【摘要】：幽門螺桿菌(Helicobacter pylori,H. pylori)是一種螺旋狀、微需氧革蘭陰性桿菌,主要定植于人胃粘膜,已造成全世界50%以上人口感染。H. pylori感染是慢性胃炎、消化性潰瘍及胃粘膜相關(guān)淋巴組織淋巴瘤(MALT)等疾病的重要致病因子,與胃癌的發(fā)生密切相關(guān),已被WHO列為Ⅰ類致癌因子。H. pylori感染能夠引起機體較強的天然和獲得性免疫應(yīng)答,但自然感染H. pylori后的免疫反應(yīng)并不能清除細菌,反而由于細菌的持續(xù)感染導致胃粘膜免疫病理損害。到目前為止,H. pylori慢性持續(xù)性感染及相關(guān)免疫機制并不清楚。 細胞因子作為細胞間的信使分子,通過和靶細胞上的受體相結(jié)合,產(chǎn)生特定的生物學效應(yīng)。H. pylori的慢性感染是細菌與宿主相互作用的結(jié)果,在此過程中有許多細胞因子參與并發(fā)揮了不同的功能。現(xiàn)已證明:CD4~+T細胞(Th細胞)在H. pylori感染過程中發(fā)揮重要作用。因此,目前關(guān)于H. pylori感染激發(fā)的細胞因子的研究多集中于Th細胞相關(guān)的細胞因子上。以往研究認為,IFN-γ主要參與宿主的炎癥反應(yīng),并導致胃粘膜損傷甚至潰瘍;而IL-4在一定程度上能夠緩解胃炎,并降低H. pylori的定植。 近年來研究發(fā)現(xiàn)一些新型Th細胞亞群如Th17,Th22,Th9等,這些細胞亞群在多種慢性炎癥性疾病中發(fā)揮著重要作用。探明新型細胞亞群相關(guān)重要細胞因子的功能,將有助于增加以慢性炎癥為機制相關(guān)疾病的理解,為慢性炎癥疾病的免疫防治提供新的思路。IL-22是Th17及Th22細胞產(chǎn)生的重要效應(yīng)因子,目前報道顯示,IL-22通過誘導角質(zhì)化細胞產(chǎn)生促炎癥因子和趨化因子,介導炎癥反應(yīng),在皮膚炎癥性疾病中參與致病過程,而在肺炎克雷伯菌及嚙齒枸椽酸桿菌感染模型中,IL-22通過調(diào)控局部炎癥反應(yīng)及刺激上皮細胞分泌抗菌肽等參與宿主防御反應(yīng)。提示IL-22依據(jù)其所處的炎癥微環(huán)境不同,具有發(fā)揮促炎致病或防御保護雙重作用的特性。在我們的預(yù)實驗中首次發(fā)現(xiàn):H. pylori感染患者胃組織中IL-22呈異常高表達。那么在H. pylori引起的以慢性炎癥為特征的感染性疾病中,IL-22發(fā)揮什么樣的功能呢?目前尚未見報道。 【研究目的】 1.本課題擬以Th細胞重要效應(yīng)因子IL-22作為主要研究對象,研究在H. pylori感染中的表達特性; 2.初步探明IL-22在H. pylori感染中的作用及機制。 【研究方法】 1. IL-22在H. pylori感染中的表達特性研究收集消化內(nèi)科胃炎患者胃粘膜組織,提取組織RNA,采用定量PCR檢測細胞因子mRNA水平情況及H. pylori定植拷貝數(shù);提取組織蛋白,ELISA檢測IL-22蛋白表達;病理切片HE染色檢測胃組織炎癥。部分患者采用耐信、阿莫西林克拉維酸鉀和痢特靈三聯(lián)療法治療,同時收集治療后胃粘膜標本,定量PCR檢測IL-22表達,病理切片HE染色檢測胃組織炎癥,分析IL-22表達與H. pylori定植及胃組織炎癥的相關(guān)性。 2. IL-22~+ T細胞在H. pylori感染中的應(yīng)答研究 首先,建立H. pylori 26695感染細胞模型,定量PCR在細胞感染模型中檢測分泌IL-22的細胞類型,并采用雙重免疫熒光染色及流式在胃組織中進一步驗證。隨后,采用流式檢測分泌IL-22的T細胞亞群在H. pylori感染患者胃組織中的應(yīng)答情況。最后,采用定量PCR在CagA、UreB基因敲除株及出發(fā)菌株H. pylori 26695感染細胞模型及胃粘膜標本中鑒定誘導IL-22表達的H. pylori毒力因子。 3. IL-22在H. pylori感染中的作用機制研究 采用流式檢測不同刺激因素下AGS細胞表面IL-22R1表達情況,定量PCR及組織免疫熒光染色檢測胃組織中IL-22R1表達,明確H. pylori感染胃粘膜組織后IL-22R1的表達情況;IL-22刺激胃上皮細胞24h后,收集細胞,定量PCR檢測促炎癥因子及基質(zhì)金屬蛋白酶(MMP)表達,檢測IL-22對胃上皮細胞的作用;采用定量PCR檢測胃組織中促炎癥因子及MMPs表達并分析與IL-22表達的相關(guān)性,初步探討IL-22在H. pylori感染中的功能;體外采用Transwell細胞趨化實驗檢測IL-22對淋巴細胞的趨化作用,探討IL-22促炎作用的機制。 【研究結(jié)果】 1. IL-22在H. pylori感染中的表達特性研究 1.1 H. pylori陽性患者胃粘膜組織中,IL-22 mRNA水平及蛋白表達量顯著增高(P 0.05),同時檢測結(jié)果表明,與H. pylori感染相關(guān)的細胞因子IL-17A,IL-17F和IFN-γmRNA水平亦顯著增高(P 0.05)。結(jié)果提示H. pylori感染后能夠引起IL-22表達增加。 1.2進一步分析發(fā)現(xiàn)胃粘膜組織IL-22 mRNA水平與H. pylori拷貝數(shù)呈顯著正相關(guān)(r = 0.404, P 0.01);根據(jù)病理切片HE染色對胃炎嚴重程度進行分類統(tǒng)計,結(jié)果顯示:中度和重度胃炎患者胃粘膜組織IL-22 mRNA水平顯著高于輕度胃炎患者(P 0.05),而輕度胃炎患者胃粘膜組織IL-22 mRNA水平也顯著高于正常胃粘膜組織(P 0.05)。結(jié)果提示IL-22表達水平與胃粘膜炎癥程度有關(guān)。 1.3 H. pylori陽性患者經(jīng)清除治療后,胃粘膜組織IL-22 mRNA水平較治療前顯著降低(P 0.05),并且H. pylori清除后胃組織炎癥程度減輕(P 0.05)。結(jié)果再次驗證IL-22表達水平與H. pylori感染及炎癥密切相關(guān)。 2. IL-22~+ T細胞在H. pylori感染中的應(yīng)答研究 2.1 H. pylori 26695與AGS細胞共培養(yǎng)24h后,細胞形態(tài)呈明顯“蜂鳥樣”改變;細胞分泌大量促炎細胞因子IL-8,說明成功建立H. pylori感染細胞模型。H. pylori 26695感染胃上皮細胞株及T細胞株后檢測到IL-22 mRNA水平顯著增高(P 0.05),同時胃組織雙重免疫熒光染色IL-22蛋白及細胞表面標志發(fā)現(xiàn),上皮細胞及CD4~+、CD8~+細胞均能夠分泌IL-22。結(jié)果提示,H. pylori感染后胃上皮細胞和T細胞是胃組織分泌IL-22的細胞類型。 2.2流式檢測胃粘膜組織中分泌IL-22的細胞亞群類型:以CD3~+細胞圈門,CD4~+及CD8~+兩個細胞亞群都能夠分泌IL-22,且主要由記憶型T細胞分泌。進一步分析H. pylori感染陽性及陰性患者胃粘膜組織中細胞比率差異:以CD3~+細胞圈門,分別檢測CD4~+及CD8~+ T細胞分泌細胞因子的比率。統(tǒng)計結(jié)果顯示,H. pylori感染患者胃粘膜組織的IL-22~+ CD4~+, IL-22~+ CD8~+, IL-17~+ CD4~+, IL-17~+ CD8~+, IFN-γ~+ CD4~+細胞比率顯著高于未感染者(P 0.05),而IFN-γ~+ CD8~+細胞比率在兩者間并無顯著差異(P 0.05);分別以CD4~+及CD8~+ T細胞圈門,H. pylori感染患者胃粘膜組織的IL-22~+ IL-17~+及IL-22~+ IFN-γ~+共表達細胞比率均顯著高于未感染者(P 0.05)。以上結(jié)果提示,IL-22~+ T淋巴細胞在H. pylori感染后應(yīng)答增強。 2.3分別采用CagA或UreB基因敲除株及出發(fā)菌株H. pylori 26695感染胃上皮細胞株及T細胞株,結(jié)果顯示:CagA基因敲除株感染組相對于出發(fā)菌株H. pylori 26695感染組IL-22 mRNA水平明顯降低(P 0.05),而UreB基因敲除株組沒有明顯變化。隨后,對胃組織標本進行CagA基因檢測后發(fā)現(xiàn),CagA基因陽性的H. pylori感染患者胃組織中IL-22 mRNA水平顯著高于CagA基因陰性的H. pylori感染患者(P 0.05),但IL-22mRNA水平在CagA基因陰性的H. pylori感染患者與無H. pylori感染者之間沒有差異。結(jié)果提示,CagA是調(diào)控胃組織中IL-22表達的分子。 3. IL-22在H. pylori感染中的作用機制研究 3.1采用流式檢測不同刺激因素下AGS細胞表面IL-22R1表達的結(jié)果顯示,細胞因子及重組蛋白刺激AGS細胞后,IL-22R1表達沒有明顯變化,但H. pylori 26695菌株感染后,在一定感染范圍內(nèi),IL-22R1表達量隨細菌量增加而增加;胃組織免疫熒光染色顯示胃組織中IL-22R1表達陽性,同時定量PCR檢測結(jié)果顯示,H. pylori陽性患者胃粘膜組織中IL-22R1 mRNA水平顯著增高(P 0.05),提示H. pylori感染后能夠上調(diào)胃上皮細胞表達IL-22R1。 3.2 IL-22刺激胃上皮細胞系24 h后,S100A8,S100A9,IL-8,MMP-1,MMP-10 mRNA水平均顯著增高(P 0.05);同時檢測到H. pylori感染者胃組織中IL-8,S100A8,S100A9 mRNA水平亦顯著增高(P 0.05),而MMP-1,MMP-10 mRNA水平無明顯變化;相關(guān)性分析顯示胃粘膜組織中IL-22的表達與S100A8,S100A9,IL-8表達存在顯著正相關(guān)(P 0.05),而與MMP-1,MMP-10表達無明顯相關(guān)性。結(jié)果提示,IL-22可能通過誘導上皮細胞產(chǎn)生促炎癥因子等,參與炎癥反應(yīng)。 3.3進一步采用Transwell細胞趨化實驗檢測IL-22對淋巴細胞的趨化作用,結(jié)果顯示IL-22單獨并不能趨化淋巴細胞,但與胃上皮細胞共培養(yǎng)24 h后能夠趨化Transwell小室內(nèi)的淋巴細胞(P 0.05),而加入IL-8中和性抗體后,趨化的淋巴細胞數(shù)量顯著降低(P 0.05)。結(jié)果提示,IL-22通過誘導胃上皮細胞產(chǎn)生IL-8等趨化因子進而趨化炎癥細胞,參與炎癥反應(yīng)。 【結(jié)論】 1. CagA~+H. pylori感染后能夠誘導IL-22轉(zhuǎn)錄水平與蛋白表達上調(diào),且IL-22表達與H. pylori定植拷貝數(shù)及粘膜炎癥程度呈顯著相關(guān)。 2.胃組織中分泌IL-22的細胞主要為上皮細胞和記憶型T淋巴細胞,并且分泌IL-22的T淋巴細胞亞群在H. pylori感染患者的胃粘膜中應(yīng)答增強;鑒定H. pylori毒力因子CagA是調(diào)控IL-22表達的分子。 3.在H. pylori感染過程中,IL-22通過調(diào)控多種促炎癥因子的表達,誘導炎癥細胞浸潤等參與炎癥反應(yīng)過程。 【意義】 深入研究H. pylori感染后IL-22的功能及其調(diào)控,將有助于我們更全面認識H. pylori感染的免疫應(yīng)答規(guī)律及其致病機制,為H. pylori相關(guān)疾病的防治提供更充分的理論依據(jù)。
[Abstract]:Helicobacter pylori (H. pylori) is a spiral, microaerobic gram-negative bacilli, mainly colonized in human gastric mucosa, has caused infection in more than 50% of the world's population. H. pylori infection is an important pathogenic factor of chronic gastritis, peptic ulcer and gastric mucosa-associated lymphoid tissue lymphoma (MALT), and gastric cancer. H. pylori infection can induce strong natural and acquired immune response, but the immune response after natural infection can not eliminate bacteria, but because of the persistent infection of bacteria, gastric mucosal immune pathological damage. So far, H. pylori chronic persistent sexuality. The mechanism of infection and related immunity is not clear.
Cytokines, as messenger molecules between cells, produce specific biological effects by binding to receptors on target cells. Chronic infection of H.pylori is the result of interaction between bacteria and host. Many cytokines participate in and play different roles in this process. It has been proved that CD4~+T cells (Th cells) are sensitive to H.pylori. Therefore, the current research on cytokines stimulated by H. pylori infection is mostly focused on Th cell-related cytokines. Previous studies have shown that IFN-gamma is mainly involved in the host inflammatory response, leading to gastric mucosal injury and even ulcer; and IL-4 can alleviate gastritis to a certain extent, and reduce H. pylori. Colonization.
In recent years, some new Th cell subsets, such as Th17, Th22, Th9, have been found to play an important role in many chronic inflammatory diseases. Interleukin-22 is an important effector factor produced by Th17 and Th22 cells. Current reports show that IL-22 mediates inflammation by inducing keratinocytes to produce pro-inflammatory and chemokines. IL-22 is involved in the pathogenesis of skin inflammatory diseases. In Klebsiella pneumoniae and Citrobacter ronatus infection models, IL-22 is linked. Overregulation of local inflammation and stimulation of antimicrobial peptides secreted by epithelial cells are involved in host defense responses, suggesting that IL-22 plays a dual role in promoting inflammation, pathogenesis and defense protection depending on its inflammatory microenvironment. So what function does IL-22 play in H.pylori-induced infectious diseases characterized by chronic inflammation? It has not been reported yet.
[research purposes]
1. In this study, IL-22, an important effector factor of Th cells, was used to study the expression characteristics of H. pylori infection.
2. preliminarily ascertain the role and mechanism of IL-22 in H. pylori infection.
[research methods]
1. Expression characteristics of IL-22 in gastric mucosa of patients with gastritis in digestive medicine were studied. RNA was extracted from gastric mucosa, cytokine mRNA level and H.pylori colonization copy number were detected by quantitative PCR, tissue protein was extracted, IL-22 protein was detected by ELISA, gastric inflammation was detected by HE staining in pathological section. Neoxin, amoxicillin, clavulanate potassium and dysentery triple therapy were used to treat gastric mucosa. After treatment, gastric mucosa samples were collected, IL-22 expression was detected by quantitative PCR, gastric inflammation was detected by HE staining in pathological sections, and the correlation between IL-22 expression and H.pylori colonization and gastric inflammation was analyzed.
Study on the response of 2. IL-22~+ T cells to H. pylori infection
Firstly, the H.pylori 26695 infected cell model was established, and the type of IL-22 secreting cells was detected by quantitative PCR in the model of H.pylori infection, and further verified by double immunofluorescence staining and flow cytometry. Then, the response of IL-22 secreting T cell subsets in the gastric tissues of H.pylori infected patients was detected by flow cytometry. Quantitative PCR was used to identify H.pylori virulence factors inducing IL-22 expression in CagA, UreB knockout strain, H.pylori 26695 infected cell model and gastric mucosa samples.
Study on the mechanism of action of 3. IL-22 in H. pylori infection
The expression of IL-22R1 on the surface of AGS cells was detected by flow cytometry, the expression of IL-22R1 in gastric tissues was detected by quantitative PCR and tissue immunofluorescence staining, and the expression of IL-22R1 in gastric mucosa after H.pylori infection was determined. To detect the expression of IL-22 in gastric epithelial cells, detect the expression of pro-inflammatory factors and MMPs in gastric tissues by quantitative PCR, and analyze the correlation with the expression of IL-22. To explore the function of IL-22 in H.pylori infection, the chemotaxis of IL-22 on lymphocytes was detected by Transwell cell chemotaxis assay in vitro, and to explore the role of IL-22 in promoting the expression of IL-22 in gastric epithelial cells. The mechanism of inflammation.
[results]
Study on the expression characteristics of 1. IL-22 in H. pylori infection
1.1 The levels of IL-22 mRNA and protein expression in gastric mucosa of H.pylori positive patients were significantly increased (P 0.05). The results also showed that the levels of cytokines IL-17A, IL-17F and IFN-gamma mRNA related to H.pylori infection were significantly increased (P 0.05).
1.2 Further analysis showed that the level of IL-22 mRNA in gastric mucosa was positively correlated with the copy number of H.pylori (r = 0.404, P 0.01), and the severity of gastritis was classified according to HE staining of pathological sections. The results showed that the level of IL-22 mRNA in gastric mucosa of patients with moderate and severe gastritis was significantly higher than that of patients with mild gastritis (P 0.05). The level of IL-22 mRNA in gastric mucosa of patients with severe gastritis was also significantly higher than that of normal gastric mucosa (P 0.05).
1.3 After clearance treatment, the level of IL-22 mRNA in gastric mucosa decreased significantly (P 0.05), and the degree of gastric inflammation decreased (P 0.05) after clearance of H.pylori.
Study on the response of 2. IL-22~+ T cells to H. pylori infection
2.1 H.pylori 26695 and AGS cells co-cultured for 24 hours, the cell morphology showed a significant "hummingbird-like" change; cells secreted a large number of pro-inflammatory cytokines IL-8, indicating the successful establishment of H.pylori infection cell model. H.pylori 26695 infected gastric epithelial cell lines and T cell lines detected IL-22 mRNA levels significantly increased (P 0.05), while gastric tissue double-fold (P 0.05). IL-22 protein and cell surface markers showed that both epithelial cells and CD4~+, CD8~+ cells could secrete IL-22. The results suggested that gastric epithelial cells and T cells were the cell types secreting IL-22 in gastric tissues after H. pylori infection.
2.2 Flow cytometry was used to detect the subtypes of IL-22 secreted in gastric mucosa: CD3~+ cell circle gates, CD4~+ and CD8~+ cell subgroups could secrete IL-22, mainly secreted by memory T cells. The ratio of IL-22~+CD4~+, IL-22~+CD8~+, IL-17~+CD4~+, IL-17~+CD8~+, IFN-gamma~+CD4~+ cells in gastric mucosa of H.pylori infected patients was significantly higher than that of uninfected patients (P 0.05), but there was no significant difference in the ratio of IFN-gamma~+CD8~+ cells between the two groups (P 0.05). The co-expression ratio of IL-22~+IL-17~+ and IL-22~+IFN-gamma~+ in gastric mucosa of patients with H.pylori infection was significantly higher than that of patients without H.pylori infection (P 0.05).
2.3 The gastric epithelial cell lines and T cell lines were infected with CagA or UreB knockout strains and H.pylori 26695 respectively. The results showed that the level of IL-22 mRNA in CagA knockout strains was significantly lower than that in H.pylori 26695 infected strains (P 0.05), but there was no significant change in UreB knockout strains. The results of CagA gene detection showed that the level of IL-22 mRNA in gastric tissues of CagA gene positive patients with H.pylori infection was significantly higher than that of CagA gene negative patients with H.pylori infection (P 0.05), but there was no difference in the level of IL-22 mRNA between CagA gene negative patients with H.pylori infection and those without H.pylori infection. IL-22 molecules expressed in tissues.
Study on the mechanism of action of 3. IL-22 in H. pylori infection
3.1 The expression of IL-22R1 on the surface of AGS cells stimulated by cytokines and recombinant proteins was detected by flow cytometry. The results showed that IL-22R1 expression did not change significantly after AGS cells were stimulated by cytokines and recombinant proteins. The expression of IL-22R1 was positive in gastric tissues. The results of quantitative PCR showed that the expression of IL-22R1 mRNA in gastric mucosa of H.pylori positive patients was significantly increased (P 0.05), suggesting that H.pylori infection could up-regulate the expression of IL-22R1 in gastric epithelial cells.
3.2 IL-22 stimulated gastric epithelial cell line 24 hours later, the levels of S100A8, S100A9, IL-8, MMP-1, MMP-10 mRNA were significantly increased (P 0.05); at the same time, the levels of IL-8, S100A8, S100A9 mRNA in gastric tissues of H.pylori infected patients were also significantly increased (P 0.05), while the levels of MMP-1, MMP-10 mRNA were not significantly changed; correlation analysis showed that the expression of IL-22 in gastric mucosa was significantly increased. The expression of IL-22 was positively correlated with the expression of S100A8, S100A9 and IL-8 (P 0.05), but not with the expression of MMP-1 and MMP-10.
3.3 The chemotactic effect of IL-22 on lymphocytes was detected by Transwell cell chemotaxis assay. The results showed that IL-22 alone could not chemotactic lymphocytes, but could chemotactic lymphocytes in the Transwell compartment after co-culture with gastric epithelial cells for 24 hours (P 0.05). The number of chemotactic lymphocytes decreased significantly after adding neutral antibody to IL-8. The results suggest that IL-22 may be involved in inflammatory reaction by inducing gastric epithelial cells to produce chemokines such as IL-8.
[Conclusion]
1. CagA~+H.pylori infection could induce the up-regulation of IL-22 transcription and protein expression, and IL-22 expression was significantly correlated with H.pylori copy number and mucosal inflammation.
2. The secreting cells of IL-22 in gastric tissue were mainly epithelial cells and memory T lymphocytes, and the secreting T lymphocyte subsets of IL-22 were enhanced in gastric mucosa of patients with H. pylori infection.
3. In the process of H. pylori infection, IL-22 participates in the inflammatory process by regulating the expression of various pro-inflammatory factors and inducing inflammatory cell infiltration.
[meaning]
A thorough study of the function and regulation of IL-22 after H.pylori infection will help us to understand the immune response and pathogenesis of H.pylori infection more comprehensively, and provide a more sufficient theoretical basis for the prevention and treatment of H.pylori-related diseases.
【學位授予單位】：第三軍醫(yī)大學
【學位級別】：博士
【學位授予年份】：2011
【分類號】：R378

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