Toll样受体和趋化因子受体在原发性胆汁性肝硬化中致病机制的研究
|
摘要
原发性胆汁性肝硬化是一种由于免疫系统对自身肝脏进行攻击而引起的慢性胆汁淤积性肝脏自身免疫性疾病,高发于中年女性。患者发病后会导致胆管阻塞和胆汁淤积,造成特异性的胆管上皮细胞损伤,从而引发肝脏的纤维化,最后演变为肝硬化和肝功能衰竭,严重威胁患者的生命。由于获取早期发病的临床肝脏样本十分困难,因此对原发性胆汁性肝硬化发病机制的探索及治疗靶点的开发均主要以该疾病的动物模型-dnTGF-β RⅡ小鼠作为研究工具。该模型很好地模拟了人类原发性胆汁性肝硬化的主要表型特征：自发产生抗线粒体的自身抗体；血清中炎性细胞因子水平升高；病理组织学检查可发现伴随肝内胆管的破坏,肝脏汇管区有大量的CD4T细胞、CD8T细胞等淋巴细胞的浸润；此外dnTGF-β小鼠还有自发的结肠炎,也可以作为研究肝脏炎症和肠道微环境相互作用的模型。
虽然以往的工作利用dnTGF-β RⅡ小鼠这一疾病模型对于该自身免疫性肝病发病早期的一些免疫学致病机制进行了初步探究,包括CD8T细胞的致病性,细胞因子和调节性B细胞对疾病进程的影响等；但是对该疾病的致病机制仍未有全面的了解,还有很多未知的领域,包括天然免疫在该疾病中所发挥的作用以及趋化因子及其配体在介导该疾病炎性浸润中的机制等均未有明确的报道。
因此,本研究以dnTGF-β RⅡ小鼠以及Toll样受体缺失或者趋化因子受体缺失的dnTGF-β RⅡ小鼠为研究原发性胆汁性肝硬化的动物模型,利用细胞免疫学、分子生物学以及医学病理学的实验方法方法对该疾病致病过程中天然免疫受体Toll样受体以及趋化因子受体CXCR3发挥作用的机制进行深入探讨,为阐明原发性胆汁性肝硬化的致病机制以及开发该疾病有效的治疗靶点提供证据支持。本研究得到的实验结果如下：
1.环境因素的改变(肠道菌群清除)影响了原发性胆汁性肝硬化小鼠模型的发病程度
我们用含有甲硝锉,氨苄青霉素,新霉素以及万古霉素这四种抗生素的水从4周龄起饲养SPF级的dnTGF-β RⅡ (TG)小鼠以清除肠道中绝大多数的共生菌。在抗生素喂养12周,即小鼠15周龄时杀鼠,对其肝脏的病理学分析发现与非抗生素水喂养的对照组相比,抗生素喂养加重了TG小鼠的胆管炎,表现为肝脏炎性浸润的增多以及胆管破坏的加重。
2. Toll样受体2缺失加重了dnTGF-β RⅡ小鼠自发的胆管炎及结肠炎
与野生型(WT)小鼠相比,tlr2在dnTGF-β RⅡ (TG)小鼠中有较高的表达,因此我们将TG小鼠与Toll样受体2(TLR2)敲除小鼠进行杂交,得到TLR2-/-dnTGF-β RⅡ (TGT2)小鼠。首先,对其肝脏的病理学分析发现,与TG小鼠相比,TGT2小鼠肝脏汇管区的炎性浸润及肝内胆管的破坏有明显的加重。细胞学分析的结果显示与TG小鼠相比,TGT2小鼠肝脏中T细胞尤其是CD4T细胞的浸润增加了,并且这些浸润的CD4T和CD8T中呈现效应性记忆性表型(CD44highCD62Llow)的细胞明显增多。其次,肠道病理学的分析发现TLR2敲除加重了TG小鼠的自发结肠炎。与TG小鼠相比TGT2小鼠不仅体重明显下降,结肠重量显著上升,而且结肠中的炎性浸润已经扩展到整个粘膜的厚度,腺体和杯状细胞受到严重破坏,并伴随有隐窝囊肿的存在。再次,对细胞因子的检测结果表明,与TG小鼠相比,TGT2小鼠血清中TNF-α和IFN-γ的浓度明显升高,并且在TGT2小鼠的肝脏中il6的基因表达显著增加。对于肝脏中IL-6相关的信号通路的检测发现与TG小鼠相比,TGT2小鼠肝脏中STAT3磷酸化的水平明显升高。最后,为了从相反的方向证明TLR2在TG小鼠发病过程中的作用,我们计划用TLR2的特异性配体Pam3CSK4来对TG小鼠进行高剂量单次注射和低剂量连续注射的处理,从而更加全面地阐明TLR2在TG小鼠发病中的作用机制。
3. Toll样受体4缺失有加重dnTGF-β RⅡ小鼠肝脏炎症及肠道炎症的趋势
与WT小鼠相比,tlr4在TG小鼠中的表达升高,因此我们对杂交所得到的TLR4-/-dnTGF-β RⅡ (TGT4)小鼠进行了一系列的细胞免疫学和医学病理学的分析。结果发现：与TG小鼠相比TGT4小鼠肝脏中浸润的T淋巴细胞的比例有所增加；并且CD8T细胞在总的T细胞中所占的比例有明显的上升；其肝脏中浸润的效应性记忆CD8T细胞(CD8Tem)无论在CD8T细胞中所占的比例还是其绝对数都有明显的增加。虽然TLR4敲除对于dnTGF-β RⅡ小鼠结肠炎症的影响没有统计学上的显著性差异,但是无论是通过病理切片的观察还是统计数据的分析,我们都可以发现TGT4小鼠与TG小鼠相比结肠炎有加重的趋势。
4. CXCR3在dnTGF-β RⅡ小鼠致病过程中作用的初步探讨
首先,我们发现与WT小鼠相比TG小鼠肝脏中趋化因子CXCL9和CXCL10的浓度有明显上升。然后,流式分析的结果显示在TG小鼠肝脏中表达这两种趋化因子的受体CXCR3的T细胞比WT明显增多。接下来,来自TG小鼠或者敲除了CXCR3的TG小鼠中的T细胞的过继转输实验将为证明CXCR3介导T细胞向TG小鼠肝脏迁移提供更加有力的证据。
综上所述,本研究证明了TLR2缺失可以加重原发性胆汁性肝硬化小鼠模型中的胆管炎以及自发性结肠炎。并且发现CXCR3可能介导了该小鼠模型中T细胞向肝脏炎性部位的迁移。我们的研究首次证明了在该疾病模型中天然免疫受体TLR2的敲除促进了肝脏和肠道的炎症。并且首次在该疾病模型中探讨肠道微环境与肝脏炎症之间的关系,这为阐明原发性胆汁性肝硬化的致病机制以及寻找该疾病有效的治疗靶点提供了理论依据。
Primary biliary cirrhosis (PBC) is a chronic cholestatic and autoimmune liver disease, which caused by abnormal immune responses to the patients' own livers. This disease occurs at high frequency among middle-aged women. After onset, the following symptoms show up:biliary obstruction and cholestasis, biliary epithelial cells injury, liver fibrosis, and ultimately, cirrhosis and liver failure, which seriously threaten patients' lives. As it is very difficult to acquire clinical liver samples of patients in the early onset, the pathogenesis studies and therapeutic developments of primary biliary cirrhosis are mainly based on an animal model-dnTGF-βRⅡ mice. The mice spontaneously develop an autoimmune biliary disease closely resembling human PBC. High level of anti-mitochondrial antibodies (AMAs) and increased serum cytokines have been detected in the mice.Histologically, dnTGF-βRⅡ mice manifest extensive CD4and CD8lymphocytic infiltration in portal tracts, associated with biliary destruction. Moreover, dnTGF-β R Ⅱ mice, developing colitis spontaneously as well, could be established as a model to investigate the interactions between hepatic inflammation and intestinal microenvironment.
Primary studies based on dnTGF-βRⅡ mouse model about the pathogenesis of autoimmune liver disease in early onset have been reported, including the pathogenic role of CD8T, the regulatory role of Bregs, and the functions of different cytokines. However, the pathogenic mechanisms of this disease have not been fully understood. Many unknown areas still exist in this disease, such as the role of innate immune responses, and the complexity of chemokines and their receptors, which induce inflammatory infiltration.
Therefore, in this study, dnTGF-βRⅡ mice and dnTGF-βRⅡ mice lacking either Toll-like receptors or chemokine receptor were established as mouse models to investigate the role of innate immune receptors-Toll-like receptor2and4, as well as chemokine receptors, CXCR3, in the progress of this autoimmune liver disease. Methods used in this study were supported by cellular immunology, molecular biology and medical pathology. The aim of this study is to elucidate the pathogenesis of primary biliary cirrhosis and to search for therapeutic targets. The results obtained in this study are as follows:
1. Changed environmental factors (intestinal flora depletion) affected the severity of primary biliary cirrhosis-like disease in mouse model
We added antibiotics including metronidazole, ampicillin, neomycin, and vancomycin into drinking water of dnTGF-βR Ⅱ (TG) mice (at SPF level) since the fourth week after birth to deplete the vast majority of the gut symbionts.12weeks later, when15-week-old, the mice were sacrificed and the liver pathology analysis demonstrated that drinking antibiotic water could aggravate cholangitis in TG mice compared with control group without antibiotic water. TG mice in antibiotic water drinking group had increased hepatic inflammatory infiltrations and worse bile duct injury.
2. Toll-like receptor2depletion aggravated cholangitis and colitis in dnTGF-βR Ⅱ mice
Compared with wild-type (WT) mice, dnTGF-βR Ⅱ (TG) mice have higher expression of tlr2gene in liver. Thus, we crossed TG mice with Toll-like receptor2(TLR2) knockout mice and got TLR2-/-dnTGF-βR Ⅱ (TGT2) mice. First, liver pathology analysis showed that, compared with TG mice, TGT2mice had more severe portal inflammation and bile duct damage in liver. Cytological analysis revealed that, compared with TG mice, infiltrating T cells in TGT2mice liver, especially CD4T cells, were increased. There were also more infiltrating CD4T and CD8T cells presenting effector memory phenotype (CD44highCD62Llow) in TGT2mice than in TG mice. Secondly, intestinal pathology analysis showed aggravated colitis in TGT2mice. Compared with TG mice, the body weight of TGT2mice decreased significantly, but colon weight increased. In the colon of TGT2mice, ulceration with transmural inflammatory cell infiltrates was observed. Moreover, crypts were destroyed and goblet cells were inconspicuous in the colon of TGT2mice, which due to the dense inflammatory cell infiltrates, and accompanied by crypt abscesses and mucin depletion. Again, analysis of cytokines exhibited that compared with TG mice, serum TNF-α and IFN-γ levels were significantly increased and il6gene expression in liver was distinctly up-regulated in TGT2mice. By detecting IL-6related signaling pathway, we found up-regulated phosphorylation of STAT3in the liver of TGT2mice compared with TG mice. Finally, in order to define the role of TLR2in the pathogenesis of primary biliary cirrhosis-like disease in TG mice in another way, we plan to treat TG mice with TLR2specific ligand Pam3CSK4by administrating a single injection at high-dose or a series of injections weekly at low-does. The results will provide us more evidence to elucidate the pathogenic role of TLR2in TG mice.
3. Increasing trend of aggravated liver inflammation and colitis in TLR4-/-dnTGF-βRⅡ
Compared with wide type (WT) mice, tlr4gene expression was up-regulated in TG mice in liver. We obtained TLR4-/-dnTGF-βR Ⅱ (TGT4) mice by crossing TLR4-/-micewith dnTGF-βR Ⅱ mice. Cellular immunology and medical pathology analysis showed that compared with TG mice, TGT4mice had increased proportion of T lymphocytes in liver mononuclear cells. Among these infiltrating T cells, the percentage of CD8T cells was higher than in TG mice. Furthermore, the frequency and absolute number of effector memory CD8T cells in liver of TGT4mice were increased compared with TG mice. Although there was no significant difference in colitis between TG and TGT4mice, increasing trend of aggravated liver inflammation and colitis in TLR4-/-dnTGF-βR Ⅱ mice was observed in both pathological analysis and statistical analysis.
4. The exploration of pathogenic role of CXCR3in dnTGF-βR Ⅱ mice
First, the concentration of chemokine CXCL9and CXCL10was up-regulated in the liver of TG mice compared with wide type mice. Then, the flow cytometry analysis revealed increased CXCR3(receptor of CXCL9and CXCL10) expressing T cells in the liver of TG mice compared with wide type mice. Next, we plan to adoptively transfer T cells from TG mice or CXCR3-/-TG mice, to elucidate the role of CXCR3in T cell migration to liver in TG mice.
In summary, this study demonstrated that the absence of TLR2led to aggravated spontaneous cholangitis and colitis in the mouse model of primary biliary cirrhosis. And we also found that CXCR3may participate in guiding T cell migration to inflammatory sites of liver in this mouse model. Our study demonstrated for the first time that depletion of innate immune receptor TLR2aggravated inflammation in liver and colon in TG mice. And we explored the relationship between intestinal micro-environment and liver inflammation in TG mice firstly. All the evidence we provided in this study could shed light on the pathogenic mechanism of primary biliary cirrhosis and make a contribution to the therapeutic developments.
虽然以往的工作利用dnTGF-β RⅡ小鼠这一疾病模型对于该自身免疫性肝病发病早期的一些免疫学致病机制进行了初步探究,包括CD8T细胞的致病性,细胞因子和调节性B细胞对疾病进程的影响等；但是对该疾病的致病机制仍未有全面的了解,还有很多未知的领域,包括天然免疫在该疾病中所发挥的作用以及趋化因子及其配体在介导该疾病炎性浸润中的机制等均未有明确的报道。
因此,本研究以dnTGF-β RⅡ小鼠以及Toll样受体缺失或者趋化因子受体缺失的dnTGF-β RⅡ小鼠为研究原发性胆汁性肝硬化的动物模型,利用细胞免疫学、分子生物学以及医学病理学的实验方法方法对该疾病致病过程中天然免疫受体Toll样受体以及趋化因子受体CXCR3发挥作用的机制进行深入探讨,为阐明原发性胆汁性肝硬化的致病机制以及开发该疾病有效的治疗靶点提供证据支持。本研究得到的实验结果如下：
1.环境因素的改变(肠道菌群清除)影响了原发性胆汁性肝硬化小鼠模型的发病程度
我们用含有甲硝锉,氨苄青霉素,新霉素以及万古霉素这四种抗生素的水从4周龄起饲养SPF级的dnTGF-β RⅡ (TG)小鼠以清除肠道中绝大多数的共生菌。在抗生素喂养12周,即小鼠15周龄时杀鼠,对其肝脏的病理学分析发现与非抗生素水喂养的对照组相比,抗生素喂养加重了TG小鼠的胆管炎,表现为肝脏炎性浸润的增多以及胆管破坏的加重。
2. Toll样受体2缺失加重了dnTGF-β RⅡ小鼠自发的胆管炎及结肠炎
与野生型(WT)小鼠相比,tlr2在dnTGF-β RⅡ (TG)小鼠中有较高的表达,因此我们将TG小鼠与Toll样受体2(TLR2)敲除小鼠进行杂交,得到TLR2-/-dnTGF-β RⅡ (TGT2)小鼠。首先,对其肝脏的病理学分析发现,与TG小鼠相比,TGT2小鼠肝脏汇管区的炎性浸润及肝内胆管的破坏有明显的加重。细胞学分析的结果显示与TG小鼠相比,TGT2小鼠肝脏中T细胞尤其是CD4T细胞的浸润增加了,并且这些浸润的CD4T和CD8T中呈现效应性记忆性表型(CD44highCD62Llow)的细胞明显增多。其次,肠道病理学的分析发现TLR2敲除加重了TG小鼠的自发结肠炎。与TG小鼠相比TGT2小鼠不仅体重明显下降,结肠重量显著上升,而且结肠中的炎性浸润已经扩展到整个粘膜的厚度,腺体和杯状细胞受到严重破坏,并伴随有隐窝囊肿的存在。再次,对细胞因子的检测结果表明,与TG小鼠相比,TGT2小鼠血清中TNF-α和IFN-γ的浓度明显升高,并且在TGT2小鼠的肝脏中il6的基因表达显著增加。对于肝脏中IL-6相关的信号通路的检测发现与TG小鼠相比,TGT2小鼠肝脏中STAT3磷酸化的水平明显升高。最后,为了从相反的方向证明TLR2在TG小鼠发病过程中的作用,我们计划用TLR2的特异性配体Pam3CSK4来对TG小鼠进行高剂量单次注射和低剂量连续注射的处理,从而更加全面地阐明TLR2在TG小鼠发病中的作用机制。
3. Toll样受体4缺失有加重dnTGF-β RⅡ小鼠肝脏炎症及肠道炎症的趋势
与WT小鼠相比,tlr4在TG小鼠中的表达升高,因此我们对杂交所得到的TLR4-/-dnTGF-β RⅡ (TGT4)小鼠进行了一系列的细胞免疫学和医学病理学的分析。结果发现：与TG小鼠相比TGT4小鼠肝脏中浸润的T淋巴细胞的比例有所增加；并且CD8T细胞在总的T细胞中所占的比例有明显的上升；其肝脏中浸润的效应性记忆CD8T细胞(CD8Tem)无论在CD8T细胞中所占的比例还是其绝对数都有明显的增加。虽然TLR4敲除对于dnTGF-β RⅡ小鼠结肠炎症的影响没有统计学上的显著性差异,但是无论是通过病理切片的观察还是统计数据的分析,我们都可以发现TGT4小鼠与TG小鼠相比结肠炎有加重的趋势。
4. CXCR3在dnTGF-β RⅡ小鼠致病过程中作用的初步探讨
首先,我们发现与WT小鼠相比TG小鼠肝脏中趋化因子CXCL9和CXCL10的浓度有明显上升。然后,流式分析的结果显示在TG小鼠肝脏中表达这两种趋化因子的受体CXCR3的T细胞比WT明显增多。接下来,来自TG小鼠或者敲除了CXCR3的TG小鼠中的T细胞的过继转输实验将为证明CXCR3介导T细胞向TG小鼠肝脏迁移提供更加有力的证据。
综上所述,本研究证明了TLR2缺失可以加重原发性胆汁性肝硬化小鼠模型中的胆管炎以及自发性结肠炎。并且发现CXCR3可能介导了该小鼠模型中T细胞向肝脏炎性部位的迁移。我们的研究首次证明了在该疾病模型中天然免疫受体TLR2的敲除促进了肝脏和肠道的炎症。并且首次在该疾病模型中探讨肠道微环境与肝脏炎症之间的关系,这为阐明原发性胆汁性肝硬化的致病机制以及寻找该疾病有效的治疗靶点提供了理论依据。
Primary biliary cirrhosis (PBC) is a chronic cholestatic and autoimmune liver disease, which caused by abnormal immune responses to the patients' own livers. This disease occurs at high frequency among middle-aged women. After onset, the following symptoms show up:biliary obstruction and cholestasis, biliary epithelial cells injury, liver fibrosis, and ultimately, cirrhosis and liver failure, which seriously threaten patients' lives. As it is very difficult to acquire clinical liver samples of patients in the early onset, the pathogenesis studies and therapeutic developments of primary biliary cirrhosis are mainly based on an animal model-dnTGF-βRⅡ mice. The mice spontaneously develop an autoimmune biliary disease closely resembling human PBC. High level of anti-mitochondrial antibodies (AMAs) and increased serum cytokines have been detected in the mice.Histologically, dnTGF-βRⅡ mice manifest extensive CD4and CD8lymphocytic infiltration in portal tracts, associated with biliary destruction. Moreover, dnTGF-β R Ⅱ mice, developing colitis spontaneously as well, could be established as a model to investigate the interactions between hepatic inflammation and intestinal microenvironment.
Primary studies based on dnTGF-βRⅡ mouse model about the pathogenesis of autoimmune liver disease in early onset have been reported, including the pathogenic role of CD8T, the regulatory role of Bregs, and the functions of different cytokines. However, the pathogenic mechanisms of this disease have not been fully understood. Many unknown areas still exist in this disease, such as the role of innate immune responses, and the complexity of chemokines and their receptors, which induce inflammatory infiltration.
Therefore, in this study, dnTGF-βRⅡ mice and dnTGF-βRⅡ mice lacking either Toll-like receptors or chemokine receptor were established as mouse models to investigate the role of innate immune receptors-Toll-like receptor2and4, as well as chemokine receptors, CXCR3, in the progress of this autoimmune liver disease. Methods used in this study were supported by cellular immunology, molecular biology and medical pathology. The aim of this study is to elucidate the pathogenesis of primary biliary cirrhosis and to search for therapeutic targets. The results obtained in this study are as follows:
1. Changed environmental factors (intestinal flora depletion) affected the severity of primary biliary cirrhosis-like disease in mouse model
We added antibiotics including metronidazole, ampicillin, neomycin, and vancomycin into drinking water of dnTGF-βR Ⅱ (TG) mice (at SPF level) since the fourth week after birth to deplete the vast majority of the gut symbionts.12weeks later, when15-week-old, the mice were sacrificed and the liver pathology analysis demonstrated that drinking antibiotic water could aggravate cholangitis in TG mice compared with control group without antibiotic water. TG mice in antibiotic water drinking group had increased hepatic inflammatory infiltrations and worse bile duct injury.
2. Toll-like receptor2depletion aggravated cholangitis and colitis in dnTGF-βR Ⅱ mice
Compared with wild-type (WT) mice, dnTGF-βR Ⅱ (TG) mice have higher expression of tlr2gene in liver. Thus, we crossed TG mice with Toll-like receptor2(TLR2) knockout mice and got TLR2-/-dnTGF-βR Ⅱ (TGT2) mice. First, liver pathology analysis showed that, compared with TG mice, TGT2mice had more severe portal inflammation and bile duct damage in liver. Cytological analysis revealed that, compared with TG mice, infiltrating T cells in TGT2mice liver, especially CD4T cells, were increased. There were also more infiltrating CD4T and CD8T cells presenting effector memory phenotype (CD44highCD62Llow) in TGT2mice than in TG mice. Secondly, intestinal pathology analysis showed aggravated colitis in TGT2mice. Compared with TG mice, the body weight of TGT2mice decreased significantly, but colon weight increased. In the colon of TGT2mice, ulceration with transmural inflammatory cell infiltrates was observed. Moreover, crypts were destroyed and goblet cells were inconspicuous in the colon of TGT2mice, which due to the dense inflammatory cell infiltrates, and accompanied by crypt abscesses and mucin depletion. Again, analysis of cytokines exhibited that compared with TG mice, serum TNF-α and IFN-γ levels were significantly increased and il6gene expression in liver was distinctly up-regulated in TGT2mice. By detecting IL-6related signaling pathway, we found up-regulated phosphorylation of STAT3in the liver of TGT2mice compared with TG mice. Finally, in order to define the role of TLR2in the pathogenesis of primary biliary cirrhosis-like disease in TG mice in another way, we plan to treat TG mice with TLR2specific ligand Pam3CSK4by administrating a single injection at high-dose or a series of injections weekly at low-does. The results will provide us more evidence to elucidate the pathogenic role of TLR2in TG mice.
3. Increasing trend of aggravated liver inflammation and colitis in TLR4-/-dnTGF-βRⅡ
Compared with wide type (WT) mice, tlr4gene expression was up-regulated in TG mice in liver. We obtained TLR4-/-dnTGF-βR Ⅱ (TGT4) mice by crossing TLR4-/-micewith dnTGF-βR Ⅱ mice. Cellular immunology and medical pathology analysis showed that compared with TG mice, TGT4mice had increased proportion of T lymphocytes in liver mononuclear cells. Among these infiltrating T cells, the percentage of CD8T cells was higher than in TG mice. Furthermore, the frequency and absolute number of effector memory CD8T cells in liver of TGT4mice were increased compared with TG mice. Although there was no significant difference in colitis between TG and TGT4mice, increasing trend of aggravated liver inflammation and colitis in TLR4-/-dnTGF-βR Ⅱ mice was observed in both pathological analysis and statistical analysis.
4. The exploration of pathogenic role of CXCR3in dnTGF-βR Ⅱ mice
First, the concentration of chemokine CXCL9and CXCL10was up-regulated in the liver of TG mice compared with wide type mice. Then, the flow cytometry analysis revealed increased CXCR3(receptor of CXCL9and CXCL10) expressing T cells in the liver of TG mice compared with wide type mice. Next, we plan to adoptively transfer T cells from TG mice or CXCR3-/-TG mice, to elucidate the role of CXCR3in T cell migration to liver in TG mice.
In summary, this study demonstrated that the absence of TLR2led to aggravated spontaneous cholangitis and colitis in the mouse model of primary biliary cirrhosis. And we also found that CXCR3may participate in guiding T cell migration to inflammatory sites of liver in this mouse model. Our study demonstrated for the first time that depletion of innate immune receptor TLR2aggravated inflammation in liver and colon in TG mice. And we explored the relationship between intestinal micro-environment and liver inflammation in TG mice firstly. All the evidence we provided in this study could shed light on the pathogenic mechanism of primary biliary cirrhosis and make a contribution to the therapeutic developments.
引文
Abt, M. C., L. C. Osborne, L. A. Monticelli, T. A. Doering, T. Alenghat, G. F. Sonnenberg, M. A. Paley, M. Antenus, K. L. Williams, J. Erikson, E. J. Wherry and D. Artis (2012). "Commensal bacteria calibrate the activation threshold of innate antiviral immunity." Immunity37(1):158-170.
Abu-Shanab, A. and E. M. Quigley (2010). "The role of the gut microbiota in nonalcoholic fatty liver disease." Nat Rev Gastroenterol Hepatol7(12):691-701.
Akira, S. and K. Takeda (2004). "Toll-like receptor signalling." Nat Rev Immunol4(7): 499-511.
Akira, S., S. Uematsu and O. Takeuchi (2006). "Pathogen recognition and innate immunity." Cell124(4):783-801.
Alexopoulou, L., A. C. Holt, R. Medzhitov and R. A. Flavell (2001). "Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3."Nature413(6857): 732-738.
Anderson, G. D., S. D. Hauser, K. L. McGarity, M. E. Bremer, P. C. Isakson and S. A. Gregory (1996). "Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis." J Clin Invest97(11):2672-2679.
Aoki, C. A., C. M. Roifman, Z. X. Lian, C. L. Bowlus, G. L. Norman, Y. Shoenfeld, I. R. Mackay and M. E. Gershwin (2006). "IL-2 receptor alpha deficiency and features of primary biliary cirrhosis." J Autoimmun27(1):50-53.
Balogh, S., I. Kiss and A. Csaszar (2009). "Toll-like receptors:link between "danger" ligands and plaque instability." Curr Drug Targets10(6):513-518.
Barton, G. M. and J. C. Kagan (2009). "A cell biological view of Toll-like receptor function: regulation through compartmentalization." Nat Rev Immunol9(8):535-542.
Barton, G. M. and R. Medzhitov (2002). "Control of adaptive immune responses by Toll-like receptors." Curr Opin Immunoll4(3):380-383.
Bataller, R. and D. A. Brenner (2001). "Hepatic stellate cells as a target for the treatment of liver fibrosis." Seminars in Liver Disease21(3):437-451.
Bataller, R. and D. A. Brenner (2001). "Hepatic stellate cells as a target for the treatment of liver fibrosis." Semin Liver Dis21(3):437-451.
Bataller, R. and D. A. Brenner (2005). "Liver fibrosis." J Clin Invest115(2):209-218.
Bataller, R., K. E. North and D. A. Brenner (2003). "Genetic polymorphisms and the progression of liver fibrosis:a critical appraisal." Hepatology37(3):493-503.
Bendele, A., J. McComb, T. Gould, T. McAbee, G. Sennello, E. Chlipala and M. Guy (1999). "Animal models of arthritis:relevance to human disease." Toxicol Pathol27(1):134-142.
Berg, D. J., N. Davidson, R. Kuhn, W. Muller, S. Menon, G. Holland, L. Thompson-Snipes, M. W. Leach and D. Rennick (1996). "Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses." J Clin Invest98(4):1010-1020.
Boberg, K. M. (2002). "Prevalence and epidemiology of autoimmune hepatitis." Clin Liver Dis6(3):635-647.
Boonstra, K., K. J. van Erpecum, K. M. van Nieuwkerk, J. P. Drenth, A. C. Poen, B. J. Witteman, H. A. Tuynman, U. Beuers and C. Y. Ponsioen (2012). "Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease." Inflamm Bowel Dis18(12):2270-2276.
Bouaziz, J. D., K. Yanaba and T. F. Tedder (2008). "Regulatory B cells as inhibitors of immune responses and inflammation." Immunol Rev224:201-214.
Broering, R., M. Lu and J. F. Schlaak (2011). "Role of Toll-like receptors in liver health and disease." Clin Sci (Lond)121(10):415-426.
Brummel, R. and P. Lenert (2005). "Activation of marginal zone B cells from lupus mice with type A(D) CpG-oligodeoxynucleotides." J Immunol174(4):2429-2434.
Calne, R. Y., R. A. Sells, J. R. Pena, D. R. Davis, P. R. Millard, B. M. Herbertson, R. M. Binns and D. A. Davies (1969). "Induction of immunological tolerance by porcine liver allografts." Nature223(5205):472-476.
Cario, E., G. Gerken and D. K. Podolsky (2007). "Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function." Gastroenterology132(4):1359-1374.
Cario, E. and D. K. Podolsky (2005). "Intestinal epithelial TOLLerance versus inTOLLerance of commensals." Mol Immunol42(8):887-893.
Charles, P., M. J. Elliott, D. Davis, A. Potter, J. R. Kalden, C. Antoni, F. C. Breedveld, J. S. Smolen, G. Eberl, K. deWoody, M. Feldmann and R. N. Maini (1999). "Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis." J Immunol163(3):1521-1528.
Charo, I. F. and R. M. Ransohoff (2006). "The many roles of chemokines and chemokine receptors in inflammation." N Engl J Med354(6):610-621.
Chen, Y. L., J. Lv, X. L. Ye, M. Y. Sun, Q. Xu, C. H. Liu, L. H. Min, H. P. Li, P. Liu and X. Ding (2011). "Sorafenib inhibits transforming growth factor betal-mediated epithelial-mesenchymal transition and apoptosis in mouse hepatocytes." Hepatologv53(5): 1708-1718.
Chuang, Y. H., Z. X. Lian, C. M. Cheng, R. Y. Lan, G. X. Yang, Y. Moritoki, B. L. Chiang, A. A. Ansari, K. Tsuneyama, R. L. Coppel and M. E. Gershwin (2005). "Increased levels of chemokine receptor CXCR3 and chemokines IP-10 and MIG in patients with primary biliary cirrhosis and their first degree relatives." J Autoimmun25(2):126-132.
Chuang, Y. H., Z. X. Lian, K. Tsuneyama, B. L. Chiang, A. A. Ansari, R. L. Coppel and M. E. Gershwin (2006). "Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis." J Autoimmun26(4):232-240.
Cook, D. N., D. S. Pisetsky and D. A. Schwartz (2004). "Toll-like receptors in the pathogenesis of human disease." Nat Immunol5(10):975-979.
Crispe, I. N. (2009). "The liver as a lymphoid organ." Annu Rev Immunol27:147-163.
Czaja, A. J. (2009). "Autoimmune liver disease." Curr Opin Gastroenterol25(3):215-222.
Czaja, A. J. (2010). "Autoantibodies as prognostic markers in autoimmune liver disease." Dig Dis Sci55(8):2144-2161.
Czaja, A. J. and M. P. Manns (2010). "Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis." Gastroenterology 139(1):58-72 e54.
Dianda, L., A. M. Hanby, N. A. Wright, A. Sebesteny, A. C. Hayday and M. J. Owen (1997). "T cell receptor-alpha beta-deficient mice fail to develop colitis in the absence of a microbial environment." Am J Pathol150(1):91-97.
Diebold, S. S., T. Kaisho, H. Hemmi, S. Akira and C. Reis e Sousa (2004). "Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA." Science303(5663): 1529-1531.
Dieleman, L. A., M. J. H. J. Palmen, H. Akol, E. Bloemena, A. S. Pena, S. G. M. Meuwissen and E. P. van Rees (1998). "Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Thl and Th2 cytokines." Clinical and Experimental Immunology114(3):385-391.
Dinarello, C. A. (2009). "Immunological and inflammatory functions of the interleukin-1 family." Annu Rev Immunol27:519-550.
Elsharkawy, A. M., F. Oakley and D. A. Mann (2005). "The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis." Apoptosis10(5):927-939.
Evans, J. G., K. A. Chavez-Rueda, A. Eddaoudi, A. Meyer-Bahlburg, D. J. Rawlings, M. R. Ehrenstein and C. Mauri (2007). "Novel suppressive function of transitional 2 B cells in experimental arthritis." J Immunol178(12):7868-7878.
Forbes, S. J., F. P. Russo, V. Rey, P. Burra, M. Rugge, N. A. Wright and M. R Alison (2004). "A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis." Gastroenterologv126(4):955-963.
Friedman, S. L. (2003). "Liver fibrosis--from bench to bedside." J Hepatol38 Suppl 1: S38-53.
Friedman, S. L. (2008). "Hepatic fibrosis-Overview." Toxicologv254(3):120-129.
Frieri, M. (2013). "Mechanisms of disease for the clinician:systemic lupus erythematosus." Ann Allergy Asthma Immunol110(4):228-232.
Gershwin, M. E., A. A. Ansari, I. R. Mackay, Y. Nakanuma, A. Nishio, M. J. Rowley and R. L. Coppel (2000). "Primary biliary cirrhosis:an orchestrated immune response against epithelial cells." Immunol Rev174:210-225.
Gershwin, M. E. and I. R. Mackay (2008). "The causes of primary biliary cirrhosis: Convenient and inconvenient truths." Hepatology47(2):737-745.
Gershwin, M. E., C. Selmi, H. J. Worman, E. B. Gold, M. Watnik, J. Utts, K. D. Lindor, M. M. Kaplan, J. M. Vierling and U. P. E. Group (2005). "Risk factors and comorbidities in primary biliary cirrhosis:a controlled interview-based study of 1032 patients." Hepatology42(5): 1194-1202.
Gillevet, P., M. Sikaroodi, A. Keshavarzian and E. A. Mutlu (2010). "Quantitative assessment of the human gut microbiome using multitag pyrosequencing." Chem Biodivers7(5): 1065-1075.
Godessart, N. and S. L. Kunkel (2001). "Chemokines in autoimmune disease." Curr Opin Immunol13(6):670-675.
Gorelik, L. and R. A. Flavell (2000). "Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease." Immunity12(2):171-181.
Gray, M., K. Miles, D. Salter, D. Gray and J. Savill (2007). "Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells." Proc Natl Acad Sci U S A104(35):14080-14085.
Gurevitz, S. L., J. A. Snyder, E. K. Wessel, J. Frey and B. A. Williamson (2013). "Systemic lupus erythematosus:a review of the disease and treatment options." Consult Pharm28(2): 110-121.
Harada, K., K. Isse, K. Tsuneyama, H. Ohta and Y. Nakanuma (2003). "Accumulating CD57+CD3+natural killer T cells are related to intrahepatic bile duct lesions in primary biliary cirrhosis." Liver Int23(2):94-100.
Harada, K. and Y. Nakanuma (2010). "Biliary innate immunity in the pathogenesis of biliary diseases." Inflamm Allergy Drug Targets9(2):83-90.
Harada, K. and Y. Nakanuma (2010). "Biliary Innate Immunity:Function and Modulation." Mediators of Inflammation.
Harada, K., S. Ozaki, M. E. Gershwin and Y. Nakanuma (1997). "Enhanced apoptosis relates to bile duct loss in primary biliary cirrhosis." Hepatology26(6):1399-1405.
Hartmann, P., M. Haimerl, M. Mazagova, D. A. Brenner and B. Schnabl (2012). "Toll-like receptor 2-mediated intestinal injury and enteric tumor necrosis factor receptor I contribute to liver fibrosis in mice." Gasfroenterology143(5):1330-1340 e1331.
Helbig, K. J., A. Ruszkiewicz, L. Semendric, H. A. Harley, S. R. McColl and M. R. Beard (2004). "Expression of the CXCR3 ligand I-TAC by hepatocytes in chronic hepatitis C and its correlation with hepatic inflammation." Hepatology39(5):1220-1229.
Hemmi, H., O. Takeuchi, T. Kawai, T. Kaisho, S. Sato, H. Sanjo, M. Matsumoto, K. Hoshino, H. Wagner, K. Takeda and S. Akira (2000). "A Toll-like receptor recognizes bacterial DNA." Nature408(6813):740-745.
Henao-Mejia, J., E. Elinav, C. Jin, L. Hao, W. Z. Mehal, T. Strowig, C. A. Thaiss, A. L. Kau, S. C. Eisenbarth, M. J. Jurczak, J. P. Camporez, G. I. Shulman, J. I. Gordon, H. M. Hoffman and R. A. Flavell (2012). "Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity." Nature482(7384):179-185.
Hintermann, E., M. Bayer, J. M. Pfeilschifter, A. D. Luster and U. Christen (2010). "CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation." J Autoimmun35(4):424-435.
Hoentjen, F., H. J. Harmsen, H. Braat, C. D. Torrice, B. A. Mann, R. B. Sartor and L. A. Dieleman (2003). "Antibiotics with a selective aerobic or anaerobic spectrum have different therapeutic activities in various regions of the colon in interleukin 10 gene deficient mice." Gut52(12):1721-1727.
Homey, B., A. Muller and A. Zlotnik (2002). "Chemokines:agents for the immunotherapy of cancer?" Nat Rev Immunol2(3):175-184.
Hora, C., P. Romanque and J. F. Dufour (2011). "Effect of sorafenib on murine liver regeneration." Hepatology53(2):577-586.
Horiguchi, N., L. Wang, P. Mukhopadhyay, O. Park, W. I. Jeong, F. Lafdil, D. Osei-Hyiaman, A. Moh, X. Y. Fu, P. Pacher, G. Kunos and B. Gao (2008). "Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury." Gastroenterologv134(4):1148-1158.
Horwood, N. J., T. H. Page, J. P. McDaid, C. D. Palmer, J. Campbell, T. Mahon, F. M. Brennan, D. Webster and B. M. Foxwell (2006). "Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production." J Immunol176(6):3635-3641.
Huynh, J. L. and P. Casaccia (2013). "Epigenetic mechanisms in multiple sclerosis: implications for pathogenesis and treatment." Lancet Neuroll2(2):195-206.
Iavarone, M., G. Cabibbo, F. Piscaglia, C. Zavaglia, A. Grieco, E. Villa, C. Camma, M. Colombo and S. S. I. Assessment (2011). "Field-Practice Study of Sorafenib Therapy for Hepatocellular Carcinoma:A Prospective Multicenter Study in Italy." Hepatology54(6): 2055-2063.
Iredale, J. P. (2001). "Hepatic stellate cell behavior during resolution of liver injury." Semin Liver Dis21(3):427-436.
Irie, J., Y. Wu, L. S. Wicker, D. Rainbow, M. A. Nalesnik, R. Hirsch, L. B. Peterson, P. S. Leung, C. Cheng, I. R. Mackay, M. E. Gershwin and W. M. Ridgway (2006). "NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis." J Exp Med203(5):1209-1219.
Jansen, P. L. (2004). "Non-alcoholic steatohepatitis." Eur J Gastroenterol Hepatoll6(11): 1079-1085.
Jiang, D., J. Liang, J. Fan, S. Yu, S. Chen, Y. Luo, G. D. Prestwich, M. M. Mascarenhas, H. G. Garg, D. A. Quinn, R. J. Homer, D. R. Goldstein, R. Bucala, P. J. Lee, R. Medzhitov and P. W. Noble (2005). "Regulation of lung injury and repair by Toll-like receptors and hyaluronan." Nat Med11(11):1173-1179.
Kaimori, A., J. Potter, J. Y. Kaimori, C. Wang, E. Mezey and A. Koteish (2007). "Transforming growth factor-betal induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro." J Biol Chem282(30):22089-22101.
Kang, S. S., S. M. Bloom, L. A. Norian, M. J. Geske, R. A. Flavell, T. S. Stappenbeck and P. M. Allen (2008). "An antibiotic-responsive mouse model of fulminant ulcerative colitis." PLoS Med5(3):e41.
Kaplan, M. M. and M. E. Gershwin (2005). "Primary biliary cirrhosis." N Engl J Med353(12):1261-1273.
Kaur, S., S. White and P. M. Bartold (2013). "Periodontal disease and rheumatoid arthritis: a systematic review." J Dent Res92(5):399-408.
Kikuchi, K., Z. X. Lian, G. X. Yang, A. A. Ansari, S. Ikehara, M. Kaplan, H. Miyakawa, R. L. Coppel and M. E. Gershwin (2005). "Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis." Gastroenterology 128(2):304-312.
Kishimoto, T. (2005). "Interleukin-6:from basic science to medicine--40 years in immunology" Annu Rev Immunol23:1-21.
Kita, H., M. Imawari and M. E. Gershwin (2004). "Cellular immune response in primary biliary cirrhosis." Hepatol Res28(1):12-17.
Kita, H., Z. X. Lian, J. Van de Water, X. S. He, S. Matsumura, M. Kaplan, V. Luketic, R. L. Coppel, A. A. Ansari and M. E. Gershwin (2002). "Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis:T cell activation is augmented by immune complexes cross-presented by dendritic cells." J Exp Med195(1):113-123.
Kita, H., S. Matsumura, X. S. He, A. A. Ansari, Z. X. Lian, J. Van de Water, R. L. Coppel, M. M. Kaplan and M. E. Gershwin (2002). "Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis." J Clin Invest109(9):1231-1240.
Kita, H., O. V. Naidenko, M. Kronenberg, A. A. Ansari, P. Rogers, X. S. He, F. Koning, T. Mikayama, J. Van De Water, R. L. Coppel, M. Kaplan and M. E. Gershwin (2002). "Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer." Gastroenterology123(4):1031-1043.
Kita, H., O. V. Naidenko, M. Kronenberg, A. A. Ansari, P. Rogers, X. S. He, F. Koning, T. Mikayama, J. Van de Water, R. L. Coppel, M. Kaplan and M. E. Gershwin (2002). "Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human mid tetramer." Gastoenterology123(4):1031-1043.
Kleiveland, C. R., L. T. Hult, S. Spetalen, M. Kaldhusdal, T. E. Christofferesen, O. Bengtsson, O. H. Romarheim, M. Jacobsen and T. Lea (2013). "The noncommensal bacterium Methylococcus capsulatus (Bath) ameliorates dextran sulfate (Sodium Salt)-Induced Ulcerative Colitis by influencing mechanisms essential for maintenance of the colonic barrier function." Appl Environ Microbiol79(1):48-56.
Knight, A. K. and C. Cunningham-Rundles (2006). "Inflammatory and autoimmune complications of common variable immune deficiency." Autoimmun Rev5(2):156-159.
Kobayashi, N., T. Kondo, H. Takata, S. Yokota and M. Takiguchi (2006). "Functional and phenotypic analysis of human memory CD8+ T cells expressing CXCR3." J Leukoc Biol80(2): 320-329.
Krasilnikov, M., V. N. Ivanov, J. Dong and Z. Ronai (2003). "ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells:implications towards sensitization to apoptosis." Oncogene22(26):4092-4101.
Kubo, T., Y. Uchida, Y. Watanabe, M. Abe, A. Nakamura, M. Ono, S. Akira and T. Takai (2009). "Augmented TLR9-induced Btk activation in PIR-B-deficient B-1 cells provokes excessive autoantibody production and autoimmunity." J Exp Med206(9):1971-1982.
Kunkel, S. L. and N. Godessart (2002). "Chemokines in autoimmunity:from pathology to therapeutics." Autoimmun Rev1(6):313-320.
Kuroki, T., S. Seki, N. Kawakita, K. Nakatani, T. Hisa, T. Kitada and H. Sakaguchi (1996). "Expression of antigens related to apoptosis and cell proliferation in chronic nonsuppurative destructive cholangitis in primary biliary cirrhosis." Virchows Arch429(2-3):119-129.
Lalor, P. F., P. Shields, A. Grant and D. H. Adams (2002). "Recruitment of lymphocytes to the human liver." Immunol Cell Biol80(1):52-64.
Lam-Tse, W. K., A. Lernmark and H. A. Drexhage (2002). "Animal models of endocrine/organ-specific autoimmune diseases:do they really help us to understand human autoimmunity?" Springer Semin Immunopathol24(3):297-321.
Lan, R. Y., A. A. Ansari, Z. X. Lian and M. E. Gershwin (2005). "Regulatory T cells: development, function and role in autoimmunity." Autoimmun Rev4(6):351-363.
Lan, R. Y., C. Cheng, Z. X. Lian, K. Tsuneyama, G. X. Yang, Y. Moritoki, Y. H. Chuang, T. Nakamura, S. Saito, S. Shimoda, A. Tanaka, C. L. Bowlus, Y. Takano, A. A. Ansari, R. L. Coppel and M. E. Gershwin (2006). "Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis." Heptology43(4):729-737.
Laragione, T., M. Brenner, B. Sherry and P. S. Gulko (2011). "CXCL10 and its receptor CXCR3 regulate synovial fibroblast invasion in rheumatoid arthritis." Arthritis Rheum63(11): 3274-3283.
Lemoine, S., A. Morva, P. Youinou and C. Jamin (2009). "Regulatory B cells in autoimmune diseases:how do they work?" Ann N Y Acad Scil173:260-267.
Leon, M. P., G. Spickett, D. E. Jones and M. F. Bassendine (1995). "CD4+ T cell subsets defined by isoforms of CD45 in primary biliary cirrhosis." Clin Exp Immunol99(2):233-239.
Leulier, F. and B. Lemaitre (2008). "Toll-like receptors--taking an evolutionary approach." Nat Rev Genet9(3):165-178.
Li, D. and S. L. Friedman (1999). "Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy." J Gastroenterol Hepatol14(7):618-633.
Liu, L., M. K. Callahan, D. Huang and R. M. Ransohoff (2005). "Chemokine receptor CXCR3:an unexpected enigma." Curr Top Dev Biol68:149-181.
Llovet, J. M., S. Ricci, V. Mazzaferro, P. Hilgard, E. Gane, J. F. Blanc, A. C. de Oliveira, A. Santoro, J. L. Raoul, A. Forner, M. Schwartz, C. Porta, S. Zeuzem, L. Bolondi, T. F. Greten, P. R. Galle, J. F. Seitz, I. Borbath, D. Haussinger, T. Giannaris, M. Shan, M. Moscovici, D. Voliotis and J. Bruix (2008). "Sorafenib in Advanced Hepatocellular Carcinoma (vol 359, pg 378,2008)." New England Journal of Medicine359(23):2508-2508.
Loftus, E. V., Jr., G. C. Harewood, C. G. Loftus, W. J. Tremaine, W. S. Harmsen, A. R. Zinsmeister, D. A. Jewell and W. J. Sandborn (2005). "PSC-IBD:a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis." Gut54(1):91-96.
Longhi, M. S., Y. Ma, G. Mieli-Vergani and D. Vergani (2010). "Aetiopathogenesis of autoimmune hepatitis." J Autoimmun34(1):7-14.
Lund, J. M., L. Alexopoulou, A. Sato, M. Karow, N. C. Adams, N. W. Gale, A. Iwasaki and R. A. Flavell (2004). "Recognition of single-stranded RNA viruses by Toll-like receptor 7." Proc Natl Acad Sci U S A101(15):5598-5603.
Machado, M. V. and H. Cortez-Pinto (2012). "Gut microbiota and nonalcoholic fatty liver disease." Ann Hepatol11(4):440-449.
Mackay, I. R. (2008). "Historical reflections on autoimmune hepatitis." World J Gastroenterol14(21):3292-3300.
Madsen, K. L., J. S. Doyle, M. M. Tavernini, L. D. Jewell, R. P. Rennie and R. N. Fedorak (2000). "Antibiotic therapy attenuates colitis in interleukin 10 gene-deficient mice." Gastroenterology118(6):1094-1105.
Maharshak, N., C. D. Packey, M. Ellermann, S. Manick, J. P. Siddle, E. Y. Huh, S. Plevy, R. B. Sartor and I. M. Carroll (2013). "Altered enteric microbiota ecology in interleukin 10-deficient mice during development and progression of intestinal inflammation." Gut Microbes4(4):316-324.
Mann, M. K., K. Maresz, L. P. Shriver, Y. Tan and B. N. Dittel (2007). "B cell regulation of CD4+CD25+ T regulatory cells and IL-10 via B7 is essential for recovery from experimental autoimmune encephalomyelitis." J Immunol178(6):3447-3456.
Mao, T. K., Z. X. Lian, C. Selmi, Y. Ichiki, P. Ashwood, A. A. Ansari, R. L. Coppel, S. Shimoda, H. Ishibashi and M. E. Gershwin (2005). "Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis." Hepatology42(4):802-808.
Martinon, F., X. Chen, A. H. Lee and L. H. Glimcher (2010). "TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages." Nat Immunol11(5):411-418.
Matkowskyj, K. A., Z. E. Chen, M. S. Rao and G. Y. Yang (2013). "Dysplastic lesions in inflammatory bowel disease:molecular pathogenesis to morphology." Arch Pathol Lab Med137(3):338-350.
Mauri, C. and M. R. Ehrenstein (2008). "The 'short' history of regulatory B cells." Trends Immunol29(1):34-40.
Mehal, W. Z. (2012). "The gut-liver axis:a busy two-way street." Hepatology55(6): 1647-1649.
Mejias, M., E. Garcia-Pras, C. Tiani, R. Miquel, J. Bosch and M. Fernandez (2009). "Beneficial Effects of Sorafenib on Splanchnic, Intrahepatic, and Portocollateral Circulations in Portal Hypertensive and Cirrhotic Rats." Hepatology49(4):1245-1256.
Miyake, Y. and K. Yamamoto (2013). "Role of gut microbiota in liver diseases." Hepatol Res43(2):139-146.
Mohan, K. and T. B. Issekutz (2007). "Blockade of chemokine receptor CXCR3 inhibits T cell recruitment to inflamed joints and decreases the severity of adjuvant arthritis." J Immunol179(12):8463-8469.
Moritoki, Y., Z. X. Lian, Y. Ohsugi, Y. Ueno and M. E. Gershwin (2006). "B cells and autoimmune liver diseases." Autoimmun Rev5(7):449-457.
Moritoki, Y., W. Zhang, K. Tsuneyama, K. Yoshida, K. Wakabayashi, G. X. Yang, C. Bowlus, W. M. Ridgway, Y. Ueno, A. A. Ansari, R. L. Coppel, I. R. Mackay, R. A. Flavell, M. E. Gershwin and Z. X. Lian (2009). "B cells suppress the inflammatory response in a mouse model of primary biliary cirrhosis." Gastroenterology136(3):1037-1047.
Muller, G., U. E. Hopken, H. Stein and M. Lipp (2002). "Systemic immunoregulatory and pathogenic functions of homeostatic chemokine receptors." J Leukoc Biol72(1):1-8.
Murdoch, C. and A. Finn (2000). "Chemokine receptors and their role in inflammation and infectious diseases." Blood95(10):3032-3043.
Neumann, K., N. Kruse, B. Szilagyi, U. Erben, C. Rudolph, A. Flach, M. Zeitz, A. Hamann and K. Klugewitz (2012). "Connecting liver and gut:murine liver sinusoidal endothelium induces gut tropism of CD4+ T cells via retinoic acid." Hepatology55(6):1976-1984.
O'Neill, L. A. (2008). "The interleukin-1 receptor/Toll-like receptor superfamily:10 years of progress." Immunol Rev226:10-18.
O'Neill, L. A. (2008). "When signaling pathways collide:positive and negative regulation of toll-like receptor signal transduction." Immunity29(1):12-20.
Odin, J. A., R. C. Huebert, L. Casciola-Rosen, N. F. LaRusso and A. Rosen (2001). "Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis." J Clin Invest108(2):223-232.
Oertelt, S., Z. X. Lian, C. M. Cheng, Y. H. Chuang, K. A. Padgett, X. S. He, W. M. Ridgway, A. A. Ansari, R. L. Coppel, M. O. Li, R. A. Flavell, M. Kronenberg, I. R. Mackay and M. E. Gershwin (2006). "Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor Ⅱ dominant-negative mice." J Immunol177(3):1655-1660.
Pares, A., L. Caballeria, J. Rodes, M. Bruguera, L. Rodrigo, A. Garcia-Plaza, J. Berenguer, D. Rodriguez-Martinez, J. Mercader and R. Velicia (2000). "Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis:results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver." J Hepatol32(4):561-566.
Popov, Y. and D. Schuppan (2009). "Targeting liver fibrosis:strategies for development and validation of antifibrotic therapies." Hepatology50(4):1294-1306.
Powrie, F. (1995). "T cells in inflammatory bowel disease:protective and pathogenic roles." Immunity3(2):171-174.
Powrie, F., M. W. Leach, S. Mauze, S. Menon, L. B. Caddle and R. L. Coffman (1994). "Inhibition of Thl responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells." Immunity1(7):553-562.
Racanelli, V. and B. Rehermann (2006). "The liver as an immunological organ." Hepatology43(2 Suppl 1):S54-62.
Rahimi, R. S. and D. C. Rockey (2011). "Complications and outcomes in chronic liver disease." Curr Opin Gastroenterol27(3):204-209.
Ramadori, G. and B. Saile (2004). "Portal tract fibrogenesis in the liver." Lab Invest84(2): 153-159.
Reiberger, T., B. Angermayr, P. Schwabl, N. Rohr-Udilova, M. Mitterhauser, A. Gangl and M. Peck-Radosavljevic (2009). "Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats." J Hepatol51(5):865-873.
Robinson, C. J., B. J. Bohannan and V. B. Young (2010). "From structure to function:the ecology of host-associated microbial communities." Microbiol Mol Biol Rev74(3):453-476.
Rosman, Z., Y. Shoenfeld and G. Zandman-Goddard (2013). "Biologic therapy for autoimmune diseases:an update." BMC Med11:88.
Rossi, D. and A. Zlotnik (2000). "The biology of chemokines and their receptors." Annu Rev Immunoll8:217-242.
Sakaguchi, S., T. Yamaguchi, T. Nomura and M. Ono (2008). "Regulatory T cells and immune tolerance." Cell133(5):775-787.
Sakurai, H., H. Chiba, H. Miyoshi, T. Sugita and W. Toriumi (1999). "IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain." J Biol Chem274(43):30353-30356.
Santodomingo-Garzon, T. and M. G. Swain (2011). "Role of NKT cells in autoimmune liver disease." Autoimmun Rev10(12):793-800.
Sasaki, C. Y., T. J. Barberi, P. Ghosh and D. L. Longo (2005). "Phosphorylation of RelA/p65 on serine 536 defines an I{kappa}B{alpha}-independent NF-{kappa}B pathway." J Biol Chem280(41):34538-34547.
Sato, M., S. Suzuki and H. Senoo (2003). "Hepatic stellate cells:Unique characteristics in cell biology and phenotype." Cell Structure and Function28(2):105-112.
Scallon, B. J., M. A. Moore, H. Trinh, D. M. Knight and J. Ghrayeb (1995). "Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions." Cytokine7(3):251-259.
Schnare, M., G. M. Barton, A. C. Holt, K. Takeda, S. Akira and R. Medzhitov (2001). "Toll-like receptors control activation of adaptive immune responses." Nat Immunol2(10): 947-950.
Schultz, M., S. L. Tonkonogy, R. K. Sellon, C. Veltkamp, V. L. Godfrey, J. Kwon, W. B. Grenther, E. Balish, I. Horak and R. B. Sartor (1999). "IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation." Am J Physiol276(6 Pt 1):G1461-1472.
Seki, E. and D. A. Brenner (2008). "Toll-like receptors and adaptor molecules in liver disease:update." Hepatology48(1):322-335.
Seki, E., S. De Minicis, C. H. Osterreicher, J. Kluwe, Y. Osawa, D. A. Brenner and R. F. Schwabe (2007). "TLR4 enhances TGF-beta signaling and hepatic fibrosis." Nat Med13(11): 1324-1332.
Sellon, R. K., S. Tonkonogy, M. Schultz, L. A. Dieleman, W. Grenther, E. Balish, D. M. Rennick and R. B. Sartor (1998). "Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice." Infect Immun66(11):5224-5231.
Shi, H., M. V. Kokoeva, K. Inouye, I. Tzameli, H. Yin and J. S. Flier (2006). "TLR4 links innate immunity and fatty acid-induced insulin resistance." J Clin Invest116(11):3015-3025.
Shimomura, Y., E. Mizoguchi, K. Sugimoto, R. Kibe, Y. Benno, A. Mizoguchi and A. K. Bhan (2008). "Regulatory role of B-1 B cells in chronic colitis." Int Immunol20(6):729-737.
Shindo, M., G. E. Mullin, L. Braun-Elwert, N. V. Bergasa, E. A. Jones and S. P. James (1996). "Cytokine mRNA expression in the liver of patients with primary biliary cirrhosis (PBC) and chronic hepatitis B (CHB)." Clin Exp Immunol105(2):254-259.
Son, G., M. Kremer and I. N. Hines (2010). "Contribution of gut bacteria to liver pathobiology." Gastroenterol Res Pract2010.
Sorensen, H. T., A. M. Thulstrup, P. Blomqvist, B. Norgaard, K. Fonager and A. Ekbom (1999). "Risk of primary biliary liver cirrhosis in patients with coeliac disease:Danish and Swedish cohort data." Gut44(5):736-738.
Stepankova, R., F. Powrie, O. Kofronova, H. Kozakova, T. Hudcovic, T. Hrncir, H. Uhlig, S. Read, Z. Rehakova, O. Benada, P. Heczko, M. Strus, P. Bland and H. Tlaskalova-Hogenova (2007). "Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells." Inflamm Bowel Dis13(10):1202-1211.
Sugimoto, K., A. Ogawa, Y. Shimomura, K. Nagahama, A. Mizoguchi and A. K. Bhan (2007). "Inducible IL-12-producing B cells regulate Th2-mediated intestinal inflammation." Gastroenterology133(1):124-136.
Sutmuller, R. P., M. H. den Brok, M. Kramer, E. J. Bennink, L. W. Toonen, B. J. Kullberg, L. A. Joosten, S. Akira, M. G. Netea and G. J. Adema (2006). "Toll-like receptor 2 controls expansion and function of regulatory T cells." J Clin Invest116(2):485-494.
Szabo, G., S. Bala, J. Petrasek and A. Gattu (2010). "Gut-liver axis and sensing microbes." Dig Dis28(6):737-744.
Tacke, F., H. W. Zimmermann, M. L. Berres, C. Trautwein and H. E. Wasmuth (2011). "Serum chemokine receptor CXCR3 ligands are associated with progression, organ dysfunction and complications of chronic liver diseases." Liver Int31(6):840-849.
Takeda, K. and S. Akira (2005). "Toll-like receptors in innate immunity." Int Immunol17(1):1-14.
Takii, Y., M. Nakamura, M. Ito, T. Yokoyama, A. Komori, Y. K. Shimizu-Yoshida, R. Nakao, K. Kusumoto, S. Nagaoka, K. Yano, S. Abiru, T. Ueki, T. Matsumoto, M. Daikoku, K. Taniguchi, H. Fujioka, K. Migita, H. Yasuhashi, M. Nakashima, M. Harada and H. Ishibashi (2005). "Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis." Laboratory Investigation85(7):908-920.
Tanimoto, K., F. Akbar, K. Michitaka and M. Onji (1999). "Immunohistochemical localization of antigen presenting cells in liver from patients with primary biliary cirrhosis; Highly restricted distribution of CD83-positive activated dendritic cells." Pathology Research and Practice195(3):157-162.
Testro, A. G. and K. Visvanathan (2009). "Toll-like receptors and their role in gastrointestinal disease." J Gastroenterol Hepatol24(6):943-954.
Tsukada, S., C. J. Parsons and R. A. Rippe (2006). "Mechanisms of liver fibrosis." Clinica chimica acta:international journal of clinical chemistry364(1-2):33-60.
Tsuneyama, K., K. Harada, N. Kono, K. Hiramatsu, Y. Zen, Y. Sudo, M. E. Gershwin, M. Ikemoto, H. Arai and Y. Nakanuma (2001). "Scavenger cells with gram-positive bacterial lipoteichoic acid infiltrate around the damaged interlobular bile ducts of primary biliary cirrhosis." J Hepatol35(2):156-163.
Tsung, A., R. Sahai, H. Tanaka, A. Nakao, M. P. Fink, M. T. Lotze, H. Yang, J. Li, K. J. Tracey, D. A. Geller and T. R. Billiar (2005). "The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion." J Exp Med201(7):1135-1143.
Vergani, D., K. Choudhuri, D. P. Bogdanos and G. Mieli-Vergani (2002). "Pathogenesis of autoimmune hepatitis." Clin Liver Dis6(3):727-737.
Villanueva, A. and J. M. Llovet (2011). "Targeted therapies for hepatocellular carcinoma." Gastroenterology140(5):1410-1426.
Vleggaar, F. P. and H. R. van Buuren (2004). "No prognostic significance of antimitochondrial antibody profile testing in primary biliary cirrhosis." Hepato-Gastroenterology51(58):937-940.
Vogel, A., M. P. Manns and C. P. Strassburg (2002). "Autoimmunity and viruses." Clin Liver Dis6(3):739-753.
Wakabayashi, K., Z. X. Lian, Y. Moritoki, R. Y. Lan, K. Tsuneyama, Y. H. Chuang, G. X. Yang, W. Ridgway, Y. Ueno, A. A. Ansari, R. L. Coppel, I. R. Mackay and M. E. Gershwin (2006). "IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis." Hepatology44(5):1240-1249.
Wald, O., I. D. Weiss, E. Galun and A. Peled (2007). "Chemokines in hepatitis C virus infection:pathogenesis, prognosis and therapeutics." Cytokine39(l):50-62.
Wang, H., F. Lafdil, X. Kong and B. Gao (2011). "Signal transducer and activator of transcription 3 in liver diseases:a novel therapeutic target." Int J Biol Sci7(5):536-550.
Wang, J., Y. Hu, W. W. Deng and B. Sun (2009). "Negative regulation of Toll-like receptor signaling pathway." Microbes Infect11(3):321-327.
Wilhelm, S., C. Carter, M. Lynch, T. Lowinger, J. Dumas, R. A. Smith, B. Schwartz, R. Simantov and S. Kelley (2006). "Discovery and development of sorafenib:a multikinase inhibitor for treating cancer." Nat Rev Drug Discov5(10):835-844.
Wilhelm, S. M., L. Adnane, P. Newell, A. Villanueva, J. M. Llovet and M. Lynch (2008). "Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling." Mol Cancer Ther7(10):3129-3140.
Yang, G. X., Z. X. Lian, Y. H. Chuang, Y. Moritoki, R. Y. Lan, K. Wakabayashi, A. A. Ansari, R. A. Flavell, W. M. Ridgway, R. L. Coppel, K. Tsuneyama, I. R. Mackay and M. E. Gershwin (2008). "Adoptive transfer of CD8(+) T cells from transforming growth factor beta receptor type Ⅱ (dominant negative form) induces autoimmune cholangitis in mice." Hepatology47(6):1974-1982.
Yasoshima, M., N. Kono, H. Sugawara, K. Katayanagi, K. Harada and Y. Nakanuma (1998). "Increased expression of interleukin-6 and tumor necrosis factor-alpha in pathologic biliary epithelial cells:in situ and culture study." Lab Invest78(1):89-100.
Zeisberg, M., C. Yang, M. Martino, M. B. Duncan, F. Rieder, H. Tanjore and R. Kalluri (2007). "Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition." J Biol Chem282(32):23337-23347.
Zeremski, M., L. M. Petrovic, L. Chiriboga, Q. B. Brown, H. T. Yee, M. Kinkhabwala, I. M. Jacobson, R. Dimova, M. Markatou and A. H. Talal (2008). "Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C." Hepatology48(5):1440-1450.
Zhang, W., R. Sharma, S. T. Ju, X. S. He, Y. Tao, K. Tsuneyama, Z. Tian, Z. X. Lian, S. M. Fu and M. E. Gershwin (2009). "Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis." Hepatology49(2):545-552.
Zlotnik, A. and O. Yoshie (2000). "Chemokines:a new classification system and their role in immunity." Immunity12(2):121-127.
Abu-Shanab, A. and E. M. Quigley (2010). "The role of the gut microbiota in nonalcoholic fatty liver disease." Nat Rev Gastroenterol Hepatol7(12):691-701.
Akira, S. and K. Takeda (2004). "Toll-like receptor signalling." Nat Rev Immunol4(7): 499-511.
Akira, S., S. Uematsu and O. Takeuchi (2006). "Pathogen recognition and innate immunity." Cell124(4):783-801.
Alexopoulou, L., A. C. Holt, R. Medzhitov and R. A. Flavell (2001). "Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3."Nature413(6857): 732-738.
Anderson, G. D., S. D. Hauser, K. L. McGarity, M. E. Bremer, P. C. Isakson and S. A. Gregory (1996). "Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis." J Clin Invest97(11):2672-2679.
Aoki, C. A., C. M. Roifman, Z. X. Lian, C. L. Bowlus, G. L. Norman, Y. Shoenfeld, I. R. Mackay and M. E. Gershwin (2006). "IL-2 receptor alpha deficiency and features of primary biliary cirrhosis." J Autoimmun27(1):50-53.
Balogh, S., I. Kiss and A. Csaszar (2009). "Toll-like receptors:link between "danger" ligands and plaque instability." Curr Drug Targets10(6):513-518.
Barton, G. M. and J. C. Kagan (2009). "A cell biological view of Toll-like receptor function: regulation through compartmentalization." Nat Rev Immunol9(8):535-542.
Barton, G. M. and R. Medzhitov (2002). "Control of adaptive immune responses by Toll-like receptors." Curr Opin Immunoll4(3):380-383.
Bataller, R. and D. A. Brenner (2001). "Hepatic stellate cells as a target for the treatment of liver fibrosis." Seminars in Liver Disease21(3):437-451.
Bataller, R. and D. A. Brenner (2001). "Hepatic stellate cells as a target for the treatment of liver fibrosis." Semin Liver Dis21(3):437-451.
Bataller, R. and D. A. Brenner (2005). "Liver fibrosis." J Clin Invest115(2):209-218.
Bataller, R., K. E. North and D. A. Brenner (2003). "Genetic polymorphisms and the progression of liver fibrosis:a critical appraisal." Hepatology37(3):493-503.
Bendele, A., J. McComb, T. Gould, T. McAbee, G. Sennello, E. Chlipala and M. Guy (1999). "Animal models of arthritis:relevance to human disease." Toxicol Pathol27(1):134-142.
Berg, D. J., N. Davidson, R. Kuhn, W. Muller, S. Menon, G. Holland, L. Thompson-Snipes, M. W. Leach and D. Rennick (1996). "Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses." J Clin Invest98(4):1010-1020.
Boberg, K. M. (2002). "Prevalence and epidemiology of autoimmune hepatitis." Clin Liver Dis6(3):635-647.
Boonstra, K., K. J. van Erpecum, K. M. van Nieuwkerk, J. P. Drenth, A. C. Poen, B. J. Witteman, H. A. Tuynman, U. Beuers and C. Y. Ponsioen (2012). "Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease." Inflamm Bowel Dis18(12):2270-2276.
Bouaziz, J. D., K. Yanaba and T. F. Tedder (2008). "Regulatory B cells as inhibitors of immune responses and inflammation." Immunol Rev224:201-214.
Broering, R., M. Lu and J. F. Schlaak (2011). "Role of Toll-like receptors in liver health and disease." Clin Sci (Lond)121(10):415-426.
Brummel, R. and P. Lenert (2005). "Activation of marginal zone B cells from lupus mice with type A(D) CpG-oligodeoxynucleotides." J Immunol174(4):2429-2434.
Calne, R. Y., R. A. Sells, J. R. Pena, D. R. Davis, P. R. Millard, B. M. Herbertson, R. M. Binns and D. A. Davies (1969). "Induction of immunological tolerance by porcine liver allografts." Nature223(5205):472-476.
Cario, E., G. Gerken and D. K. Podolsky (2007). "Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function." Gastroenterology132(4):1359-1374.
Cario, E. and D. K. Podolsky (2005). "Intestinal epithelial TOLLerance versus inTOLLerance of commensals." Mol Immunol42(8):887-893.
Charles, P., M. J. Elliott, D. Davis, A. Potter, J. R. Kalden, C. Antoni, F. C. Breedveld, J. S. Smolen, G. Eberl, K. deWoody, M. Feldmann and R. N. Maini (1999). "Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis." J Immunol163(3):1521-1528.
Charo, I. F. and R. M. Ransohoff (2006). "The many roles of chemokines and chemokine receptors in inflammation." N Engl J Med354(6):610-621.
Chen, Y. L., J. Lv, X. L. Ye, M. Y. Sun, Q. Xu, C. H. Liu, L. H. Min, H. P. Li, P. Liu and X. Ding (2011). "Sorafenib inhibits transforming growth factor betal-mediated epithelial-mesenchymal transition and apoptosis in mouse hepatocytes." Hepatologv53(5): 1708-1718.
Chuang, Y. H., Z. X. Lian, C. M. Cheng, R. Y. Lan, G. X. Yang, Y. Moritoki, B. L. Chiang, A. A. Ansari, K. Tsuneyama, R. L. Coppel and M. E. Gershwin (2005). "Increased levels of chemokine receptor CXCR3 and chemokines IP-10 and MIG in patients with primary biliary cirrhosis and their first degree relatives." J Autoimmun25(2):126-132.
Chuang, Y. H., Z. X. Lian, K. Tsuneyama, B. L. Chiang, A. A. Ansari, R. L. Coppel and M. E. Gershwin (2006). "Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis." J Autoimmun26(4):232-240.
Cook, D. N., D. S. Pisetsky and D. A. Schwartz (2004). "Toll-like receptors in the pathogenesis of human disease." Nat Immunol5(10):975-979.
Crispe, I. N. (2009). "The liver as a lymphoid organ." Annu Rev Immunol27:147-163.
Czaja, A. J. (2009). "Autoimmune liver disease." Curr Opin Gastroenterol25(3):215-222.
Czaja, A. J. (2010). "Autoantibodies as prognostic markers in autoimmune liver disease." Dig Dis Sci55(8):2144-2161.
Czaja, A. J. and M. P. Manns (2010). "Advances in the diagnosis, pathogenesis, and management of autoimmune hepatitis." Gastroenterology 139(1):58-72 e54.
Dianda, L., A. M. Hanby, N. A. Wright, A. Sebesteny, A. C. Hayday and M. J. Owen (1997). "T cell receptor-alpha beta-deficient mice fail to develop colitis in the absence of a microbial environment." Am J Pathol150(1):91-97.
Diebold, S. S., T. Kaisho, H. Hemmi, S. Akira and C. Reis e Sousa (2004). "Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA." Science303(5663): 1529-1531.
Dieleman, L. A., M. J. H. J. Palmen, H. Akol, E. Bloemena, A. S. Pena, S. G. M. Meuwissen and E. P. van Rees (1998). "Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Thl and Th2 cytokines." Clinical and Experimental Immunology114(3):385-391.
Dinarello, C. A. (2009). "Immunological and inflammatory functions of the interleukin-1 family." Annu Rev Immunol27:519-550.
Elsharkawy, A. M., F. Oakley and D. A. Mann (2005). "The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis." Apoptosis10(5):927-939.
Evans, J. G., K. A. Chavez-Rueda, A. Eddaoudi, A. Meyer-Bahlburg, D. J. Rawlings, M. R. Ehrenstein and C. Mauri (2007). "Novel suppressive function of transitional 2 B cells in experimental arthritis." J Immunol178(12):7868-7878.
Forbes, S. J., F. P. Russo, V. Rey, P. Burra, M. Rugge, N. A. Wright and M. R Alison (2004). "A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis." Gastroenterologv126(4):955-963.
Friedman, S. L. (2003). "Liver fibrosis--from bench to bedside." J Hepatol38 Suppl 1: S38-53.
Friedman, S. L. (2008). "Hepatic fibrosis-Overview." Toxicologv254(3):120-129.
Frieri, M. (2013). "Mechanisms of disease for the clinician:systemic lupus erythematosus." Ann Allergy Asthma Immunol110(4):228-232.
Gershwin, M. E., A. A. Ansari, I. R. Mackay, Y. Nakanuma, A. Nishio, M. J. Rowley and R. L. Coppel (2000). "Primary biliary cirrhosis:an orchestrated immune response against epithelial cells." Immunol Rev174:210-225.
Gershwin, M. E. and I. R. Mackay (2008). "The causes of primary biliary cirrhosis: Convenient and inconvenient truths." Hepatology47(2):737-745.
Gershwin, M. E., C. Selmi, H. J. Worman, E. B. Gold, M. Watnik, J. Utts, K. D. Lindor, M. M. Kaplan, J. M. Vierling and U. P. E. Group (2005). "Risk factors and comorbidities in primary biliary cirrhosis:a controlled interview-based study of 1032 patients." Hepatology42(5): 1194-1202.
Gillevet, P., M. Sikaroodi, A. Keshavarzian and E. A. Mutlu (2010). "Quantitative assessment of the human gut microbiome using multitag pyrosequencing." Chem Biodivers7(5): 1065-1075.
Godessart, N. and S. L. Kunkel (2001). "Chemokines in autoimmune disease." Curr Opin Immunol13(6):670-675.
Gorelik, L. and R. A. Flavell (2000). "Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease." Immunity12(2):171-181.
Gray, M., K. Miles, D. Salter, D. Gray and J. Savill (2007). "Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells." Proc Natl Acad Sci U S A104(35):14080-14085.
Gurevitz, S. L., J. A. Snyder, E. K. Wessel, J. Frey and B. A. Williamson (2013). "Systemic lupus erythematosus:a review of the disease and treatment options." Consult Pharm28(2): 110-121.
Harada, K., K. Isse, K. Tsuneyama, H. Ohta and Y. Nakanuma (2003). "Accumulating CD57+CD3+natural killer T cells are related to intrahepatic bile duct lesions in primary biliary cirrhosis." Liver Int23(2):94-100.
Harada, K. and Y. Nakanuma (2010). "Biliary innate immunity in the pathogenesis of biliary diseases." Inflamm Allergy Drug Targets9(2):83-90.
Harada, K. and Y. Nakanuma (2010). "Biliary Innate Immunity:Function and Modulation." Mediators of Inflammation.
Harada, K., S. Ozaki, M. E. Gershwin and Y. Nakanuma (1997). "Enhanced apoptosis relates to bile duct loss in primary biliary cirrhosis." Hepatology26(6):1399-1405.
Hartmann, P., M. Haimerl, M. Mazagova, D. A. Brenner and B. Schnabl (2012). "Toll-like receptor 2-mediated intestinal injury and enteric tumor necrosis factor receptor I contribute to liver fibrosis in mice." Gasfroenterology143(5):1330-1340 e1331.
Helbig, K. J., A. Ruszkiewicz, L. Semendric, H. A. Harley, S. R. McColl and M. R. Beard (2004). "Expression of the CXCR3 ligand I-TAC by hepatocytes in chronic hepatitis C and its correlation with hepatic inflammation." Hepatology39(5):1220-1229.
Hemmi, H., O. Takeuchi, T. Kawai, T. Kaisho, S. Sato, H. Sanjo, M. Matsumoto, K. Hoshino, H. Wagner, K. Takeda and S. Akira (2000). "A Toll-like receptor recognizes bacterial DNA." Nature408(6813):740-745.
Henao-Mejia, J., E. Elinav, C. Jin, L. Hao, W. Z. Mehal, T. Strowig, C. A. Thaiss, A. L. Kau, S. C. Eisenbarth, M. J. Jurczak, J. P. Camporez, G. I. Shulman, J. I. Gordon, H. M. Hoffman and R. A. Flavell (2012). "Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity." Nature482(7384):179-185.
Hintermann, E., M. Bayer, J. M. Pfeilschifter, A. D. Luster and U. Christen (2010). "CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation." J Autoimmun35(4):424-435.
Hoentjen, F., H. J. Harmsen, H. Braat, C. D. Torrice, B. A. Mann, R. B. Sartor and L. A. Dieleman (2003). "Antibiotics with a selective aerobic or anaerobic spectrum have different therapeutic activities in various regions of the colon in interleukin 10 gene deficient mice." Gut52(12):1721-1727.
Homey, B., A. Muller and A. Zlotnik (2002). "Chemokines:agents for the immunotherapy of cancer?" Nat Rev Immunol2(3):175-184.
Hora, C., P. Romanque and J. F. Dufour (2011). "Effect of sorafenib on murine liver regeneration." Hepatology53(2):577-586.
Horiguchi, N., L. Wang, P. Mukhopadhyay, O. Park, W. I. Jeong, F. Lafdil, D. Osei-Hyiaman, A. Moh, X. Y. Fu, P. Pacher, G. Kunos and B. Gao (2008). "Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury." Gastroenterologv134(4):1148-1158.
Horwood, N. J., T. H. Page, J. P. McDaid, C. D. Palmer, J. Campbell, T. Mahon, F. M. Brennan, D. Webster and B. M. Foxwell (2006). "Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production." J Immunol176(6):3635-3641.
Huynh, J. L. and P. Casaccia (2013). "Epigenetic mechanisms in multiple sclerosis: implications for pathogenesis and treatment." Lancet Neuroll2(2):195-206.
Iavarone, M., G. Cabibbo, F. Piscaglia, C. Zavaglia, A. Grieco, E. Villa, C. Camma, M. Colombo and S. S. I. Assessment (2011). "Field-Practice Study of Sorafenib Therapy for Hepatocellular Carcinoma:A Prospective Multicenter Study in Italy." Hepatology54(6): 2055-2063.
Iredale, J. P. (2001). "Hepatic stellate cell behavior during resolution of liver injury." Semin Liver Dis21(3):427-436.
Irie, J., Y. Wu, L. S. Wicker, D. Rainbow, M. A. Nalesnik, R. Hirsch, L. B. Peterson, P. S. Leung, C. Cheng, I. R. Mackay, M. E. Gershwin and W. M. Ridgway (2006). "NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis." J Exp Med203(5):1209-1219.
Jansen, P. L. (2004). "Non-alcoholic steatohepatitis." Eur J Gastroenterol Hepatoll6(11): 1079-1085.
Jiang, D., J. Liang, J. Fan, S. Yu, S. Chen, Y. Luo, G. D. Prestwich, M. M. Mascarenhas, H. G. Garg, D. A. Quinn, R. J. Homer, D. R. Goldstein, R. Bucala, P. J. Lee, R. Medzhitov and P. W. Noble (2005). "Regulation of lung injury and repair by Toll-like receptors and hyaluronan." Nat Med11(11):1173-1179.
Kaimori, A., J. Potter, J. Y. Kaimori, C. Wang, E. Mezey and A. Koteish (2007). "Transforming growth factor-betal induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro." J Biol Chem282(30):22089-22101.
Kang, S. S., S. M. Bloom, L. A. Norian, M. J. Geske, R. A. Flavell, T. S. Stappenbeck and P. M. Allen (2008). "An antibiotic-responsive mouse model of fulminant ulcerative colitis." PLoS Med5(3):e41.
Kaplan, M. M. and M. E. Gershwin (2005). "Primary biliary cirrhosis." N Engl J Med353(12):1261-1273.
Kaur, S., S. White and P. M. Bartold (2013). "Periodontal disease and rheumatoid arthritis: a systematic review." J Dent Res92(5):399-408.
Kikuchi, K., Z. X. Lian, G. X. Yang, A. A. Ansari, S. Ikehara, M. Kaplan, H. Miyakawa, R. L. Coppel and M. E. Gershwin (2005). "Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis." Gastroenterology 128(2):304-312.
Kishimoto, T. (2005). "Interleukin-6:from basic science to medicine--40 years in immunology" Annu Rev Immunol23:1-21.
Kita, H., M. Imawari and M. E. Gershwin (2004). "Cellular immune response in primary biliary cirrhosis." Hepatol Res28(1):12-17.
Kita, H., Z. X. Lian, J. Van de Water, X. S. He, S. Matsumura, M. Kaplan, V. Luketic, R. L. Coppel, A. A. Ansari and M. E. Gershwin (2002). "Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis:T cell activation is augmented by immune complexes cross-presented by dendritic cells." J Exp Med195(1):113-123.
Kita, H., S. Matsumura, X. S. He, A. A. Ansari, Z. X. Lian, J. Van de Water, R. L. Coppel, M. M. Kaplan and M. E. Gershwin (2002). "Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis." J Clin Invest109(9):1231-1240.
Kita, H., O. V. Naidenko, M. Kronenberg, A. A. Ansari, P. Rogers, X. S. He, F. Koning, T. Mikayama, J. Van De Water, R. L. Coppel, M. Kaplan and M. E. Gershwin (2002). "Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer." Gastroenterology123(4):1031-1043.
Kita, H., O. V. Naidenko, M. Kronenberg, A. A. Ansari, P. Rogers, X. S. He, F. Koning, T. Mikayama, J. Van de Water, R. L. Coppel, M. Kaplan and M. E. Gershwin (2002). "Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human mid tetramer." Gastoenterology123(4):1031-1043.
Kleiveland, C. R., L. T. Hult, S. Spetalen, M. Kaldhusdal, T. E. Christofferesen, O. Bengtsson, O. H. Romarheim, M. Jacobsen and T. Lea (2013). "The noncommensal bacterium Methylococcus capsulatus (Bath) ameliorates dextran sulfate (Sodium Salt)-Induced Ulcerative Colitis by influencing mechanisms essential for maintenance of the colonic barrier function." Appl Environ Microbiol79(1):48-56.
Knight, A. K. and C. Cunningham-Rundles (2006). "Inflammatory and autoimmune complications of common variable immune deficiency." Autoimmun Rev5(2):156-159.
Kobayashi, N., T. Kondo, H. Takata, S. Yokota and M. Takiguchi (2006). "Functional and phenotypic analysis of human memory CD8+ T cells expressing CXCR3." J Leukoc Biol80(2): 320-329.
Krasilnikov, M., V. N. Ivanov, J. Dong and Z. Ronai (2003). "ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells:implications towards sensitization to apoptosis." Oncogene22(26):4092-4101.
Kubo, T., Y. Uchida, Y. Watanabe, M. Abe, A. Nakamura, M. Ono, S. Akira and T. Takai (2009). "Augmented TLR9-induced Btk activation in PIR-B-deficient B-1 cells provokes excessive autoantibody production and autoimmunity." J Exp Med206(9):1971-1982.
Kunkel, S. L. and N. Godessart (2002). "Chemokines in autoimmunity:from pathology to therapeutics." Autoimmun Rev1(6):313-320.
Kuroki, T., S. Seki, N. Kawakita, K. Nakatani, T. Hisa, T. Kitada and H. Sakaguchi (1996). "Expression of antigens related to apoptosis and cell proliferation in chronic nonsuppurative destructive cholangitis in primary biliary cirrhosis." Virchows Arch429(2-3):119-129.
Lalor, P. F., P. Shields, A. Grant and D. H. Adams (2002). "Recruitment of lymphocytes to the human liver." Immunol Cell Biol80(1):52-64.
Lam-Tse, W. K., A. Lernmark and H. A. Drexhage (2002). "Animal models of endocrine/organ-specific autoimmune diseases:do they really help us to understand human autoimmunity?" Springer Semin Immunopathol24(3):297-321.
Lan, R. Y., A. A. Ansari, Z. X. Lian and M. E. Gershwin (2005). "Regulatory T cells: development, function and role in autoimmunity." Autoimmun Rev4(6):351-363.
Lan, R. Y., C. Cheng, Z. X. Lian, K. Tsuneyama, G. X. Yang, Y. Moritoki, Y. H. Chuang, T. Nakamura, S. Saito, S. Shimoda, A. Tanaka, C. L. Bowlus, Y. Takano, A. A. Ansari, R. L. Coppel and M. E. Gershwin (2006). "Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis." Heptology43(4):729-737.
Laragione, T., M. Brenner, B. Sherry and P. S. Gulko (2011). "CXCL10 and its receptor CXCR3 regulate synovial fibroblast invasion in rheumatoid arthritis." Arthritis Rheum63(11): 3274-3283.
Lemoine, S., A. Morva, P. Youinou and C. Jamin (2009). "Regulatory B cells in autoimmune diseases:how do they work?" Ann N Y Acad Scil173:260-267.
Leon, M. P., G. Spickett, D. E. Jones and M. F. Bassendine (1995). "CD4+ T cell subsets defined by isoforms of CD45 in primary biliary cirrhosis." Clin Exp Immunol99(2):233-239.
Leulier, F. and B. Lemaitre (2008). "Toll-like receptors--taking an evolutionary approach." Nat Rev Genet9(3):165-178.
Li, D. and S. L. Friedman (1999). "Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy." J Gastroenterol Hepatol14(7):618-633.
Liu, L., M. K. Callahan, D. Huang and R. M. Ransohoff (2005). "Chemokine receptor CXCR3:an unexpected enigma." Curr Top Dev Biol68:149-181.
Llovet, J. M., S. Ricci, V. Mazzaferro, P. Hilgard, E. Gane, J. F. Blanc, A. C. de Oliveira, A. Santoro, J. L. Raoul, A. Forner, M. Schwartz, C. Porta, S. Zeuzem, L. Bolondi, T. F. Greten, P. R. Galle, J. F. Seitz, I. Borbath, D. Haussinger, T. Giannaris, M. Shan, M. Moscovici, D. Voliotis and J. Bruix (2008). "Sorafenib in Advanced Hepatocellular Carcinoma (vol 359, pg 378,2008)." New England Journal of Medicine359(23):2508-2508.
Loftus, E. V., Jr., G. C. Harewood, C. G. Loftus, W. J. Tremaine, W. S. Harmsen, A. R. Zinsmeister, D. A. Jewell and W. J. Sandborn (2005). "PSC-IBD:a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis." Gut54(1):91-96.
Longhi, M. S., Y. Ma, G. Mieli-Vergani and D. Vergani (2010). "Aetiopathogenesis of autoimmune hepatitis." J Autoimmun34(1):7-14.
Lund, J. M., L. Alexopoulou, A. Sato, M. Karow, N. C. Adams, N. W. Gale, A. Iwasaki and R. A. Flavell (2004). "Recognition of single-stranded RNA viruses by Toll-like receptor 7." Proc Natl Acad Sci U S A101(15):5598-5603.
Machado, M. V. and H. Cortez-Pinto (2012). "Gut microbiota and nonalcoholic fatty liver disease." Ann Hepatol11(4):440-449.
Mackay, I. R. (2008). "Historical reflections on autoimmune hepatitis." World J Gastroenterol14(21):3292-3300.
Madsen, K. L., J. S. Doyle, M. M. Tavernini, L. D. Jewell, R. P. Rennie and R. N. Fedorak (2000). "Antibiotic therapy attenuates colitis in interleukin 10 gene-deficient mice." Gastroenterology118(6):1094-1105.
Maharshak, N., C. D. Packey, M. Ellermann, S. Manick, J. P. Siddle, E. Y. Huh, S. Plevy, R. B. Sartor and I. M. Carroll (2013). "Altered enteric microbiota ecology in interleukin 10-deficient mice during development and progression of intestinal inflammation." Gut Microbes4(4):316-324.
Mann, M. K., K. Maresz, L. P. Shriver, Y. Tan and B. N. Dittel (2007). "B cell regulation of CD4+CD25+ T regulatory cells and IL-10 via B7 is essential for recovery from experimental autoimmune encephalomyelitis." J Immunol178(6):3447-3456.
Mao, T. K., Z. X. Lian, C. Selmi, Y. Ichiki, P. Ashwood, A. A. Ansari, R. L. Coppel, S. Shimoda, H. Ishibashi and M. E. Gershwin (2005). "Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis." Hepatology42(4):802-808.
Martinon, F., X. Chen, A. H. Lee and L. H. Glimcher (2010). "TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages." Nat Immunol11(5):411-418.
Matkowskyj, K. A., Z. E. Chen, M. S. Rao and G. Y. Yang (2013). "Dysplastic lesions in inflammatory bowel disease:molecular pathogenesis to morphology." Arch Pathol Lab Med137(3):338-350.
Mauri, C. and M. R. Ehrenstein (2008). "The 'short' history of regulatory B cells." Trends Immunol29(1):34-40.
Mehal, W. Z. (2012). "The gut-liver axis:a busy two-way street." Hepatology55(6): 1647-1649.
Mejias, M., E. Garcia-Pras, C. Tiani, R. Miquel, J. Bosch and M. Fernandez (2009). "Beneficial Effects of Sorafenib on Splanchnic, Intrahepatic, and Portocollateral Circulations in Portal Hypertensive and Cirrhotic Rats." Hepatology49(4):1245-1256.
Miyake, Y. and K. Yamamoto (2013). "Role of gut microbiota in liver diseases." Hepatol Res43(2):139-146.
Mohan, K. and T. B. Issekutz (2007). "Blockade of chemokine receptor CXCR3 inhibits T cell recruitment to inflamed joints and decreases the severity of adjuvant arthritis." J Immunol179(12):8463-8469.
Moritoki, Y., Z. X. Lian, Y. Ohsugi, Y. Ueno and M. E. Gershwin (2006). "B cells and autoimmune liver diseases." Autoimmun Rev5(7):449-457.
Moritoki, Y., W. Zhang, K. Tsuneyama, K. Yoshida, K. Wakabayashi, G. X. Yang, C. Bowlus, W. M. Ridgway, Y. Ueno, A. A. Ansari, R. L. Coppel, I. R. Mackay, R. A. Flavell, M. E. Gershwin and Z. X. Lian (2009). "B cells suppress the inflammatory response in a mouse model of primary biliary cirrhosis." Gastroenterology136(3):1037-1047.
Muller, G., U. E. Hopken, H. Stein and M. Lipp (2002). "Systemic immunoregulatory and pathogenic functions of homeostatic chemokine receptors." J Leukoc Biol72(1):1-8.
Murdoch, C. and A. Finn (2000). "Chemokine receptors and their role in inflammation and infectious diseases." Blood95(10):3032-3043.
Neumann, K., N. Kruse, B. Szilagyi, U. Erben, C. Rudolph, A. Flach, M. Zeitz, A. Hamann and K. Klugewitz (2012). "Connecting liver and gut:murine liver sinusoidal endothelium induces gut tropism of CD4+ T cells via retinoic acid." Hepatology55(6):1976-1984.
O'Neill, L. A. (2008). "The interleukin-1 receptor/Toll-like receptor superfamily:10 years of progress." Immunol Rev226:10-18.
O'Neill, L. A. (2008). "When signaling pathways collide:positive and negative regulation of toll-like receptor signal transduction." Immunity29(1):12-20.
Odin, J. A., R. C. Huebert, L. Casciola-Rosen, N. F. LaRusso and A. Rosen (2001). "Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis." J Clin Invest108(2):223-232.
Oertelt, S., Z. X. Lian, C. M. Cheng, Y. H. Chuang, K. A. Padgett, X. S. He, W. M. Ridgway, A. A. Ansari, R. L. Coppel, M. O. Li, R. A. Flavell, M. Kronenberg, I. R. Mackay and M. E. Gershwin (2006). "Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor Ⅱ dominant-negative mice." J Immunol177(3):1655-1660.
Pares, A., L. Caballeria, J. Rodes, M. Bruguera, L. Rodrigo, A. Garcia-Plaza, J. Berenguer, D. Rodriguez-Martinez, J. Mercader and R. Velicia (2000). "Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis:results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver." J Hepatol32(4):561-566.
Popov, Y. and D. Schuppan (2009). "Targeting liver fibrosis:strategies for development and validation of antifibrotic therapies." Hepatology50(4):1294-1306.
Powrie, F. (1995). "T cells in inflammatory bowel disease:protective and pathogenic roles." Immunity3(2):171-174.
Powrie, F., M. W. Leach, S. Mauze, S. Menon, L. B. Caddle and R. L. Coffman (1994). "Inhibition of Thl responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells." Immunity1(7):553-562.
Racanelli, V. and B. Rehermann (2006). "The liver as an immunological organ." Hepatology43(2 Suppl 1):S54-62.
Rahimi, R. S. and D. C. Rockey (2011). "Complications and outcomes in chronic liver disease." Curr Opin Gastroenterol27(3):204-209.
Ramadori, G. and B. Saile (2004). "Portal tract fibrogenesis in the liver." Lab Invest84(2): 153-159.
Reiberger, T., B. Angermayr, P. Schwabl, N. Rohr-Udilova, M. Mitterhauser, A. Gangl and M. Peck-Radosavljevic (2009). "Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats." J Hepatol51(5):865-873.
Robinson, C. J., B. J. Bohannan and V. B. Young (2010). "From structure to function:the ecology of host-associated microbial communities." Microbiol Mol Biol Rev74(3):453-476.
Rosman, Z., Y. Shoenfeld and G. Zandman-Goddard (2013). "Biologic therapy for autoimmune diseases:an update." BMC Med11:88.
Rossi, D. and A. Zlotnik (2000). "The biology of chemokines and their receptors." Annu Rev Immunoll8:217-242.
Sakaguchi, S., T. Yamaguchi, T. Nomura and M. Ono (2008). "Regulatory T cells and immune tolerance." Cell133(5):775-787.
Sakurai, H., H. Chiba, H. Miyoshi, T. Sugita and W. Toriumi (1999). "IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain." J Biol Chem274(43):30353-30356.
Santodomingo-Garzon, T. and M. G. Swain (2011). "Role of NKT cells in autoimmune liver disease." Autoimmun Rev10(12):793-800.
Sasaki, C. Y., T. J. Barberi, P. Ghosh and D. L. Longo (2005). "Phosphorylation of RelA/p65 on serine 536 defines an I{kappa}B{alpha}-independent NF-{kappa}B pathway." J Biol Chem280(41):34538-34547.
Sato, M., S. Suzuki and H. Senoo (2003). "Hepatic stellate cells:Unique characteristics in cell biology and phenotype." Cell Structure and Function28(2):105-112.
Scallon, B. J., M. A. Moore, H. Trinh, D. M. Knight and J. Ghrayeb (1995). "Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions." Cytokine7(3):251-259.
Schnare, M., G. M. Barton, A. C. Holt, K. Takeda, S. Akira and R. Medzhitov (2001). "Toll-like receptors control activation of adaptive immune responses." Nat Immunol2(10): 947-950.
Schultz, M., S. L. Tonkonogy, R. K. Sellon, C. Veltkamp, V. L. Godfrey, J. Kwon, W. B. Grenther, E. Balish, I. Horak and R. B. Sartor (1999). "IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation." Am J Physiol276(6 Pt 1):G1461-1472.
Seki, E. and D. A. Brenner (2008). "Toll-like receptors and adaptor molecules in liver disease:update." Hepatology48(1):322-335.
Seki, E., S. De Minicis, C. H. Osterreicher, J. Kluwe, Y. Osawa, D. A. Brenner and R. F. Schwabe (2007). "TLR4 enhances TGF-beta signaling and hepatic fibrosis." Nat Med13(11): 1324-1332.
Sellon, R. K., S. Tonkonogy, M. Schultz, L. A. Dieleman, W. Grenther, E. Balish, D. M. Rennick and R. B. Sartor (1998). "Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice." Infect Immun66(11):5224-5231.
Shi, H., M. V. Kokoeva, K. Inouye, I. Tzameli, H. Yin and J. S. Flier (2006). "TLR4 links innate immunity and fatty acid-induced insulin resistance." J Clin Invest116(11):3015-3025.
Shimomura, Y., E. Mizoguchi, K. Sugimoto, R. Kibe, Y. Benno, A. Mizoguchi and A. K. Bhan (2008). "Regulatory role of B-1 B cells in chronic colitis." Int Immunol20(6):729-737.
Shindo, M., G. E. Mullin, L. Braun-Elwert, N. V. Bergasa, E. A. Jones and S. P. James (1996). "Cytokine mRNA expression in the liver of patients with primary biliary cirrhosis (PBC) and chronic hepatitis B (CHB)." Clin Exp Immunol105(2):254-259.
Son, G., M. Kremer and I. N. Hines (2010). "Contribution of gut bacteria to liver pathobiology." Gastroenterol Res Pract2010.
Sorensen, H. T., A. M. Thulstrup, P. Blomqvist, B. Norgaard, K. Fonager and A. Ekbom (1999). "Risk of primary biliary liver cirrhosis in patients with coeliac disease:Danish and Swedish cohort data." Gut44(5):736-738.
Stepankova, R., F. Powrie, O. Kofronova, H. Kozakova, T. Hudcovic, T. Hrncir, H. Uhlig, S. Read, Z. Rehakova, O. Benada, P. Heczko, M. Strus, P. Bland and H. Tlaskalova-Hogenova (2007). "Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells." Inflamm Bowel Dis13(10):1202-1211.
Sugimoto, K., A. Ogawa, Y. Shimomura, K. Nagahama, A. Mizoguchi and A. K. Bhan (2007). "Inducible IL-12-producing B cells regulate Th2-mediated intestinal inflammation." Gastroenterology133(1):124-136.
Sutmuller, R. P., M. H. den Brok, M. Kramer, E. J. Bennink, L. W. Toonen, B. J. Kullberg, L. A. Joosten, S. Akira, M. G. Netea and G. J. Adema (2006). "Toll-like receptor 2 controls expansion and function of regulatory T cells." J Clin Invest116(2):485-494.
Szabo, G., S. Bala, J. Petrasek and A. Gattu (2010). "Gut-liver axis and sensing microbes." Dig Dis28(6):737-744.
Tacke, F., H. W. Zimmermann, M. L. Berres, C. Trautwein and H. E. Wasmuth (2011). "Serum chemokine receptor CXCR3 ligands are associated with progression, organ dysfunction and complications of chronic liver diseases." Liver Int31(6):840-849.
Takeda, K. and S. Akira (2005). "Toll-like receptors in innate immunity." Int Immunol17(1):1-14.
Takii, Y., M. Nakamura, M. Ito, T. Yokoyama, A. Komori, Y. K. Shimizu-Yoshida, R. Nakao, K. Kusumoto, S. Nagaoka, K. Yano, S. Abiru, T. Ueki, T. Matsumoto, M. Daikoku, K. Taniguchi, H. Fujioka, K. Migita, H. Yasuhashi, M. Nakashima, M. Harada and H. Ishibashi (2005). "Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis." Laboratory Investigation85(7):908-920.
Tanimoto, K., F. Akbar, K. Michitaka and M. Onji (1999). "Immunohistochemical localization of antigen presenting cells in liver from patients with primary biliary cirrhosis; Highly restricted distribution of CD83-positive activated dendritic cells." Pathology Research and Practice195(3):157-162.
Testro, A. G. and K. Visvanathan (2009). "Toll-like receptors and their role in gastrointestinal disease." J Gastroenterol Hepatol24(6):943-954.
Tsukada, S., C. J. Parsons and R. A. Rippe (2006). "Mechanisms of liver fibrosis." Clinica chimica acta:international journal of clinical chemistry364(1-2):33-60.
Tsuneyama, K., K. Harada, N. Kono, K. Hiramatsu, Y. Zen, Y. Sudo, M. E. Gershwin, M. Ikemoto, H. Arai and Y. Nakanuma (2001). "Scavenger cells with gram-positive bacterial lipoteichoic acid infiltrate around the damaged interlobular bile ducts of primary biliary cirrhosis." J Hepatol35(2):156-163.
Tsung, A., R. Sahai, H. Tanaka, A. Nakao, M. P. Fink, M. T. Lotze, H. Yang, J. Li, K. J. Tracey, D. A. Geller and T. R. Billiar (2005). "The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion." J Exp Med201(7):1135-1143.
Vergani, D., K. Choudhuri, D. P. Bogdanos and G. Mieli-Vergani (2002). "Pathogenesis of autoimmune hepatitis." Clin Liver Dis6(3):727-737.
Villanueva, A. and J. M. Llovet (2011). "Targeted therapies for hepatocellular carcinoma." Gastroenterology140(5):1410-1426.
Vleggaar, F. P. and H. R. van Buuren (2004). "No prognostic significance of antimitochondrial antibody profile testing in primary biliary cirrhosis." Hepato-Gastroenterology51(58):937-940.
Vogel, A., M. P. Manns and C. P. Strassburg (2002). "Autoimmunity and viruses." Clin Liver Dis6(3):739-753.
Wakabayashi, K., Z. X. Lian, Y. Moritoki, R. Y. Lan, K. Tsuneyama, Y. H. Chuang, G. X. Yang, W. Ridgway, Y. Ueno, A. A. Ansari, R. L. Coppel, I. R. Mackay and M. E. Gershwin (2006). "IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis." Hepatology44(5):1240-1249.
Wald, O., I. D. Weiss, E. Galun and A. Peled (2007). "Chemokines in hepatitis C virus infection:pathogenesis, prognosis and therapeutics." Cytokine39(l):50-62.
Wang, H., F. Lafdil, X. Kong and B. Gao (2011). "Signal transducer and activator of transcription 3 in liver diseases:a novel therapeutic target." Int J Biol Sci7(5):536-550.
Wang, J., Y. Hu, W. W. Deng and B. Sun (2009). "Negative regulation of Toll-like receptor signaling pathway." Microbes Infect11(3):321-327.
Wilhelm, S., C. Carter, M. Lynch, T. Lowinger, J. Dumas, R. A. Smith, B. Schwartz, R. Simantov and S. Kelley (2006). "Discovery and development of sorafenib:a multikinase inhibitor for treating cancer." Nat Rev Drug Discov5(10):835-844.
Wilhelm, S. M., L. Adnane, P. Newell, A. Villanueva, J. M. Llovet and M. Lynch (2008). "Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling." Mol Cancer Ther7(10):3129-3140.
Yang, G. X., Z. X. Lian, Y. H. Chuang, Y. Moritoki, R. Y. Lan, K. Wakabayashi, A. A. Ansari, R. A. Flavell, W. M. Ridgway, R. L. Coppel, K. Tsuneyama, I. R. Mackay and M. E. Gershwin (2008). "Adoptive transfer of CD8(+) T cells from transforming growth factor beta receptor type Ⅱ (dominant negative form) induces autoimmune cholangitis in mice." Hepatology47(6):1974-1982.
Yasoshima, M., N. Kono, H. Sugawara, K. Katayanagi, K. Harada and Y. Nakanuma (1998). "Increased expression of interleukin-6 and tumor necrosis factor-alpha in pathologic biliary epithelial cells:in situ and culture study." Lab Invest78(1):89-100.
Zeisberg, M., C. Yang, M. Martino, M. B. Duncan, F. Rieder, H. Tanjore and R. Kalluri (2007). "Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition." J Biol Chem282(32):23337-23347.
Zeremski, M., L. M. Petrovic, L. Chiriboga, Q. B. Brown, H. T. Yee, M. Kinkhabwala, I. M. Jacobson, R. Dimova, M. Markatou and A. H. Talal (2008). "Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C." Hepatology48(5):1440-1450.
Zhang, W., R. Sharma, S. T. Ju, X. S. He, Y. Tao, K. Tsuneyama, Z. Tian, Z. X. Lian, S. M. Fu and M. E. Gershwin (2009). "Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis." Hepatology49(2):545-552.
Zlotnik, A. and O. Yoshie (2000). "Chemokines:a new classification system and their role in immunity." Immunity12(2):121-127.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |