 ox-LDL increased the expression of cytokines IL-6 and IL-10 in DC supernatant, and down regulated the expression of IL-12p70.
The expression of cytokines IL-6 and IL-10 in DC supernatant of ox-LDL group was higher than that of control group, and IL-12p70 was lower than that of control group.
3.3.2 IL - 27 upregulated ox-LDL induced mature DC expression IL-6 and down regulated IL-10 expression.
After DC maturation was induced by ox-LDL and stimulated by IL-27, the expression of cytokine IL-6 in DC supernatant was higher than that of ox-LDL and IL-10 was lower than that of ox-LDL.
Through the above three parts of experiments, we can draw the following conclusions:
1. The levels of plasma IL-27 and hs-CRP in patients with different types of CHD were higher than those in the control group, indicating that the levels of IL-27 and hs-CRP were correlated with the severity of CHD.
2. ox-LDL up-regulates the expression of IL-27 subunit (P28 and EBI3) mRNA in DC, suggesting that ox-LDL can secrete IL-27 from activated PBMC-derived DC.
3, ox-LDL can promote immune differentiation and maturation of DC.
4, ox-LDL can promote DC immune maturation and promote DC to secrete IL-6 and IL-10..
5. IL-27 up-regulates the immune maturation of DC induced by ox-LDL and further promotes the secretion of IL-6 and inhibits the secretion of IL-10.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2011
【分類號】：R392.1

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