肠黏膜屏障损伤对自身免疫性肝炎患者枯否细胞免疫调节功能影响的研究
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摘要
背景：自身免疫性肝炎(AIH)发病机制尚未阐明,目前认为是具有遗传易感性个体在环境因素的诱发下丧失了对自身肝细胞的免疫耐受,通过激活多种针对肝脏自身抗原的免疫应答引起了肝脏损伤。而枯否细胞(KC)作为定居在肝脏的巨噬细胞,在免疫耐受的形成和维持中具有重要作用。有研究认为KC被肠源性毒素激活,生物学功能发生改变并释放一系列炎性因子,可进一步造成免疫耐受破坏。因此,明确AIH患者是否存在肠黏膜屏障损伤,细菌移位活化KC并诱导KC出现一系列生物学功能改变,导致免疫耐受缺失,从而启动免疫反应值得进一步探讨。
目的：本研究拟评价AIH患者肠黏膜屏障功能,从Toll样受体(TLR)激活的角度研究肠源性毒素活化KC的情况,进一步评价活化的KC细胞骨架相关蛋白、外周血单核细胞吞噬功能及抗原递呈功能的变化情况,明确AIH患者肠黏膜屏障功能破坏及其对KC的影响以及KC生物学功能变化情况,将为揭示KC在免疫反应中的作用提供理论依据,加深其在肠道—肝脏互作中的理解,而且将为深入研究AIH的发病机制提供新的视角和思路。
方法：
第一部分取我院2012年～2013年诊断为AIH行胃镜检查患者十二指肠降段黏膜组织,并留取患者外周血及粪便标本,同时设健康体检者为对照组。检测肝功能ALT水平；在光镜下及电镜下观察十二指肠黏膜组织结构的病理变化并应用免疫组织化学法分析十二指肠黏膜组织中紧密连接蛋白ZO-1、occludin的表达水平；以细菌16SrDNA荧光定量PCR方法测定粪便中关键细菌的含量；采用鲎珠实验测定血浆内毒素(LPS)水平。
第二部分取我院2011年～2013年诊断为AIH行肝活检患者肝组织,同时取非酒精性脂肪性肝病行肝活检患者肝组织设为对照组。采用Western blot检测肝组织TLR4的表达量；采用免疫荧光双标的方法确定KC上TLR4的表达情况。
第三部分采用Western blot检测肝组织Rac1通路上下游VAV1和PAK1的表达量并采用免疫荧光双标的方法明确其在KC上的表达情况；采用梯度离心法获得外周血单个核细胞(PBMC),用荧光抗体偶联的特异性抗体标记CD80、HLA-DR单核细胞表面分子,用流式细胞仪测定这两种抗原递呈分子在单核细胞表面的表达情况,从而判断单核细胞的抗原递呈能力；单核细胞通过CD14单克隆磁珠抗体分选获得,将单核细胞与FITC标记的大肠杆菌共培养,利用流式细胞仪评价单核细胞的吞噬能力。
结果：
第一部分(1)AIH肝功异常组、AIH肝硬化组血清ALT水平较健康对照组均明显升高(AIH肝功异常组VS健康对照组为:263.7±57.2U/L vs22.3±5.7U/L, P=0.000; AIH肝硬化组VS健康对照组为：286.4±36.8U/L vs22.3±5.7U/L,P=0.000)；(2)病理检查发现AIH患者十二指肠黏膜微绒毛受损,变短,密度减低,上皮细胞间隙增宽,胞核固缩,且损伤程度与疾病严重程度一致；(3)AIH肝功正常组、AIH肝功异常组及AIH肝硬化组ZO-1蛋白均存在分布不均,并且胞质染色程度较健康对照组明显减低,4组染色评分差异有统计学意义(χ2=14.775,P=0.0389)；AIH各组occludin染色散乱,染色程度明显低于健康对照组,4组染色评分差异有统计学意义(χ2=16.351,P=0.0216)；(4)AIH患者存在肠道菌群失调,最突出的改变为双歧杆菌和乳酸杆菌为代表的厌氧菌数量下降(P均<0.05),大肠杆菌和肠球菌为代表的需氧菌数量变化不大；双歧杆菌／大肠杆菌(Bifidobacteria/escherichia coli, B/E)值下降(P均<0.05),且三组间两两比较均有差异(P均<0.05)；(5)AIH肝功正常组、AIH肝功异常组、AIH肝硬化组血浆LPS水平较健康对照组均升高(AIH肝功正常组VS健康对照组为：7.47±1.64pg/ml vs5.26±0.86pg/ml, P=0.026; AIH肝功异常组VS健康对照组为：9.75±1.53pg/ml vs5.26±0.86pg/ml,P=0.012; AIH肝硬化组VS健康对照组为：14.23±4.23pg/ml vs5.26±0.86pg/ml,P=0.006),AIH三组间两两比较均有差异(P均<0.05)。
第二部分(1)AIH肝功正常组、AIH肝功异常组、AIH肝硬化组肝组织TLR4蛋白表达量明显高于对照组(P均<0.05),且三组间两两比较均有差异(P均<0.05)；(2)AIH患者组定位于KC上的TLR4明显高于对照组。
第三部分(1)AIH肝功正常组、AIH肝功异常组、AIH肝硬化组肝组织VAV1和PAK1蛋白表达量明显高于对照组(P均<0.05),且三组间两两比较均有差异(P均<0.05)；(2)AIH患者组定位于KC上的VAV1和PAK1明显高于对照组；(3)AIH肝功正常组、AIH肝功异常组、AIH肝硬化组外周血单核细胞HLA-DR+细胞所占比例较对照组明显降低(AIH肝功正常组VS对照组为：97.06±2.73%vs99.21±0.52%,P=0.036；AIH肝功异常组VS对照组为：92.57±6.93%vs99.21±0.52%,P=0.027；AIH肝硬化组VS对照组为：89.74±10.41%vs99.21±0.52%,P=0.018),AIH三组间两两比较均有差异(P均<0.05)；AIH肝功正常组、AIH肝功异常组、AIH肝硬化组外周血单核细胞CD80+细胞所占比例较对照组均明显降低(AIH肝功正常组VS对照组为：79.15±10.29%vs82.34±5.38%,P=0.032；AIH肝功异常组VS对照组为：74.72±10.74%vs82.34±5.38%,P=0.019；A1H肝硬化组VS对照组为：70.84±12.47%vs82.34±5.38%,P=0.012),AIH三组间两两比较均有差异(P均<0.05)；(4)AIH各组吞噬率较对照组均明显降低(AIH肝功正常组VS对照组为：4.34±1.82%vs6.144±2.23%,P=0.027；AIH肝功异常组VS对照组为：3.27±2.04%vs6.14±2.23%,P=0.016；AIH肝硬化组VS对照组为：2.03±±1.47%vs6.14±2.23%,P=0.011),AIH三组间两两比较均存在差异(P均<0.05)。
结论：
(1)AIH患者肠黏膜上皮破坏、紧密连接蛋白减少、肠道菌群失调致肠黏膜屏障功能损伤,肠黏膜通透性增高致细菌移位,血浆LPS升高,且肠黏膜屏障损伤程度与肝脏发病严重程度相关,提示肠黏膜屏障功能受损与AIH的发生发展相关。
(2)AIH患者肠源性内毒素LPS通过TLR4激活KC。
(3)AIH患者KC的Rac1通路过度激活,结合外周血单核细胞抗原提呈能力减低,吞噬能力减低,推测患者单核-巨噬细胞系统细胞骨架变化影响其功能状态。
综上所述,AIH患者存在肠黏膜屏障损伤,LPS可能沿肠黏膜通透性升高→细菌移位→TLR4激活→KC活化并出现生物学功能改变→免疫耐受缺失这条轴线诱发自身免疫反应。本研究不仅能打开LPS与KC相互作用的新视角,而且能帮助证实“肠-肝轴”理论即肠黏膜通透性升高致细菌移位,LPS诱发AIH的免疫耐受损伤机制,最终改善肠道屏障功能可能成为治疗AIH的新靶点。
Background and Objects:The pathogenesis of autoimmune hepatitis (AIH) was still unknown. Attack against liver cell self antigens following the breakdown of immune tolerance were believed to be the major mechanism. Kupffer cells (KC), the resident liver macrophages, with the function of TLR signal pathway, played an important role in immune tolerance induction and maintenance. Recent studies have demonstrated that intestinal-derived toxin could promote production of cytokines and disfunction of biological system of the liver. Based on these observations, we hypothesized that intestinal injury and increased intestinal permeability combined with bacteria translocation could promote. TLR4-dependent KC activation as an early event in the pathogenesis of AIH.
Methods:Part1The mucous membrane of duodenum were observed by electron microscope and immunohistochemistry technique was used to examine the tight junction proteins Zonula occludens-1(ZO-1)、Occludin.16SrDNA fluorescent quantitative PCR was applied in determining the content of bifidobacterium, lactobacillus, escherichia coli and enterococcus in feces. And the level of endotoxin (LPS) and alanine aminotransferase (ALT) were detected in the peripheral blood.
Part2Western blot and double immunofluorescence staining techniques were used to examine the expression and the resource of TLR4in liver tissues. Part3Western blot and double immunofluorescence staining techniques were used to examine the expression and the resource of Racl signaling makers (Vavl and PAK1) in liver tissues. The function of antigen presentation of peripheral blood monocyte was analyzed by CD80and HLA-DR using flow cytometry. Phagocytosis of peripheral blood monocytes was analyzed by challenging cells with fluorescein isothiocyanate (FITC) labeled Escherichia coli (E.coli) using flow cytometry.
Results:Part1(1) The level of serum ALT in AIH group was obviously higher than that in control group (P<0.05).(2) The structure of the duodenum mucosa is obviously broken, the mucosal microvilli structure and tight junction is significantly broken in the AIH group than those in control group.(3) ZO-1and occludin were localized along the apical region of the lateral plasma membrane representing the region of tight junctions in surface and crypt epithelial cells. The positive stainings of ZO-1and occludin of AIH group were obviously decreased (P<0.05).(4) The amount of anaerobes represented by the bifidobacterium and lactobacillus declined (P <0.05). However, the amount of aerobes represented by escherichia coli and enterococcus did not change obviously, Bifidobacteria/Escherichia coli (B/E) which indicated a balance of intestinal flora declined (P<0.05). The results showed the intestinal dysbacteriosis occured in patients with AIH.(5) The level of plasma endotoxin of AIH group were obviously increased than that in control group (P<0.05). Part2The expression of TLR4in liver tissue of AIH group was obviously higher than that of control group(P<0.05), and the expression of TLR4on Kupffer cells of AIH group was obviously higher than that of control group. Part3(1) The expressions of VAV1and PAK1in liver tissue of AIH group were obviously higher(P <0.05), and the expression of VAV1and PAK1on Kupffer cells of AIH group was obviously higher than that of control group.(2) The peripheral blood monocytes antigen presentation function of AIH group was lower than control group (P<0.05).(3) The peripheral blood monocytes phagocytic function of AIH group was lower than control group (P<0.05).
Conclusions:AIH was associated with increased intestinal permeability. Intestinal-derived LPS might activate KC through TLR4signaling in early stages of AIH. The intestinal mucosal barrier fuction might be an important part in the etiology of liver injury. Thus, disfunction of intestinal mucosal barrier might bring a new vision to treatment or prevention of AIH via KC.
目的：本研究拟评价AIH患者肠黏膜屏障功能,从Toll样受体(TLR)激活的角度研究肠源性毒素活化KC的情况,进一步评价活化的KC细胞骨架相关蛋白、外周血单核细胞吞噬功能及抗原递呈功能的变化情况,明确AIH患者肠黏膜屏障功能破坏及其对KC的影响以及KC生物学功能变化情况,将为揭示KC在免疫反应中的作用提供理论依据,加深其在肠道—肝脏互作中的理解,而且将为深入研究AIH的发病机制提供新的视角和思路。
方法：
第一部分取我院2012年～2013年诊断为AIH行胃镜检查患者十二指肠降段黏膜组织,并留取患者外周血及粪便标本,同时设健康体检者为对照组。检测肝功能ALT水平；在光镜下及电镜下观察十二指肠黏膜组织结构的病理变化并应用免疫组织化学法分析十二指肠黏膜组织中紧密连接蛋白ZO-1、occludin的表达水平；以细菌16SrDNA荧光定量PCR方法测定粪便中关键细菌的含量；采用鲎珠实验测定血浆内毒素(LPS)水平。
第二部分取我院2011年～2013年诊断为AIH行肝活检患者肝组织,同时取非酒精性脂肪性肝病行肝活检患者肝组织设为对照组。采用Western blot检测肝组织TLR4的表达量；采用免疫荧光双标的方法确定KC上TLR4的表达情况。
第三部分采用Western blot检测肝组织Rac1通路上下游VAV1和PAK1的表达量并采用免疫荧光双标的方法明确其在KC上的表达情况；采用梯度离心法获得外周血单个核细胞(PBMC),用荧光抗体偶联的特异性抗体标记CD80、HLA-DR单核细胞表面分子,用流式细胞仪测定这两种抗原递呈分子在单核细胞表面的表达情况,从而判断单核细胞的抗原递呈能力；单核细胞通过CD14单克隆磁珠抗体分选获得,将单核细胞与FITC标记的大肠杆菌共培养,利用流式细胞仪评价单核细胞的吞噬能力。
结果：
第一部分(1)AIH肝功异常组、AIH肝硬化组血清ALT水平较健康对照组均明显升高(AIH肝功异常组VS健康对照组为:263.7±57.2U/L vs22.3±5.7U/L, P=0.000; AIH肝硬化组VS健康对照组为：286.4±36.8U/L vs22.3±5.7U/L,P=0.000)；(2)病理检查发现AIH患者十二指肠黏膜微绒毛受损,变短,密度减低,上皮细胞间隙增宽,胞核固缩,且损伤程度与疾病严重程度一致；(3)AIH肝功正常组、AIH肝功异常组及AIH肝硬化组ZO-1蛋白均存在分布不均,并且胞质染色程度较健康对照组明显减低,4组染色评分差异有统计学意义(χ2=14.775,P=0.0389)；AIH各组occludin染色散乱,染色程度明显低于健康对照组,4组染色评分差异有统计学意义(χ2=16.351,P=0.0216)；(4)AIH患者存在肠道菌群失调,最突出的改变为双歧杆菌和乳酸杆菌为代表的厌氧菌数量下降(P均<0.05),大肠杆菌和肠球菌为代表的需氧菌数量变化不大；双歧杆菌／大肠杆菌(Bifidobacteria/escherichia coli, B/E)值下降(P均<0.05),且三组间两两比较均有差异(P均<0.05)；(5)AIH肝功正常组、AIH肝功异常组、AIH肝硬化组血浆LPS水平较健康对照组均升高(AIH肝功正常组VS健康对照组为：7.47±1.64pg/ml vs5.26±0.86pg/ml, P=0.026; AIH肝功异常组VS健康对照组为：9.75±1.53pg/ml vs5.26±0.86pg/ml,P=0.012; AIH肝硬化组VS健康对照组为：14.23±4.23pg/ml vs5.26±0.86pg/ml,P=0.006),AIH三组间两两比较均有差异(P均<0.05)。
第二部分(1)AIH肝功正常组、AIH肝功异常组、AIH肝硬化组肝组织TLR4蛋白表达量明显高于对照组(P均<0.05),且三组间两两比较均有差异(P均<0.05)；(2)AIH患者组定位于KC上的TLR4明显高于对照组。
第三部分(1)AIH肝功正常组、AIH肝功异常组、AIH肝硬化组肝组织VAV1和PAK1蛋白表达量明显高于对照组(P均<0.05),且三组间两两比较均有差异(P均<0.05)；(2)AIH患者组定位于KC上的VAV1和PAK1明显高于对照组；(3)AIH肝功正常组、AIH肝功异常组、AIH肝硬化组外周血单核细胞HLA-DR+细胞所占比例较对照组明显降低(AIH肝功正常组VS对照组为：97.06±2.73%vs99.21±0.52%,P=0.036；AIH肝功异常组VS对照组为：92.57±6.93%vs99.21±0.52%,P=0.027；AIH肝硬化组VS对照组为：89.74±10.41%vs99.21±0.52%,P=0.018),AIH三组间两两比较均有差异(P均<0.05)；AIH肝功正常组、AIH肝功异常组、AIH肝硬化组外周血单核细胞CD80+细胞所占比例较对照组均明显降低(AIH肝功正常组VS对照组为：79.15±10.29%vs82.34±5.38%,P=0.032；AIH肝功异常组VS对照组为：74.72±10.74%vs82.34±5.38%,P=0.019；A1H肝硬化组VS对照组为：70.84±12.47%vs82.34±5.38%,P=0.012),AIH三组间两两比较均有差异(P均<0.05)；(4)AIH各组吞噬率较对照组均明显降低(AIH肝功正常组VS对照组为：4.34±1.82%vs6.144±2.23%,P=0.027；AIH肝功异常组VS对照组为：3.27±2.04%vs6.14±2.23%,P=0.016；AIH肝硬化组VS对照组为：2.03±±1.47%vs6.14±2.23%,P=0.011),AIH三组间两两比较均存在差异(P均<0.05)。
结论：
(1)AIH患者肠黏膜上皮破坏、紧密连接蛋白减少、肠道菌群失调致肠黏膜屏障功能损伤,肠黏膜通透性增高致细菌移位,血浆LPS升高,且肠黏膜屏障损伤程度与肝脏发病严重程度相关,提示肠黏膜屏障功能受损与AIH的发生发展相关。
(2)AIH患者肠源性内毒素LPS通过TLR4激活KC。
(3)AIH患者KC的Rac1通路过度激活,结合外周血单核细胞抗原提呈能力减低,吞噬能力减低,推测患者单核-巨噬细胞系统细胞骨架变化影响其功能状态。
综上所述,AIH患者存在肠黏膜屏障损伤,LPS可能沿肠黏膜通透性升高→细菌移位→TLR4激活→KC活化并出现生物学功能改变→免疫耐受缺失这条轴线诱发自身免疫反应。本研究不仅能打开LPS与KC相互作用的新视角,而且能帮助证实“肠-肝轴”理论即肠黏膜通透性升高致细菌移位,LPS诱发AIH的免疫耐受损伤机制,最终改善肠道屏障功能可能成为治疗AIH的新靶点。
Background and Objects:The pathogenesis of autoimmune hepatitis (AIH) was still unknown. Attack against liver cell self antigens following the breakdown of immune tolerance were believed to be the major mechanism. Kupffer cells (KC), the resident liver macrophages, with the function of TLR signal pathway, played an important role in immune tolerance induction and maintenance. Recent studies have demonstrated that intestinal-derived toxin could promote production of cytokines and disfunction of biological system of the liver. Based on these observations, we hypothesized that intestinal injury and increased intestinal permeability combined with bacteria translocation could promote. TLR4-dependent KC activation as an early event in the pathogenesis of AIH.
Methods:Part1The mucous membrane of duodenum were observed by electron microscope and immunohistochemistry technique was used to examine the tight junction proteins Zonula occludens-1(ZO-1)、Occludin.16SrDNA fluorescent quantitative PCR was applied in determining the content of bifidobacterium, lactobacillus, escherichia coli and enterococcus in feces. And the level of endotoxin (LPS) and alanine aminotransferase (ALT) were detected in the peripheral blood.
Part2Western blot and double immunofluorescence staining techniques were used to examine the expression and the resource of TLR4in liver tissues. Part3Western blot and double immunofluorescence staining techniques were used to examine the expression and the resource of Racl signaling makers (Vavl and PAK1) in liver tissues. The function of antigen presentation of peripheral blood monocyte was analyzed by CD80and HLA-DR using flow cytometry. Phagocytosis of peripheral blood monocytes was analyzed by challenging cells with fluorescein isothiocyanate (FITC) labeled Escherichia coli (E.coli) using flow cytometry.
Results:Part1(1) The level of serum ALT in AIH group was obviously higher than that in control group (P<0.05).(2) The structure of the duodenum mucosa is obviously broken, the mucosal microvilli structure and tight junction is significantly broken in the AIH group than those in control group.(3) ZO-1and occludin were localized along the apical region of the lateral plasma membrane representing the region of tight junctions in surface and crypt epithelial cells. The positive stainings of ZO-1and occludin of AIH group were obviously decreased (P<0.05).(4) The amount of anaerobes represented by the bifidobacterium and lactobacillus declined (P <0.05). However, the amount of aerobes represented by escherichia coli and enterococcus did not change obviously, Bifidobacteria/Escherichia coli (B/E) which indicated a balance of intestinal flora declined (P<0.05). The results showed the intestinal dysbacteriosis occured in patients with AIH.(5) The level of plasma endotoxin of AIH group were obviously increased than that in control group (P<0.05). Part2The expression of TLR4in liver tissue of AIH group was obviously higher than that of control group(P<0.05), and the expression of TLR4on Kupffer cells of AIH group was obviously higher than that of control group. Part3(1) The expressions of VAV1and PAK1in liver tissue of AIH group were obviously higher(P <0.05), and the expression of VAV1and PAK1on Kupffer cells of AIH group was obviously higher than that of control group.(2) The peripheral blood monocytes antigen presentation function of AIH group was lower than control group (P<0.05).(3) The peripheral blood monocytes phagocytic function of AIH group was lower than control group (P<0.05).
Conclusions:AIH was associated with increased intestinal permeability. Intestinal-derived LPS might activate KC through TLR4signaling in early stages of AIH. The intestinal mucosal barrier fuction might be an important part in the etiology of liver injury. Thus, disfunction of intestinal mucosal barrier might bring a new vision to treatment or prevention of AIH via KC.
引文
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