原发性胆汁性肝硬化药物治疗后的相关免疫学变化
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摘要
目的前瞻性研究熊去氧胆酸(ursodeoxycholic acid,UDCA)、UDCA联合泼尼松龙两种治疗方案对原发性胆汁性肝硬化(primary biliary cirrhosis,PBC)的治疗效果,分析PBC患者肝脏生化指标、血清免疫球蛋白、外周血淋巴细胞亚群、细胞因子、抗线粒体抗体(anti-mitochondrial antibody,AMA)、抗M2亚型的抗线粒体抗体(AMA—M2)、抗GP210抗体和抗SP100抗体的临床相关性及其在两药物治疗后的变化特点。方法30例PBC患者(男1例,女29例,年龄由33至72岁,平均年龄52.33±8.77岁),均已接受UDCA(20人)或UDCA联合泼尼松龙(10人)治疗至少2年。根据当前治疗方案分为UDCA组(U组,20人)和UDCA联合泼尼松龙组(UP组,10人),PBC患者入选标准符合美国肝脏病学会2000年制定的PBC诊疗指南;入选研究患者签署知情同意书。治疗药物剂量为UDCA 13-15mg/kg/d;泼尼松龙起始剂量0.5mg/kg/d,4周开始减量,减至7.5mg/d时维持。于治疗前采集详细的临床及实验室资料,在治疗后第3、6、24月随访病人,动态检测肝脏生化指标(包括ALT、AST、GGT、ALP、TBIL、DBIL、TBA、ALB),白细胞计数(WBC),血清IgG、IgA、IgM,外周血淋巴细胞亚群(包括B细胞、NK细胞、T细胞、CD3+CD4+T细胞、CD3+CD8+T细胞、CD4+CD28+T细胞、CD4+CD28—T细胞、CD8+CD28+T细胞、CD8+CD28-T细胞、CD4+CD25+T细胞)、血清细胞因子(包括TNF—α、IL—1β、IL—2、IL—4、IL—6、IL—10)及自身抗体(AMA、AMA-M2、抗GP210抗体、抗SP100抗体)的水平。结果U组和UP组患者在治疗后肝生化指标ALT(分别为P=0.001和P=0.016)、AST(U组P=0.009)、ALP(UP组P=0.018)、GGT(UP组P=0.027)均有所下降。治疗后3个月时,U组ALT、ALP下降迅速且明显低于UP组(分别为P=0.016和P=0.039),此后差异消失。不同治疗组PBC患者血清IgG、IgA、IgM水平,外周血白细胞计数以及淋巴细胞亚群在治疗前后均无明显变化(P＞0.05)。不同治疗组PBC患者血清IL-2、IL-4、IL-6、IL-10、TNF-α、IL-1β水平都随治疗时间的延长而降低,尤其在治疗后24个月以上时下降最为明显(P＜0.05)。自身抗体检测结果显示,30例患者中AMA阳性率90%;AMA-M2阳性率73.33%;血清AMA滴度、AMA-M2水平在治疗后无明显改变(P＞0.05)。抗GP210抗体和抗SP100抗体表达阳性率分别为33.3%和16.67%。抗GP210抗体阴性组PBC患者的ALT、AST、ALP和IgM指标随着治疗时间的延长而逐渐降低(分别为P=0.000,P=0.000,P=0.014,P=0.039)。抗SP100抗体阴性组患者ALT、AST、ALP和GGT在治疗后明显降低(分别为P=0.007,P=0.015,P=0.005,P=0.048)。相关性分析显示,PBC患者肝脏ALT、AST、ALP和GGT指标与细胞因子IL-1β,IL-2,IL-6,IL-4,IL-10等指标间均具有不同程度正相关(P＜0.05)。细胞因子IL-1β和IL-10水平与淋巴细胞比例、CD8+CD28+T细胞比例之间均具有较好的正相关,与CD8+CD28-T细胞比例之间呈较好的负相关(P＜0.05)。抗GP210抗体水平与AST、DB、TBA、IgA、IgM之间均呈明显的正相关(P＜0.05),抗SP100抗体与IgG水平之间均呈现较好的负相关(P＜0.05)。结论1、UDCA单药治疗和UDCA与泼尼松龙的联合治疗均可缓解PBC患者部分异常的肝脏生化指标,在考虑治疗副作用的情况下UDCA单药治疗仍为PBC的首选方案;2、两种治疗方案对PBC患者外周血中免疫球蛋白、Th1、Th2型T淋巴细胞,CD8+CD28—调节T细胞、CD4+CD25+调节T细胞、NK细胞和B细胞均无明显调节作用;3、两种治疗方案均有缓慢抑制Th1型细胞因子IL-2表达的作用,IL-2水平低表达可抑制T淋巴细胞的活化效应;4、两种治疗方案均有缓慢抑制PBC患者Th2型细胞因子IL-4、IL-6、IL-10水平的作用,这类细胞因子水平下降可降低对B细胞活化效应,抑制过高的体液免疫反应对自身组织的损伤;5、两种治疗方案均能缓慢抑制PBC患者炎性细胞因子TNF-α与IL-1β水平的表达,PBC患者Th2型细胞因子与炎性细胞因子水平的降低,可抑制患者体内单核巨嗜细胞增殖活化,缓解患者肝脏内小叶间胆管的免疫炎症病理损伤;6、血清AMA、AMA-M2是PBC患者标志性抗体,但与病情轻重无关;抗GP210抗体与与PBC患者病情相关,可用于评估疾病严重度;抗GP210抗体和抗SP100抗体阳性的患者对药物治疗反应不佳,提示它们对于预测药物疗效有一定临床价值。
Objective To prospectively study the therapeutic effects of ursodeoxycholic acid(UDCA) and UDCA combined with prednisolone in patients with primary biliary cirrhosis(PBC),and analyze the expression characteristic of biochemical determinations, serum immunoglobulins,peripheral blood lymphocyte subsets,cytokines,and autoantibodies (anti-mitochondrial antibody,M2 anti-mitochondrial antibody,anti-GP210 antibodies and anti-SP100 antibodies) after treatment.Methods 30 patients(1 man and 29 women,aged from 30 to 72,average aged at 52.33±8.77) were included according to the guideline for management of PBC presented by AASLD in 2000,who all signed informed consent before treatment.All patients had been treated with UDCA(Group U,20 patients) or UDCA combined with prednisolone(Group UP,10 patients) for at least 2 years.The drug dosage of UDCA was 13-15mg/kg/d,and that ofprednisolone was 0.5mg/kg/d in the beginning,then gradually decreased to7.5mg/d since the 4~(th) week.Clinical and laboratory data of these patients were collected before the treatment,3 months,6 months and over 24 months after treatment,including liver biochemical function(including ALT、AST、GGT、ALP、TBIL、DBIL、TBA、ALB),white blood cells,immunoglobulins(including IgG、IgA、IgM), lymphocytic subsets(including B cells,NK cells,T cells,CD3+CD4+T cells,CD3+CD8+ T cells,CD4+CD28+T cells,CD4+CD28-T cells,CD8+CD28+T cells,CD8+CD28 -T cells,CD4+CD25+T cells),cytokines(including TNF-α,IL-1β,IL-2,IL-4,IL-6, IL-10) and autoantibodies(AMA,AMA-M2,anti-GP210 antibody,anti-SP 100 antibody). Results The levels ofALT(P=0.001 in group U;P=0.016 in group UP),AST(P=0.009 in group U),ALP(P=0.018 in group UP) and GGT(P=0.027 in group UP) decreased in both group U and group UP after treatment.The levels of ALT and ALP in group U decreased rapidly and were obviously lower than that in group UP(P=0.016 and P=0.039 respectively) after three-month treatment.The above difference disappeared as the treatment went on. There was no significant change in the levels of IgG,IgA,IgM,WBC and lymphocytic subsets in either group U or group UP after treatment(P＞0.05).The levels of IL-2,IL-4, IL-6,IL-10,TNF-αand IL-1βin the peripheral blood of patients with PBC decreased in both group U and group UP as time went by(P＜0.05),which was especially significant when the time of therapy was over 24 months.Among the 30 patients,90%of the patients were detected with positive AMA and 73.33%with AMA-M2.There was no significant change in the titer of AMA or the level of AMA-M2 in either group after treatment(P＞0.05).33.3% and 16.67%of patients had positive anti-GP210 antibody and anti-SP100 antibody, respectively.The levels of ALT,AST,ALP and IgM among patients with negative anti-GP210 antibody gradually decreased after treatment(P=0.000,P=0.000,P=0.014 and P=0.039,respectively) as time went by.The levels of ALT,AST,ALP and GGT among patients with negative anti-SP100 antibody decreased significantly after treatment(P=0.007, P=0.015,P=0.005 and P=0.048,respectively) as time went by.Correlation test showed that levels of ALT,AST,ALP and GGT were correlated positively with different cytokines on certain level(P＜0.05).The levels of IL-1βand IL-10 were correlated positively with the percentages of lymphocytes and CD8+CD28+T cells while negatively with the percentage of CD8+CD28-T cells(P＜0.05).There was a positive correlation between anti-GP210 antibody and the levels of AST,DB,TBA,IgA and IgM(P＜0.05),while a negative correlation appeared between anti-SP 100 antibody and the level of IgG(P＜0.05). Conclusions 1.Both UDCA monotherapy and UDCA combined with prednisolone could improve part of the liver function of the patients with PBC.Considering the side effects, UDCA monotherapy is still the first-choice treatment.2.There is no regulative effect of the two therapies on expressions of immunoglobulins,Th1 and Th2 lymphocytes,CD8+CD28 -regulatory T cells,CD4+CD25+ regulatory T cells,NK cells and B cells in patients with PBC.3.Both of the two therapies could slowly inhibit the levels of Th1 cytokine-IL-2, and low-level IL-2 could inhibit the activation of T lymphocytes.4.Both of the two therapies could slowly inhibit the levels of Th2 cytokines-IL-4,IL-6,IL-10,and their decrease could inhibit the activation of B cells and the lesions due to higher immune reactions to autoantigens.5.Both of the two therapies could slowly inhibit the levels of TNF-αand IL-1β,and the reduction of TNF-αand IL-1βmight relieve the inflammatory injury of the liver,suppress the inflammatory reaction and delay the pathological lesions of the liver.6.AMA,AMA-M2 is the biomarker of PBC,but there is no relationship between them and the states of the illness.There is a relationship between anti-GP210 antibodies and the state of PBC,and the level of anti-GP210 antibodies could be used to assess the severity of PBC.Patients with positive anti-GP210 antibody and anti-SP100 antibody have bad reaction towards drug therapy,thus they could be used for prediction of the therapeutic effects.
Objective To prospectively study the therapeutic effects of ursodeoxycholic acid(UDCA) and UDCA combined with prednisolone in patients with primary biliary cirrhosis(PBC),and analyze the expression characteristic of biochemical determinations, serum immunoglobulins,peripheral blood lymphocyte subsets,cytokines,and autoantibodies (anti-mitochondrial antibody,M2 anti-mitochondrial antibody,anti-GP210 antibodies and anti-SP100 antibodies) after treatment.Methods 30 patients(1 man and 29 women,aged from 30 to 72,average aged at 52.33±8.77) were included according to the guideline for management of PBC presented by AASLD in 2000,who all signed informed consent before treatment.All patients had been treated with UDCA(Group U,20 patients) or UDCA combined with prednisolone(Group UP,10 patients) for at least 2 years.The drug dosage of UDCA was 13-15mg/kg/d,and that ofprednisolone was 0.5mg/kg/d in the beginning,then gradually decreased to7.5mg/d since the 4~(th) week.Clinical and laboratory data of these patients were collected before the treatment,3 months,6 months and over 24 months after treatment,including liver biochemical function(including ALT、AST、GGT、ALP、TBIL、DBIL、TBA、ALB),white blood cells,immunoglobulins(including IgG、IgA、IgM), lymphocytic subsets(including B cells,NK cells,T cells,CD3+CD4+T cells,CD3+CD8+ T cells,CD4+CD28+T cells,CD4+CD28-T cells,CD8+CD28+T cells,CD8+CD28 -T cells,CD4+CD25+T cells),cytokines(including TNF-α,IL-1β,IL-2,IL-4,IL-6, IL-10) and autoantibodies(AMA,AMA-M2,anti-GP210 antibody,anti-SP 100 antibody). Results The levels ofALT(P=0.001 in group U;P=0.016 in group UP),AST(P=0.009 in group U),ALP(P=0.018 in group UP) and GGT(P=0.027 in group UP) decreased in both group U and group UP after treatment.The levels of ALT and ALP in group U decreased rapidly and were obviously lower than that in group UP(P=0.016 and P=0.039 respectively) after three-month treatment.The above difference disappeared as the treatment went on. There was no significant change in the levels of IgG,IgA,IgM,WBC and lymphocytic subsets in either group U or group UP after treatment(P＞0.05).The levels of IL-2,IL-4, IL-6,IL-10,TNF-αand IL-1βin the peripheral blood of patients with PBC decreased in both group U and group UP as time went by(P＜0.05),which was especially significant when the time of therapy was over 24 months.Among the 30 patients,90%of the patients were detected with positive AMA and 73.33%with AMA-M2.There was no significant change in the titer of AMA or the level of AMA-M2 in either group after treatment(P＞0.05).33.3% and 16.67%of patients had positive anti-GP210 antibody and anti-SP100 antibody, respectively.The levels of ALT,AST,ALP and IgM among patients with negative anti-GP210 antibody gradually decreased after treatment(P=0.000,P=0.000,P=0.014 and P=0.039,respectively) as time went by.The levels of ALT,AST,ALP and GGT among patients with negative anti-SP100 antibody decreased significantly after treatment(P=0.007, P=0.015,P=0.005 and P=0.048,respectively) as time went by.Correlation test showed that levels of ALT,AST,ALP and GGT were correlated positively with different cytokines on certain level(P＜0.05).The levels of IL-1βand IL-10 were correlated positively with the percentages of lymphocytes and CD8+CD28+T cells while negatively with the percentage of CD8+CD28-T cells(P＜0.05).There was a positive correlation between anti-GP210 antibody and the levels of AST,DB,TBA,IgA and IgM(P＜0.05),while a negative correlation appeared between anti-SP 100 antibody and the level of IgG(P＜0.05). Conclusions 1.Both UDCA monotherapy and UDCA combined with prednisolone could improve part of the liver function of the patients with PBC.Considering the side effects, UDCA monotherapy is still the first-choice treatment.2.There is no regulative effect of the two therapies on expressions of immunoglobulins,Th1 and Th2 lymphocytes,CD8+CD28 -regulatory T cells,CD4+CD25+ regulatory T cells,NK cells and B cells in patients with PBC.3.Both of the two therapies could slowly inhibit the levels of Th1 cytokine-IL-2, and low-level IL-2 could inhibit the activation of T lymphocytes.4.Both of the two therapies could slowly inhibit the levels of Th2 cytokines-IL-4,IL-6,IL-10,and their decrease could inhibit the activation of B cells and the lesions due to higher immune reactions to autoantigens.5.Both of the two therapies could slowly inhibit the levels of TNF-αand IL-1β,and the reduction of TNF-αand IL-1βmight relieve the inflammatory injury of the liver,suppress the inflammatory reaction and delay the pathological lesions of the liver.6.AMA,AMA-M2 is the biomarker of PBC,but there is no relationship between them and the states of the illness.There is a relationship between anti-GP210 antibodies and the state of PBC,and the level of anti-GP210 antibodies could be used to assess the severity of PBC.Patients with positive anti-GP210 antibody and anti-SP100 antibody have bad reaction towards drug therapy,thus they could be used for prediction of the therapeutic effects.
引文
1.Selmi C,Ichiki Y,Invernizzi P,Podda M,Gershwin ME.The enigma of primary biliary cirrhosis.Clin Rev Allergy Immunol.2005;28(2):73-81.
2.Hanada S,Harada M,Koga H,Kawaguchi T,Taniguchi E,Kumashiro R,Ueno T,Ueno Y,Ishii M,Sakisaka S,Sata M.Tumor necrosis factor-alpha and interferon-gamma directly impair epithelial barrier function in cultured mouse cholangiocytes.Liver Int.2003;23(1):3-11.
3.Harada K,Van de Water J,Leung PS,Coppel RL,Ansari A,Nakanuma Y,Gershwin ME.In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis:predominance of the Th1 subset.Hepatology.1997;25(4):791-6.
4.Golovanova EV,II'chenko LIu,Tsaregorodtseva TM,Serova TI,Gudkova RB.Cytokines in primary biliary cirrhosis(diagnostic and prognostic value).Ter Arkh.2004;76(2):8-11.
5.Nagano T,Yamamoto K,Matsumoto S,Okamoto R,Tagashira M,Ibuki N,Matsumura S,Yabushita K,Okano N,Tsuji T.Cytokine profile in the liver of primary biliary cirrhosis.J Clin Immunol.1999;19(6):422-7.
6.Kakumu S,Yoshioka K,Tsutsumi Y,Wakita T,Arao M.Production of tumor necrosis factor,interleukin 1,and interferon-gamma by peripheral blood mononuclear cells from patients with primary biliary cirrhosis.Clin Immunol Immunopathol.1990;56(1):54-65.
7.Yamano T,Higashi T,Nouso K,Nakatsukasa H,Kariyama K,Yumoto E,Kobayashi Y,Yamamoto K,Iwagaki H,Yagi T,Tanimoto T,Kurimoto M,Tanaka N,Tsuji T.Serum interferon-gamma-inducing factor/IL-18 levels in primary biliary cirrhosis.Clin Exp Immunol.2000;122(2):227-31.
8.Tsutsui H,Adachi K,Seki E,Nakanishi K.Cytokine-induced inflammatory liver injuries.Curr Mol Med.2003;3(6):545-59.
9.Yan HP,Zhuang H,Liu YM,Feng X,Tan YF,Liu Y,Zhang X,Zhao CH.Immunological characteristics of primary biliary cirrhosis patients.Zhonghua Gan Zang Bing Za Zhi.2005 Jan;13(1):12-6.
10.Harada K,Isse K,Kamihira T,Shimoda S,Nakanuma Y.Th1 cytokine-induced downregulation of PPARgamma in human biliary cells relates to cholangitis in primary biliary cirrhosis.Hepatology.2005;41(6):1329-38.
11.Tjandra K,Sharkey KA,Swain MG.Progressive development of a Th1-type hepatic cytokine profile in rats with experimental cholangitis.Hepatology.2000;31(2):280-90.
12.Kita H,Matsumura S,He XS,Ansari AA,Lian ZX,Van de Water J,Coppel RL,Kaplan MM,Gershwin ME.Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis.J Clin Invest.2002;109(9):1231-40.
13.Kita H,Lian ZX,Van de Water J,He XS,Matsumura S,Kaplan M,Luketic V,Coppel RL,Ansari AA,Gershwin ME.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 Med.2002;195(1):113-23.
14.Kim JY,Kim HJ,Hurt EM,Chen X,Howard OM,Farrar WL.Functional and genomic analyses of FOXP3-transduced Jurkat-T cells as regulatory T(Treg)-like cells.Biochem Biophys Res Commun.2007;362(1):44-50.
15.Longhi MS,Hussain MJ,Mitry RR,Arora SK,Mieli-Vergani G,Vergani D,Ma Y.Functional study of CD4+CD25+regulatory T cells in health and autoimmune hepatitis.J Immunol.2006;176(7):4484-91.
16.Lan RY,Cheng C,Lian ZX,Tsuneyama K,Yang GX,Moritoki Y,Chuang YH,Nakamura T,Saito S,Shimoda S,Tanaka A,Bowlus CL,Takano Y,Ansari AA,Coppel RL,Gershwin ME.Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis.Hepatology.2006;43(4):729-37.
17.Wakabayashi K,Lian ZX,Moritoki Y,Lan RY,Tsuneyama K,Chuang YH,Yang GX,Ridgway W,Ueno Y,Ansari AA,Coppel RL,Mackay IR,Gershwin ME.IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis.Hepatology.2006;44(5):1240-9.
18.Shimoda S,Ishikawa F,Kamihira T,Komori A,Niiro H,Baba E,Harada K,Isse K,Nakanuma Y,Ishibashi H,Gershwin ME,Harada M.Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory.Gastroenterology.2006;131(2):606-18.
19.Ichiki Y,Selmi C,Shimoda S,Ishibashi H,Gordon SC,Gershwin ME.Mitochondrial antigens as targets of cellular and humoral auto-immunity in primary biliary cirrhosis.Clin Rev Allergy Immunol.2005;28(2):83-91.
20.Spengler U,M(o|¨)ller A,Jung MC,Messer G,Zachoval R,Hoffmann RM,Eisenburg J,Paumgartner G,Riethm(u|¨)ller G;Weiss EH,et al.T lymphocytes from patients with primary biliary cirrhosis produce reduced amounts of lymphotoxin,tumor necrosis factor and interferon-gamma upon mitogen stimulation.J Hepatol.1992;15(1-2):129-35.
21.Ueno Y,Moritoki Y,Shimosegawa T,Gershwin ME.Primary biliary cirrhosis:what we know and what we want to know about human PBC and spontaneous PBC mouse models.J Gastroenterol.2007;42(3):189-95.
22.II'ichenko LIu,Golovanova EV,Tsaregorodtseva TM,Serova TI,Gudkova RB.Current understanding of primary biliary cirrhosis.Ter Arkh.2005;77(2):50-4.
23.Li CP,Hwang SJ,Chan CY,Lee FY,Huang YS,Chang FY,Lee SD.Clinical evaluation of primary biliary cirrhosis in Chinese patients without serum anti-mitochondrial antibody.Zhonghua Yi Xue Za Zhi(Taipei).1997;59(6):334-40.
24.Nakamura M.The significance of anti-nuclear envelope(gp210) antibody in primary biliary cirrhosis.Nihon Rinsho Meneki Gakkai Kaishi.2005;28(3):117-22.
25.Neuman M,Angulo P,Malkiewicz I,Jorgensen R,Shear N,Dickson ER,Haber J,Katz G;Lindor K. Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis.J Gastroenterol Hepatol.2002;17(2):196-202.
26.Heathcote EJ.Management of primary biliary cirrhosis.The American Association for the Study of Liver Diseases practice guidelines.Hepatology JT-Hepatology(Baltimore,Md.)2000;31(4):1005-13.
27.Fukushima N,Nalbandian G,Van De Water J,et al.Characterization of recombinant monoclonal IgA anti-PDC-E2 autoantibodies derived from patients with PBC.Hepatology 2002;36:1383-1392
28.Itoh S,Matsuzaki Y,Kimura T,Ikegami T,Shoda J,Fujiwara M,et al.Cytokine profile of liver-infiltrating CD4+ T cells separated from murine primary biliary cirrhosis-like hepatic lesions induced by graft-versus-host reaction.J Gastroenterol Hepatol JT-Journal of gastroenterology and hepatology 2000;15(4):443-51.
29.Dienes HP,Lohse AW,Gerken G,Schirmacher P,Gallati H,Lohr HF,et al.Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis.Virchows Arch JT-Virchows Archiv:an international journal of pathology 1997;431(2):119-24.
30.Palmer JM,Kirby JA,Jones DE.The immunology of primary biliary cirrhosis:the end of the beginning? Clin Exp Immunol.2002;129(2):191-7.
31.Bjorkland A,Loof L,Mendel-Hartvig I,Totterman TH.Primary biliary cirrhosis.High proportion of B-cells in blood and liver tissue produce anti-mitochondrial antibodies of several Ig classes.J Immunol 1994;153:2750-7.
32.Leon MP,Spickett G,Jones DEJ,Bassendine MF.CD4+ T-cell subsets defined by isoforms of CD45in primary biliary cirrhosis.Clin Exp Immunol 1995;99:233-9.
33.Shimoda S,Van de Water J,Ansari A et al.Identification and precursor frequency analysis of a common T-cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis.J Clin Invest 1998;102:1831-40.
34.Falcone,M.,Lee,J.,Patstone,G.,Yeung,B.,and Sarvetnick,N.B lymphocytes are crucial antigen-presenting cells in the pathogenic autoimmune response to GAD65 antigen in nonobese diabetic mice.J.Immunol.1998;161:1163-1168.
35.Lazaridis KN,Strazzabosco M,Larusso NF:The cholangiopathies:disorders of biliary epithelia.Gastroenterology 2004;127:1565-1577.
36.Ruth YL,Aftab AA,Zhe-Xiong Lian,et al.Regulatory T cells:Development,function and role in autoimmunity.Autoimmunity Reviews,2005;4(6):351-363.
37.Mocellin S,Panelli MC,Wang E,et al.The dual role of IL-10.Trends Immunol.2003,24(1):36-43.
38.Gesser B,Leffers H,Jinquan T,et al.Identification of functional domains on human interleukin 10.Proc.Natl.Acad.Sci.USA.1997,94:14620-14625.
39.Nakahata T,Tsuji K.[Function,molecular structure and gene expression regulation of interleukin-10 (IL-10)]Nippon Rinsho.1992,50(8):1827-1832.
40.Moore KW,O'Garra A,de Waal Malefyt R,et al.Interleukin 10.Annual Review of Immunology.1993,11:165-190.
41.Conti P,Kempuraj D,Kandere K,et at.IL-10,an inflammatory/inhibitory cytokine,but not always.Immunol Lett.2003,86(2):123-129.
42.Spits H,de Waal Malefyt R.Functional characterization of human IL-10.Int Arch Allergy Immunol.1992,99(1):8-15.
43.Rousset F,Garcia E,Defiance T,et al.Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes.Proceedings of the National Academy of Sciences of the United States of America.1992,89(5):1890-1893.
44.Ishida H.[Clinical implication of IL-10 in patients with immune and inflammatory diseases].Rinsho Byori.1994,42(8):843-852.
45.Bromberg JS.IL-10 immunosuppression in transplantation.Curr Opin Immunol.1995,7(5):639-643.
46.Trinchieri G.Cytokines acting on or secreted by macrophages during intracellular infection(IL-10,IL-12,IFN-gamma).Curr Opin Immunol.1997,9(1):17-23.
47.Moore KW,de Waal Malefyt R,Coffman RL,et al.Interleukin-10 and the interleukin-10 receptor.Annu Rev Immunol.2001,19:683-765.
48.Worman HJ.Nuclear envelope protein autoantigens in primary biliary cirrhosis.Hepatol Res.2007;37Suppl 3:S406-11.
49.Miyachi K,Miyakawa H,Oda M,Horigome T,Fritzler M.Primary biliary cirrhosis and autoantibodies.Nihon Rinsho Meneki Gakkai Kaishi.2008;31:47-55.
50.Nakamura M,Takii Y,Ito M,Komori A,Yokoyama T,Shimizu-Yoshida Y,Koyabu M,Matsuyama M,Mori T,Kamihira T,Daikoku M,Migita K,Yatsuhashi H,Nozaki N,Shimoda S,Ishibashi H:Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis.J Autoimmun 2006;26:138-145.
51.Nakamura M,Shimizu-Yoshida Y,Takii Y,Komori A,Yokoyama T,Ueki T,Daikoku M,Yano K,Matsumoto T,Migita K,Yatsuhashi H,Ito M,Masaki N,Adachi H,Watanabe Y,Nakamura Y,Saoshiro T,Sodeyama T,Koga M,Shimoda S,Ishibashi H:Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis.J Hepatol 2005;42:386-392.
1. Kumagi T, Heathcote EJ.Primary biliary cirrhosis. Orphanet J Rare Dis. 2008 Jan 23;3:1.
2. Dahlan Y, Smith L, Simmons D, Jewell LD, Wanless I, Heathcote EJ, Bain VG: Pediatric-onset primary biliary cirrhosis. Gastroenterology 2003; 125:1476-1479.
3. Sakaguchi F, Mori M, Zeniya M, Toda G: A cross-sectional study of primary biliary cirrhosis in Japan: utilization of clinical data when patients applied to receive public financial aid. J Epidemiol 2005; 15:24-28.
4. Hamlyn AN, Sherlock S: The epidemiology of primary biliary cirrhosis: a survey of mortality in England and Wales. Gut 1974; 15:473-479.
5. Danielsson A, Boqvist L, Uddenfeldt P: Epidemiology of primary biliary cirrhosis in a defined rural population in the northern part of Sweden. Hepatology 1990; 11:458-464.
6. Witt-Sullivan H, Heathcote J, Cauch K, Blendis L, Ghent C, Katz A, Milner R, Pappas SC, Rankin J, Wanless IR: The demography of primary biliary cirrhosis in Ontario, Canada. Hepatology 1990; 12:98-105.
7. Villeneuve JP, Fenyves D, Infante-Rivarde C: Descriptive epidemiology of primary biliary cirrhosis in the province of Quebec. Can J Gastroenterol 1991; 5:174-178.
8. Kim WR, Lindor KD, Locke GR 3rd, Therneau TM, Homburger HA, Batts KP, Yawn BP, Petz JL, Melton LJ 3rd, Dickson ER: Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology 2000; 119:1631-1636.
9. Hurlburt KJ, McMahon BJ, Deubner H, Hsu-Trawinski B, Williams JL, Kowdley KV: Prevalence of autoimmune liver disease in Alaska Natives. Am J Gastroenterol 2002; 97:2402-2407.
10. Watson RG, Angus PW, Dewar M, Goss B, Sewell RB, Smallwood RA: Low prevalence of primary biliary cirrhosis in Victoria, Australia. Melbourne Liver Group. Gut 1995; 36:927-930.
11. James OF, Bhopal R, Howel D, Gray J, Burt AD, Metcalf JV: Primary biliary cirrhosis once rare, now common in the United Kingdom? Hepatology 1999; 30:390-394.
12. Reshetnyak VI. Concept on the pathogenesis and treatment of primary biliary cirrhosis. World J Gastroenterol. 2006; 12(45):7250-62.
13. Addison T, Gull W: On a certain affection of the skin-vitiligoidea-α-plana β-tuberosa. Guys Hosp Rept 1851;7:G265-277.
14. Ahrens EH Jr, Kunkel HG: The relationship between serum lipids and skin xanthomata in 18 patients with primary biliary cirrhosis. J Clin Invest 1949; 28:1565-1574.
15. Poupon R: Trials in primary biliary cirrhosis: need for the right drugs at the right time. Hepatology 2004; 39:900-902.
16. Reshetnyak VI. Concept on the pathogenesis and treatment of primary biliary cirrhosis. World J Gastroenterol. 2006; 12(45):7250-62.
17. Leuschner U, Fischer H, Kurtz W, Guldutuna S, Hubner K, Hellstern A, Gatzen M, Leuschner M: Ursodeoxycholic acid in primary biliary cirrhosis: results of a controlled double-blind trial. Gastroenterology 1989; 97:1268-1274.
18. Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM, Ghent CN, Michieletti P, Minuk GY, Pappas SC, Scully LJ, et al.: The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994; 19:1149-1156.
19. Pares A, Caballeria L, Rodes J, Bruguera M, Rodrigo L, Garcia-Plaza A, Berenguer J, Rodriguez-Martinez D, Mercader J, Velicia R: Longterm 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 Hepatol 2000; 32:561-566.
20. Leuschner M, Holtmeier J, Ackermann H, Leuschner U. The influence of sulindac on patients with primary biliary cirrhosis that responds incompletely to ursodeoxycholic acid: a pilot study. Eur J Gastroenterol Hepatol 2002; 14: 1369-1376
21. Corpechot C, Carrat F, Bahr A, Chretien Y, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 2005; 128: 297-303
22. Tromm A, May B, Klein CG, Klein R, Fisseler-Eckhoff A, Griga T. Long-term response of primary biliary cirrhosis (stage I) to therapy with ursodeoxycholic acid. Hepatogastroenterology 2005; 52: 753-756
23. Dohmen K, Mizuta T, Nakamuta M, Shimohashi N, Ishibashi H, Yamamoto K. Fenofibrate for patients with asymptomatic primary biliary cirrhosis. World J Gastroenterol 2004; 10: 894-898
24. Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ: Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997;113:884-890.
25. Roda E, Azzaroli F, Nigro G, Piazza F, Jaboli F, Ferrara F, Liva S, Giovanelli S, Miracolo A, Colecchia A, Festi D, Mazzeo C, Bacchi L, Roda A, Mazzella G. Improved liver tests and greater biliary enrichment with high dose ursodeoxycholic acid in early stage primary biliary cirrhosis. Dig Liver Dis 2002; 34: 523-527
26. Poupon RE, Bonnand AM, Chretien Y, Poupon R: Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology 1999; 29:1668-1671.
27. Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R: The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology 2000; 32:1196-1199.
28. Van Den Bogaert E, Francque S, Pelckmans P, Michielsen P. The use of ursodeoxycholic acid in patients with primary biliary cirrhosis: sense or nonsense. Acta Gastroenterol Belg 2003; 66: 283-287
29. Lindor KD, Jorgensen RA, Therneau TM, Malinchoc M, Dickson ER: Ursodeoxycholic acid delays the onset of esophageal varices in primary biliary cirrhosis. Mayo Clin Proc 1997; 72:1137-1140.
30. Neuman MG, Cameron RG, Haber JA, Katz GG, Blendis LM. An electron microscopic and morphometric study of ursodeoxycholic effect in primary biliary cirrhosis. Liver 2002; 22: 235-244
31. Dimoulios P, Kolios G, Notas G, Matrella E, Xidakis C, Koulentaki M, Tsagarakis N, Kouroumalis A, Kouroumalis E. Ursodeoxycholic acid reduces increased circulating endothelin 2 in primary biliary cirrhosis. Aliment Pharmacol Ther 2005; 21: 227-234
32. Shi J, Wu C, Lin Y, Chen YX, Zhu L, Xie WF: Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials. Am J Gastroenterol 2006; 101:1529-1538.
33. Leuschner M, Maier KP, Schlichting J, Strahl S, Herrmann G, Dahm HH, Ackermann H, Happ J, Leuschner U: Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology 1999; 117:918-925.
34. Rautiainen H, Karkkainen P, Karvonen AL, Nurmi H, Pikkarainen P, Nuutinen H, Farkkila M: Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three year randomized trial. Hepatology 2005; 41:747-752.
35. Angulo P, Jorgensen RA, Keach JC, Dickson ER, Smith C, Lindor KD: Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 2000; 31:318-323.
36. Mitchison HC, Palmer JM, Bassendine MF, Watson AJ, Record CO, James OF: A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results. J Hepatol 1992; 15:336-344.
37. Heathcote J, Ross A, Sherlock S: A prospective controlled trial of azathioprine in primary biliary cirrhosis. Gastroenterology 1976; 70:656-660.
38. Wiesner RH, Ludwig J, Lindor KD, Jorgensen RA, Baldus WP, Homburger HA, Dickson ER: A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med 1990; 322:1419-1424.
39. Talwalkar JA, Angulo P, Keach JC, Petz JL, Jorgensen RA, Lindor KD: Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid. J Clin Gastroenterol 2005; 39:168-171.
40. Lindor KD, Dickson ER, Jorgensen RA, Anderson ML, Wiesner RH, Gores GJ, Lange SM, Rossi SS, Hofmann AF, Baldus WP: The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study. Hepatology 1995; 22:1158-1162.
41. Hoofnagle JH, Davis GL, Schafer DF, Peters M, Avigan MI, Pappas SC, Hanson RG, Minuk GY, Dusheiko GM, Campbell G, et al.: Randomized trial of chlorambucil for primary biliary cirrhosis. Gastroenterology 1986; 91:1327-1334.
42. Dickson ER, Fleming TR, Wiesner RH, Baldus WP, Fleming CR, Ludwig J, McCall JT: Trial of
penicillamine in advanced primary biliary cirrhosis. N Engl J Med 1985; 312:1011-1015.
43. Kaplan MM, Ailing DW, Zimmerman HJ, Wolfe HJ, Sepersky RA, Hirsch GS, Elta GH, Glick KA, Eagen KA: A prospective trial of colchicine for primary biliary cirrhosis. N Engl J Med 1986; 315:1448-1454.
44. Angulo P, Patel T, Jorgensen RA, Therneau TM, Lindor KD: Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 2000; 32:897-900.
45. Kurihara T, Niimi A, Maeda A, Shigemoto M, Yamashita K: Bezafibrate in the treatment of primary biliary cirrhosis: comparison with ursodeoxycholic acid. Am J Gastroenterol 2000; 95:2990-2992.
46. Agarwal K, Jones DE, Daly AK, at al. CTAL-4 gene polymonrphism confers susceptibility to primary biliary cirrhosis . J Hepatol, 2000;32:538-541.
47. Fan LY, Zhu Y, Zhong RQ, et al. Study on the relationship of CTLA-4 -318, +49 polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in a Chinese population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2004;21:440-443.
48. Daimon Y, Yamanishi K, Murakami Y, et al. Novel single nucleotide polymorphisms of the cytokeratin 19 pseudogene are associated with primary biliary cirrhosis. Hepatol Res, 2003; 25: 281 -286.
49. Matsushita M, Miyakawa H, Tanaka A, et al. Single nucleotide polymorphisms of the mannose-binding lectin are associated with susceptibility to primary biliary cirrhosis. J Autoimmun, 2001;17: 251-257.
50. Rad R, Prinz C, Neu B, et al. Synergistic effect of Helicobacter pylori virulence factors and interleukin-1 polymorphisms for the development of severe histological changes in the gastric mucosa. J Infect Dis, 2003; 188: 272-281.
51. Donaldson P, Agarwal K, Craggs A, et al. HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: association with disease progression and disease susceptibility. Gut, 2001 ;48: 397-402.
52. Jones DE, Watt FE, Grove J, et al. Tumor necrosis factor-alpha promoter polymorphism in primary biliary cirrhosis. J Hepatol, 1999;30:232-236.
53. Matsushita M, Tanaka A, Kikuchi K, er al. Association of single nucleotide polymorphisms of the interleukin-10 promoter gene and susceptibility to primary biliary cirrhosis: immunogenetic differences in Italian and Japanese patients, Autoimmunity, 2002;35: 531-536.
54. Komuro O, Takahashi H, Sato K, et al. Significance of serum oxidative stress related markers and genotype of GST gent in the pathogeneses of primary biliary cirrhosis. Nihon Rinsho Meneki Gakkai Kaishi, 2004;27: 322-329.
55. Leung PS, Iwayama T, Coppel RL, Gershwin ME: Site-directed mutagenesis of lysine within the immunodominant autoepitope of PDC-E2. Hepatology 1990; 12:1321-1328.
56. Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A: Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J Clin Invest 2001; 108:223-232.
57. Amano K, Leung PS, Rieger R, Quan C, Wang X, Marik J, Suen YF, Kurth MJ, Nantz MH, Ansari AA, Lam KS, Zeniya M, Matsuura E, Coppel RL, Gershwin ME: Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid. J Immunol 2005; 174:5874-5883.
58. Kouroumalis E, Notas G. Pathogenesis of primary biliary cirrhosis: a unifying model. World J Gastroenterol. 2006; 12:2320-7.
59. Graham AM, Dollinger MM, Howie SE, Harrison DJ. Bile duct cells in primary biliary cirrhosis are 'primed' for apoptosis. Eur J Gastroenterol Hepatol 1998; 10: 553-557
60. Tinmouth J, Lee M, Wanless IR, Tsui FW, Inman R, Heathcote EJ. Apoptosis of biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis. Liver 2002; 22:228-234
61. Iwata M, Harada K, Kono N, Kaneko S, Kobayashi K, Nakanuma Y: Expression of Bcl-2 familial proteins is reduced in small bile duct lesions of primary biliary cirrhosis. Hum Pathol 2000; 31:179-184.
62. Worman HJ.Nuclear envelope protein autoantigens in primary biliary cirrhosis. Hepatol Res. 2007; 37 Suppl 3:S406-11.
63. Miyachi K, Miyakawa H, Oda M, Horigome T, Fritzler M. Primary biliary cirrhosis and autoantibodies. Nihon Rinsho Meneki Gakkai Kaishi. 2008;31:47-55.
64. Itoh S, Ichida T, Yoshida T, Hayakawa A, Uchida M, Tashiro-Itoh T, Matsuda Y, Ishihara K, Asakura H.Autoantibodies against a 210 kDa glycoprotein of the nuclear pore complex as a prognostic marker in patients with primary biliary cirrhosis. J Gastroenterol Hepatol. 1998; 13:257-65.
65. Nakamura M, Takii Y, Ito M, Komori A, Yokoyama T, Shimizu-Yoshida Y, Koyabu M, Matsuyama M, Mori T, Kamihira T, Daikoku M, Migita K, Yatsuhashi H, Nozaki N, Shimoda S, Ishibashi H: Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis. J Autoimmun 2006; 26:138-145.
66. Nakamura M, Shimizu-Yoshida Y, Takii Y, Komori A, Yokoyama T, Ueki T, Daikoku M, Yano K, Matsumoto T, Migita K, Yatsuhashi H, Ito M, Masaki N, Adachi H, Watanabe Y, Nakamura Y, Saoshiro T, Sodeyama T, Koga M, Shimoda S, Ishibashi H: Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis. J Hepatol 2005; 42:386-392.
67. Muratori P, Muratori L, Ferrari R, Cassani F, Bianchi G, Lenzi M, et al. Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis. Am J Gastroenterol JT -The American journal of gastroenterology 2003;98(2):431-7.
68. Bogdanos DP, Baum H, Butler P, Rigopoulou EI, Davies ET, Ma Y, et al. Association between the primary biliary cirrhosis specific anti-SP100 antibodies and recurrent urinary tract infection. Dig Liver Dis JT-Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2003;35(11):801-5.
69. Xu G, Shi Y. Apoptosis signaling pathways and lymphocyte homeostasis. Cell Research, 2007, 17(9): 759-771.
70. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136:2348-57.
71. Romagnani P, Annunziato F, Piccinni MP, Maggi E, Romagnani S. Cytokines and chemokines in T lymphopoiesis and T-cell effector function. Immunol Today JT - Immunology today 2000;21:416-8.
72. Van de Water, J., et al. The role of T cells in primary biliary cirrhosis. Semin. Liver Dis. 1997; 17:105-113.
73. Colucci, G., Schafmer, F., and Paronetto, F. In situ characterization of the cell-surface antigens of the mononuclear cell infiltrate and bile duct epithelium in primary biliary cirrhosis. Clin. Immunol. Immunopathol. 1986; 41:35-42.
74. Van de Water J, Ansari A, Prindiville T et al. Heterogeneity of autoreactive T-cell clones specific for the E2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis. J Exp Med 1995; 181:723-33.
75. Van de Water J, Ansari AA, Surh CD, Coppel R, Roche T, Donkovsky HB, Kaplan M, Gershwin ME. Evidence for the targeting by 2-oxo-dehydrogenase enzymes in the T-cell response of primary biliary cirrhosis. J Immunol 1991; 146:89-94.
76. Lohr H, Fleischer B, Gerken G, Yeaman SJ, Meyer-zum-Buschenfelds KH, Manns M. Autoreactive liver-infiltrating T cells in primary biliary cirrhosis recognise inner mitochondrial epitopes and the pyruvate dehydrogenase complex. J Hepatol 1993; 18:322-7.
77. Jones DEJ, Palmer JM, Yeaman SJ, James OFW, Bassendine MF, Diamond AG. T-cell responses to the components of pyruvate dehydrogenase complex in primary biliary cirrhosis. Hepatology 1995; 21:995-1002.
78. Shimoda S, Van de Water J, Ansari A et al. Identification and precursor frequency analysis of a common T-cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis. J Clin Invest 1998; 102:1831-40.
79. Palmer JM, Kirby JA, Jones DE. The immunology of primary biliary cirrhosis: the end of the beginning? Clin Exp Immunol. 2002;129(2):191-7.
80. Palmer JM, Diamond AG, Yeaman SJ, Bassendine MF, Jones DE: T cell responses to the putative dominant autoepitope in primary biliary cirrhosis (PBC). Clin Exp Immunol 1999; 116:133-139.
81.Kita H,Matsumura S,He XS,Ansari AA,Lian ZX,Van de Water J,Coppel RL,Kaplan MM,Gershwin ME:Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis.J Clin Invest 2002;109:1231-1240.
82.Jones DE,Palmer JM,James OF,Yeaman SJ,Bassendine MF,Diamond AG.T-cell responses to the components of pyruvate dehydrogenase complex in primary biliary cirrhosis.Hepatology 1995;21:995-1002
83.Kouroumalis E,Notas G.Pathogenesis of primary biliary cirrhosis:a unifying model.World J Gastroenterol.2006;12:2320-7.
84.Irie J,Wu Y,Wicker LS,Rainbow D,Nalesnik MA,Hirsch R,Peterson LB,Leung PS,Cheng C,Mackay IR,Gershwin ME,Ridgway WM:NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis.J Exp Med 2006;203:1209-1219.
85.Wakabayashi K,Lian ZX,Moritoki Y,Lan RY,Tsuneyama K,Chuang YH,Yang GX,Ridgway W,Ueno Y,Ansari AA,Coppel RL,Mackay IR,Gershwin ME:IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis.Hepatology 2006;44:1240-1249.
86.Oertelt S,Lian ZX,Cheng CM,Chuang YH,Padgett KA,He XS,Ridgway WM,Ansari AA,Coppel RL,Li MO,Flavell RA,Kronenberg M,Mackay IR,Gershwin ME:Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominantnegative mice.J Immunol 2006;177:1655-1660.
87.Itoh S,Matsuzaki Y,Kimura T,Ikegami T,Shoda J,Fujiwara M,et al.Cytokine profile of liver-infiltrating CD4+ T cells separated from murine primary biliary cirrhosis-like hepatic lesions induced by graft-versus-host reaction.J Gastroenterol Hepatol JT-Journal of gastroenterology and hepatology 2000;15(4):443-51.
88.Lazaridis KN,Strazzabosco M,Larusso NF:The cholangiopathies:disorders of biliary epithelia.Gastroenterology 2004;127:1565-1577.
89.Dienes HP,Lohse AW,Gerken G,Schirmacher P,Gallati H,Lohr HF,et al.Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis.Virchows Arch JT-Virchows Archiv:an international journal of pathology 1997;431(2):119-24.
90.Bjorkland A,Loof L,Mendel-Hartvig I,Totterman TH.Primary biliary cirrhosis.High proportion of B-cells in blood and liver tissue produce anti-mitochondrial antibodies of several Ig classes.J Immunol 1994;153:2750-7.
91.Leon MP,Spickett G,Jones DEJ,Bassendine MF.CD4+T-cell subsets defined by isoforms of CD45in primary biliary cirrhosis.Clin Exp Immunol 1995;99:233-9.
92.Kita,H.,et al.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.Med.2002;195:113-123.
93.Falcone,M.,Lee,J.,Patstone,G.,Yeung,B.,and Sarvetnick,N.B lymphocytes are crucial antigen-presenting cells in the pathogenic autoimmune response to GAD65 antigen in nonobese diabetic mice.J.Immunol.1998;161:1163-1168.
94.Serreze,D.V.,et al.B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice.J.Immunol.1998;161:3912-3918.
95.Shimoda.S,Nakamura,M.,Ishibashi,H.,Hayashida,K.,and Niho,Y.HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis:evidence of molecular mimicry in human autoimmune diseases.J.Exp.Med.1995;181:1835-1845.
96.Coppel,R.L.,and M.E.Gershwin.Primary biliary cirrhosis:the molecule and the mimic.Immunol.Rev.1995;144:17-49.
97.Ruth YL,Aftab AA,Lian ZX,et al.Regulatory T cells:Development,function and role in autoimmunity.Autoimmun Rev,2005,25(4):351-363.
98.Mills KH.Regulatory T cells:friend or foe in immunity to infection? Nat Rev Immunol.2004;4:841-55.
99.Akdis M,Blaser K,Akdis CA.T regulatory cells in allergy:novel concepts in the pathogenesis,prevention,and treatment of allergic diseases.J Allergy Clin Immunol.2005;116:961-8.
100.Shevach EM,McHugh RS,Piccirillo CA,Thornton AM.Control of T-cell activation by CD4+CD25+ suppressor T cells.Immunol Rev.2001;182:58-67.
101.Von Boehmer H.Mechanisms of suppression by suppressor T cells.Nat Immunol.2005;6:338-44.
102.Kim JY,Kim HJ,Hurt EM,Chen X,Howard OM,Farrar WL.Functional and genomic analyses of FOXP3-transduced Jurkat-T cells as regulatory T(Treg)-like cells.Biochem Biophys Res Commun.2007;362(1):44-50.
103.Fehervari Z,Sakaguchi S.CD4+ Tregs and immune control.J Clin Invest,2004,114(9):1209-1217.
104.Wakabayashi K,Lian ZX,Moritoki Y,Lan RY,Tsuneyama K,Chuang YH,Yang GX,Ridgway W,Ueno Y,Ansari AA,Coppel RL,Mackay IR,Gershwin ME.IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis.Hepatology.2006;44(5):1240-9.
105.Tang Q,Henriksen K J,Boden EK,Tooley AJ,Ye J,Subudhi SK,et al.Cutting edge:CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells.J Immunol.2003;171:3348-52
106.Longhi MS,Hussain MJ,Mitry RR,Arora SK,Mieli-Vergani G.Vergani D,Ma Y.Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis.J Immunol.2006;176(7):4484-91.
107.Lan RY,Cheng C,Lian ZX,Tsuneyama K,Yang GX,Moritoki Y,Chuang YH,Nakamura T,Saito S,Shimoda S,Tanaka A,Bowlus CL,Takano Y,Ansari AA,Coppel RL,Gershwin ME.Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis.Hepatology. 2006;43(4):729-37..
108.Dejaco C,Duftner C,Grubeck-Loebenstein B,Schirmer M.Imbalance of regulatory T cells in human autoimmune diseases.Immunology.2005:289-300.
109.Sasaki M,Ikeda H,Sawada S,Sato Y,Nakanuma Y.Naturally-occurring regulatory T cells are increased in inflamed portal tracts with cholangiopathy in primary biliary cirrhosis.J Clin Pathol.2007;60:1102-1107.
110.Harada K,Van de Water J,Leung PS,Coppel RL,Ansari A,Nakanuma Y,et al.In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis:predominance of the Th1 subset.Hepatology 1997;25:791-796.
111.Keir ME,Sharpe AH.The B7/CD28 costimulatory family in autoimmunity.Immunol Rev.2005;204:128-43.
112.Nurieva RI.Regulation of immune and autoimmune responses by ICOS-B7h interaction.Clin Immunol.2005 Apr;115(1):19-25.
113.Wang S,Chen L.Co-signaling molecules of the B7-CD28 family in positive and negative regulation of T lymphocyte responses.Microbes Infect.2004 Jul;6(8):759-66.
114.Gao JX,Chang X,Zheng X,et al。A new role for CD28 in the survival of autoreactive T cells in the periphery after chronic exposure to autoantigen.Int Immunol.2004 Oct;16(10):1403-9.
115.Yutaka Arimura,Hidehito Kat,Umberto Dianzani et al.A co-stimulatory molecule on activated T cells,H4/ICOS,delivers specific signals in T_h cells and regulates their responses.Intl Immunol,200214(6),555-566.
116.Watts TH.TNF/TNFR family members in costimulation of T cell responses.Annu Rev Immunol.2005;23:23-68..
117.Richter G,Burdach S.ICOS:a new costimulatory ligand/receptor pair and its role in T-cell activion.Onkologie.2004 Feb;27(1):91-5
118.Mocellin S,Panelli MC,Wang E,et al.The dual role of IL-10.Trends Immunol.2003,24(1):36-43.
119.Gesser B,Leffers H,Jinquan T,et al.Identification of functional domains on human interleukin 10.Proc.Natl.Acad.Sci.USA.1997,94:14620- 14625.
120.Nakahata T,Tsuji K.[Function,molecular structure and gene expression regulation of interleukin-10(IL-10)]Nippon Rinsho.1992,50(8):1827-1832.
121.Moore KW,O'Garra A,de Waal Malefyt R,et al.Interleukin 10.Annual Review of Immunology.1993,11:165-190.
122.Conti P,Kempuraj D,Kandere K,et al.IL-10,an inflammatory/inhibitory cytokine,but not always.Immunol Lett.2003,86(2):123-129.
123.Spits H,de Waal Malefyt R.Functional characterization of human IL-10.Int Arch Allergy Immunol.1992,99(1):8-15.
124.Rousset F,Garcia E,Defrance T,et al.Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes.Proceedings of the National Academy of Sciences of the United States of America.1992,89(5):1890-1893.
125.Ishida H.[Clinical implication of IL-10 in patients with immune and inflammatory diseases].Rinsho Byori.1994,42(8):843-852.
126.Bromberg JS.IL-10 immunosuppression in transplantation.Curr Opin Immunol.1995,7(5):639-643.
127.Trinchieri G.Cytokines acting on or secreted by macrophages during intracellular infection(IL-10,IL-12,IFN-gamma).Curr Opin Immunol.1997,9(1):17-23.
128.Moore KW,de Waal Malefyt R,Coffman RL,et al.Interleukin-10 and the interleukin-10 receptor.Annu Rev Immunol.2001,19:683-765.)
129.Nagano T,Yamamoto K,Matsumoto S,Okamato R,Tagashira M,Ibuki N,et al.Cytokine profile in the liver of primary biliary cirrhosis.J Clin Immunol.1999;19:422-7.
130.Golovanova EV,Il'chenko LIu,Tsaregorodtseva TM,Serova TI,Gudkova RB.Cytokines in primary biliary cirrhosis(diagnostic and prognostic value).Ter Arkh.2004;76:8-11.
131.Kakumu S,Yoshioka K,Tsutsumi Y,Wakita T,Arao M.Production of tumor necrosis factor,interleukin 1,and interferon-gamma by peripheral blood mononuclear cells from patients with primary biliary cirrhosis.Clin Immunol Immunopathol.1990;56:54-65.
132.Yamano T,Higashi T,Nouso K,Nakatsukasa H,Kariyama K,Yumoto E,Kobayashi Y,Yamamoto K,Iwagaki H,Yagi T,Tanimoto T,Kurimoto M,Tanaka N,Tsuji T.Serum interferon-gamma-inducing factor/IL-18 levels in primary biliary cirrhosis.Clin Exp Immunol.2000;122:227-31.
133.Tsutsui H,Adachi K,Seki E,Nakanishi K.Cytokine-induced inflammatory liver injuries.Curr Mol Med.2003;3:545-59.
134.Yan HP,Zhuang H,Liu YM,Feng X,Tan YF,Liu Y,Zhang X,Zhao CH.Immunological characteristics of primary biliary cirrhosis patients.Zhonghua Gan Zang Bing Za Zhi.2005;13:12-6.
135.Harada K,Isse K,Kamihira T,Shimoda S,Nakanuma Y.Th1 cytokine-induced downregnlation of PPARgamma in human biliary cells relates to cholangitis in primary biliary cirrhosis.Hepatology.2005;41:1329-38.
136.Tjandra K,Sharkey KA,Swain MG.Progressive development of a Th1-type hepatic cytokine profile in rats with experimental cholangitis.Hepatology.2000;31:280-90.
137.Harada K,Isse K,Tsuneyama K,Ohta H,Nakanuma Y.Accumulating CD57+CD3+natural killer T cells are related to intrahepatic bile duct lesions in primary biliary cirrhosis.Liver Int 2003;23:94-100
138.Miller LC,Kaplan MM.Serum interleukin-2 and tumor necrosis factor-alpha in primary biliary cirrhosis:decrease by colchicine and relationship to HLA-DR4.Am J Gastroenterol.1992;87:465-70.
139.Sekiya H,Komatsu T,Isono E,Furukawa M,Matsushima S,Yamaguchi N,Yamauchi K,Hayashi N.Decrease in the prevalence of IL-4-producing CD4+T cells in patients with advanced stage od primary biliary cirrhosis.Am J Gastroenterol.1999;94:3589-3594.
140.Tsikrikoni A,Kyriakou DS,Rigopoulou El,Alexandrakis MG,Zachoul K,Passam F,Dalekos GN.Markers of cell activation and apoptosis in bone marrow mononuclear cells of patients with autoimmune hepatitis type Ⅰ and primary biliary cirrhosis.Journal of Hepatology.2005;42:393-399.
141.Hanada S,Harada M,Koga H,Kawaguchi T,Taniguchi E,Kumashiro R,et al.Tumor necrosis factor-alpha and interferon-gamma directly impair epithelial barrier function in cultured mouse cholangiocytes.Liver international.2003;23:3-11.
142.Nakanuma Y,Harada K.Molecular mechanisms of cholangiopathy in primary biliary cirrhosis.Med Mol Morphol.2006;39:55-61.
2.Hanada S,Harada M,Koga H,Kawaguchi T,Taniguchi E,Kumashiro R,Ueno T,Ueno Y,Ishii M,Sakisaka S,Sata M.Tumor necrosis factor-alpha and interferon-gamma directly impair epithelial barrier function in cultured mouse cholangiocytes.Liver Int.2003;23(1):3-11.
3.Harada K,Van de Water J,Leung PS,Coppel RL,Ansari A,Nakanuma Y,Gershwin ME.In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis:predominance of the Th1 subset.Hepatology.1997;25(4):791-6.
4.Golovanova EV,II'chenko LIu,Tsaregorodtseva TM,Serova TI,Gudkova RB.Cytokines in primary biliary cirrhosis(diagnostic and prognostic value).Ter Arkh.2004;76(2):8-11.
5.Nagano T,Yamamoto K,Matsumoto S,Okamoto R,Tagashira M,Ibuki N,Matsumura S,Yabushita K,Okano N,Tsuji T.Cytokine profile in the liver of primary biliary cirrhosis.J Clin Immunol.1999;19(6):422-7.
6.Kakumu S,Yoshioka K,Tsutsumi Y,Wakita T,Arao M.Production of tumor necrosis factor,interleukin 1,and interferon-gamma by peripheral blood mononuclear cells from patients with primary biliary cirrhosis.Clin Immunol Immunopathol.1990;56(1):54-65.
7.Yamano T,Higashi T,Nouso K,Nakatsukasa H,Kariyama K,Yumoto E,Kobayashi Y,Yamamoto K,Iwagaki H,Yagi T,Tanimoto T,Kurimoto M,Tanaka N,Tsuji T.Serum interferon-gamma-inducing factor/IL-18 levels in primary biliary cirrhosis.Clin Exp Immunol.2000;122(2):227-31.
8.Tsutsui H,Adachi K,Seki E,Nakanishi K.Cytokine-induced inflammatory liver injuries.Curr Mol Med.2003;3(6):545-59.
9.Yan HP,Zhuang H,Liu YM,Feng X,Tan YF,Liu Y,Zhang X,Zhao CH.Immunological characteristics of primary biliary cirrhosis patients.Zhonghua Gan Zang Bing Za Zhi.2005 Jan;13(1):12-6.
10.Harada K,Isse K,Kamihira T,Shimoda S,Nakanuma Y.Th1 cytokine-induced downregulation of PPARgamma in human biliary cells relates to cholangitis in primary biliary cirrhosis.Hepatology.2005;41(6):1329-38.
11.Tjandra K,Sharkey KA,Swain MG.Progressive development of a Th1-type hepatic cytokine profile in rats with experimental cholangitis.Hepatology.2000;31(2):280-90.
12.Kita H,Matsumura S,He XS,Ansari AA,Lian ZX,Van de Water J,Coppel RL,Kaplan MM,Gershwin ME.Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis.J Clin Invest.2002;109(9):1231-40.
13.Kita H,Lian ZX,Van de Water J,He XS,Matsumura S,Kaplan M,Luketic V,Coppel RL,Ansari AA,Gershwin ME.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 Med.2002;195(1):113-23.
14.Kim JY,Kim HJ,Hurt EM,Chen X,Howard OM,Farrar WL.Functional and genomic analyses of FOXP3-transduced Jurkat-T cells as regulatory T(Treg)-like cells.Biochem Biophys Res Commun.2007;362(1):44-50.
15.Longhi MS,Hussain MJ,Mitry RR,Arora SK,Mieli-Vergani G,Vergani D,Ma Y.Functional study of CD4+CD25+regulatory T cells in health and autoimmune hepatitis.J Immunol.2006;176(7):4484-91.
16.Lan RY,Cheng C,Lian ZX,Tsuneyama K,Yang GX,Moritoki Y,Chuang YH,Nakamura T,Saito S,Shimoda S,Tanaka A,Bowlus CL,Takano Y,Ansari AA,Coppel RL,Gershwin ME.Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis.Hepatology.2006;43(4):729-37.
17.Wakabayashi K,Lian ZX,Moritoki Y,Lan RY,Tsuneyama K,Chuang YH,Yang GX,Ridgway W,Ueno Y,Ansari AA,Coppel RL,Mackay IR,Gershwin ME.IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis.Hepatology.2006;44(5):1240-9.
18.Shimoda S,Ishikawa F,Kamihira T,Komori A,Niiro H,Baba E,Harada K,Isse K,Nakanuma Y,Ishibashi H,Gershwin ME,Harada M.Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory.Gastroenterology.2006;131(2):606-18.
19.Ichiki Y,Selmi C,Shimoda S,Ishibashi H,Gordon SC,Gershwin ME.Mitochondrial antigens as targets of cellular and humoral auto-immunity in primary biliary cirrhosis.Clin Rev Allergy Immunol.2005;28(2):83-91.
20.Spengler U,M(o|¨)ller A,Jung MC,Messer G,Zachoval R,Hoffmann RM,Eisenburg J,Paumgartner G,Riethm(u|¨)ller G;Weiss EH,et al.T lymphocytes from patients with primary biliary cirrhosis produce reduced amounts of lymphotoxin,tumor necrosis factor and interferon-gamma upon mitogen stimulation.J Hepatol.1992;15(1-2):129-35.
21.Ueno Y,Moritoki Y,Shimosegawa T,Gershwin ME.Primary biliary cirrhosis:what we know and what we want to know about human PBC and spontaneous PBC mouse models.J Gastroenterol.2007;42(3):189-95.
22.II'ichenko LIu,Golovanova EV,Tsaregorodtseva TM,Serova TI,Gudkova RB.Current understanding of primary biliary cirrhosis.Ter Arkh.2005;77(2):50-4.
23.Li CP,Hwang SJ,Chan CY,Lee FY,Huang YS,Chang FY,Lee SD.Clinical evaluation of primary biliary cirrhosis in Chinese patients without serum anti-mitochondrial antibody.Zhonghua Yi Xue Za Zhi(Taipei).1997;59(6):334-40.
24.Nakamura M.The significance of anti-nuclear envelope(gp210) antibody in primary biliary cirrhosis.Nihon Rinsho Meneki Gakkai Kaishi.2005;28(3):117-22.
25.Neuman M,Angulo P,Malkiewicz I,Jorgensen R,Shear N,Dickson ER,Haber J,Katz G;Lindor K. Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis.J Gastroenterol Hepatol.2002;17(2):196-202.
26.Heathcote EJ.Management of primary biliary cirrhosis.The American Association for the Study of Liver Diseases practice guidelines.Hepatology JT-Hepatology(Baltimore,Md.)2000;31(4):1005-13.
27.Fukushima N,Nalbandian G,Van De Water J,et al.Characterization of recombinant monoclonal IgA anti-PDC-E2 autoantibodies derived from patients with PBC.Hepatology 2002;36:1383-1392
28.Itoh S,Matsuzaki Y,Kimura T,Ikegami T,Shoda J,Fujiwara M,et al.Cytokine profile of liver-infiltrating CD4+ T cells separated from murine primary biliary cirrhosis-like hepatic lesions induced by graft-versus-host reaction.J Gastroenterol Hepatol JT-Journal of gastroenterology and hepatology 2000;15(4):443-51.
29.Dienes HP,Lohse AW,Gerken G,Schirmacher P,Gallati H,Lohr HF,et al.Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis.Virchows Arch JT-Virchows Archiv:an international journal of pathology 1997;431(2):119-24.
30.Palmer JM,Kirby JA,Jones DE.The immunology of primary biliary cirrhosis:the end of the beginning? Clin Exp Immunol.2002;129(2):191-7.
31.Bjorkland A,Loof L,Mendel-Hartvig I,Totterman TH.Primary biliary cirrhosis.High proportion of B-cells in blood and liver tissue produce anti-mitochondrial antibodies of several Ig classes.J Immunol 1994;153:2750-7.
32.Leon MP,Spickett G,Jones DEJ,Bassendine MF.CD4+ T-cell subsets defined by isoforms of CD45in primary biliary cirrhosis.Clin Exp Immunol 1995;99:233-9.
33.Shimoda S,Van de Water J,Ansari A et al.Identification and precursor frequency analysis of a common T-cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis.J Clin Invest 1998;102:1831-40.
34.Falcone,M.,Lee,J.,Patstone,G.,Yeung,B.,and Sarvetnick,N.B lymphocytes are crucial antigen-presenting cells in the pathogenic autoimmune response to GAD65 antigen in nonobese diabetic mice.J.Immunol.1998;161:1163-1168.
35.Lazaridis KN,Strazzabosco M,Larusso NF:The cholangiopathies:disorders of biliary epithelia.Gastroenterology 2004;127:1565-1577.
36.Ruth YL,Aftab AA,Zhe-Xiong Lian,et al.Regulatory T cells:Development,function and role in autoimmunity.Autoimmunity Reviews,2005;4(6):351-363.
37.Mocellin S,Panelli MC,Wang E,et al.The dual role of IL-10.Trends Immunol.2003,24(1):36-43.
38.Gesser B,Leffers H,Jinquan T,et al.Identification of functional domains on human interleukin 10.Proc.Natl.Acad.Sci.USA.1997,94:14620-14625.
39.Nakahata T,Tsuji K.[Function,molecular structure and gene expression regulation of interleukin-10 (IL-10)]Nippon Rinsho.1992,50(8):1827-1832.
40.Moore KW,O'Garra A,de Waal Malefyt R,et al.Interleukin 10.Annual Review of Immunology.1993,11:165-190.
41.Conti P,Kempuraj D,Kandere K,et at.IL-10,an inflammatory/inhibitory cytokine,but not always.Immunol Lett.2003,86(2):123-129.
42.Spits H,de Waal Malefyt R.Functional characterization of human IL-10.Int Arch Allergy Immunol.1992,99(1):8-15.
43.Rousset F,Garcia E,Defiance T,et al.Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes.Proceedings of the National Academy of Sciences of the United States of America.1992,89(5):1890-1893.
44.Ishida H.[Clinical implication of IL-10 in patients with immune and inflammatory diseases].Rinsho Byori.1994,42(8):843-852.
45.Bromberg JS.IL-10 immunosuppression in transplantation.Curr Opin Immunol.1995,7(5):639-643.
46.Trinchieri G.Cytokines acting on or secreted by macrophages during intracellular infection(IL-10,IL-12,IFN-gamma).Curr Opin Immunol.1997,9(1):17-23.
47.Moore KW,de Waal Malefyt R,Coffman RL,et al.Interleukin-10 and the interleukin-10 receptor.Annu Rev Immunol.2001,19:683-765.
48.Worman HJ.Nuclear envelope protein autoantigens in primary biliary cirrhosis.Hepatol Res.2007;37Suppl 3:S406-11.
49.Miyachi K,Miyakawa H,Oda M,Horigome T,Fritzler M.Primary biliary cirrhosis and autoantibodies.Nihon Rinsho Meneki Gakkai Kaishi.2008;31:47-55.
50.Nakamura M,Takii Y,Ito M,Komori A,Yokoyama T,Shimizu-Yoshida Y,Koyabu M,Matsuyama M,Mori T,Kamihira T,Daikoku M,Migita K,Yatsuhashi H,Nozaki N,Shimoda S,Ishibashi H:Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis.J Autoimmun 2006;26:138-145.
51.Nakamura M,Shimizu-Yoshida Y,Takii Y,Komori A,Yokoyama T,Ueki T,Daikoku M,Yano K,Matsumoto T,Migita K,Yatsuhashi H,Ito M,Masaki N,Adachi H,Watanabe Y,Nakamura Y,Saoshiro T,Sodeyama T,Koga M,Shimoda S,Ishibashi H:Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis.J Hepatol 2005;42:386-392.
1. Kumagi T, Heathcote EJ.Primary biliary cirrhosis. Orphanet J Rare Dis. 2008 Jan 23;3:1.
2. Dahlan Y, Smith L, Simmons D, Jewell LD, Wanless I, Heathcote EJ, Bain VG: Pediatric-onset primary biliary cirrhosis. Gastroenterology 2003; 125:1476-1479.
3. Sakaguchi F, Mori M, Zeniya M, Toda G: A cross-sectional study of primary biliary cirrhosis in Japan: utilization of clinical data when patients applied to receive public financial aid. J Epidemiol 2005; 15:24-28.
4. Hamlyn AN, Sherlock S: The epidemiology of primary biliary cirrhosis: a survey of mortality in England and Wales. Gut 1974; 15:473-479.
5. Danielsson A, Boqvist L, Uddenfeldt P: Epidemiology of primary biliary cirrhosis in a defined rural population in the northern part of Sweden. Hepatology 1990; 11:458-464.
6. Witt-Sullivan H, Heathcote J, Cauch K, Blendis L, Ghent C, Katz A, Milner R, Pappas SC, Rankin J, Wanless IR: The demography of primary biliary cirrhosis in Ontario, Canada. Hepatology 1990; 12:98-105.
7. Villeneuve JP, Fenyves D, Infante-Rivarde C: Descriptive epidemiology of primary biliary cirrhosis in the province of Quebec. Can J Gastroenterol 1991; 5:174-178.
8. Kim WR, Lindor KD, Locke GR 3rd, Therneau TM, Homburger HA, Batts KP, Yawn BP, Petz JL, Melton LJ 3rd, Dickson ER: Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology 2000; 119:1631-1636.
9. Hurlburt KJ, McMahon BJ, Deubner H, Hsu-Trawinski B, Williams JL, Kowdley KV: Prevalence of autoimmune liver disease in Alaska Natives. Am J Gastroenterol 2002; 97:2402-2407.
10. Watson RG, Angus PW, Dewar M, Goss B, Sewell RB, Smallwood RA: Low prevalence of primary biliary cirrhosis in Victoria, Australia. Melbourne Liver Group. Gut 1995; 36:927-930.
11. James OF, Bhopal R, Howel D, Gray J, Burt AD, Metcalf JV: Primary biliary cirrhosis once rare, now common in the United Kingdom? Hepatology 1999; 30:390-394.
12. Reshetnyak VI. Concept on the pathogenesis and treatment of primary biliary cirrhosis. World J Gastroenterol. 2006; 12(45):7250-62.
13. Addison T, Gull W: On a certain affection of the skin-vitiligoidea-α-plana β-tuberosa. Guys Hosp Rept 1851;7:G265-277.
14. Ahrens EH Jr, Kunkel HG: The relationship between serum lipids and skin xanthomata in 18 patients with primary biliary cirrhosis. J Clin Invest 1949; 28:1565-1574.
15. Poupon R: Trials in primary biliary cirrhosis: need for the right drugs at the right time. Hepatology 2004; 39:900-902.
16. Reshetnyak VI. Concept on the pathogenesis and treatment of primary biliary cirrhosis. World J Gastroenterol. 2006; 12(45):7250-62.
17. Leuschner U, Fischer H, Kurtz W, Guldutuna S, Hubner K, Hellstern A, Gatzen M, Leuschner M: Ursodeoxycholic acid in primary biliary cirrhosis: results of a controlled double-blind trial. Gastroenterology 1989; 97:1268-1274.
18. Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM, Ghent CN, Michieletti P, Minuk GY, Pappas SC, Scully LJ, et al.: The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994; 19:1149-1156.
19. Pares A, Caballeria L, Rodes J, Bruguera M, Rodrigo L, Garcia-Plaza A, Berenguer J, Rodriguez-Martinez D, Mercader J, Velicia R: Longterm 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 Hepatol 2000; 32:561-566.
20. Leuschner M, Holtmeier J, Ackermann H, Leuschner U. The influence of sulindac on patients with primary biliary cirrhosis that responds incompletely to ursodeoxycholic acid: a pilot study. Eur J Gastroenterol Hepatol 2002; 14: 1369-1376
21. Corpechot C, Carrat F, Bahr A, Chretien Y, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 2005; 128: 297-303
22. Tromm A, May B, Klein CG, Klein R, Fisseler-Eckhoff A, Griga T. Long-term response of primary biliary cirrhosis (stage I) to therapy with ursodeoxycholic acid. Hepatogastroenterology 2005; 52: 753-756
23. Dohmen K, Mizuta T, Nakamuta M, Shimohashi N, Ishibashi H, Yamamoto K. Fenofibrate for patients with asymptomatic primary biliary cirrhosis. World J Gastroenterol 2004; 10: 894-898
24. Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ: Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997;113:884-890.
25. Roda E, Azzaroli F, Nigro G, Piazza F, Jaboli F, Ferrara F, Liva S, Giovanelli S, Miracolo A, Colecchia A, Festi D, Mazzeo C, Bacchi L, Roda A, Mazzella G. Improved liver tests and greater biliary enrichment with high dose ursodeoxycholic acid in early stage primary biliary cirrhosis. Dig Liver Dis 2002; 34: 523-527
26. Poupon RE, Bonnand AM, Chretien Y, Poupon R: Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology 1999; 29:1668-1671.
27. Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R: The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology 2000; 32:1196-1199.
28. Van Den Bogaert E, Francque S, Pelckmans P, Michielsen P. The use of ursodeoxycholic acid in patients with primary biliary cirrhosis: sense or nonsense. Acta Gastroenterol Belg 2003; 66: 283-287
29. Lindor KD, Jorgensen RA, Therneau TM, Malinchoc M, Dickson ER: Ursodeoxycholic acid delays the onset of esophageal varices in primary biliary cirrhosis. Mayo Clin Proc 1997; 72:1137-1140.
30. Neuman MG, Cameron RG, Haber JA, Katz GG, Blendis LM. An electron microscopic and morphometric study of ursodeoxycholic effect in primary biliary cirrhosis. Liver 2002; 22: 235-244
31. Dimoulios P, Kolios G, Notas G, Matrella E, Xidakis C, Koulentaki M, Tsagarakis N, Kouroumalis A, Kouroumalis E. Ursodeoxycholic acid reduces increased circulating endothelin 2 in primary biliary cirrhosis. Aliment Pharmacol Ther 2005; 21: 227-234
32. Shi J, Wu C, Lin Y, Chen YX, Zhu L, Xie WF: Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials. Am J Gastroenterol 2006; 101:1529-1538.
33. Leuschner M, Maier KP, Schlichting J, Strahl S, Herrmann G, Dahm HH, Ackermann H, Happ J, Leuschner U: Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology 1999; 117:918-925.
34. Rautiainen H, Karkkainen P, Karvonen AL, Nurmi H, Pikkarainen P, Nuutinen H, Farkkila M: Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three year randomized trial. Hepatology 2005; 41:747-752.
35. Angulo P, Jorgensen RA, Keach JC, Dickson ER, Smith C, Lindor KD: Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 2000; 31:318-323.
36. Mitchison HC, Palmer JM, Bassendine MF, Watson AJ, Record CO, James OF: A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results. J Hepatol 1992; 15:336-344.
37. Heathcote J, Ross A, Sherlock S: A prospective controlled trial of azathioprine in primary biliary cirrhosis. Gastroenterology 1976; 70:656-660.
38. Wiesner RH, Ludwig J, Lindor KD, Jorgensen RA, Baldus WP, Homburger HA, Dickson ER: A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med 1990; 322:1419-1424.
39. Talwalkar JA, Angulo P, Keach JC, Petz JL, Jorgensen RA, Lindor KD: Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid. J Clin Gastroenterol 2005; 39:168-171.
40. Lindor KD, Dickson ER, Jorgensen RA, Anderson ML, Wiesner RH, Gores GJ, Lange SM, Rossi SS, Hofmann AF, Baldus WP: The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study. Hepatology 1995; 22:1158-1162.
41. Hoofnagle JH, Davis GL, Schafer DF, Peters M, Avigan MI, Pappas SC, Hanson RG, Minuk GY, Dusheiko GM, Campbell G, et al.: Randomized trial of chlorambucil for primary biliary cirrhosis. Gastroenterology 1986; 91:1327-1334.
42. Dickson ER, Fleming TR, Wiesner RH, Baldus WP, Fleming CR, Ludwig J, McCall JT: Trial of
penicillamine in advanced primary biliary cirrhosis. N Engl J Med 1985; 312:1011-1015.
43. Kaplan MM, Ailing DW, Zimmerman HJ, Wolfe HJ, Sepersky RA, Hirsch GS, Elta GH, Glick KA, Eagen KA: A prospective trial of colchicine for primary biliary cirrhosis. N Engl J Med 1986; 315:1448-1454.
44. Angulo P, Patel T, Jorgensen RA, Therneau TM, Lindor KD: Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 2000; 32:897-900.
45. Kurihara T, Niimi A, Maeda A, Shigemoto M, Yamashita K: Bezafibrate in the treatment of primary biliary cirrhosis: comparison with ursodeoxycholic acid. Am J Gastroenterol 2000; 95:2990-2992.
46. Agarwal K, Jones DE, Daly AK, at al. CTAL-4 gene polymonrphism confers susceptibility to primary biliary cirrhosis . J Hepatol, 2000;32:538-541.
47. Fan LY, Zhu Y, Zhong RQ, et al. Study on the relationship of CTLA-4 -318, +49 polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in a Chinese population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2004;21:440-443.
48. Daimon Y, Yamanishi K, Murakami Y, et al. Novel single nucleotide polymorphisms of the cytokeratin 19 pseudogene are associated with primary biliary cirrhosis. Hepatol Res, 2003; 25: 281 -286.
49. Matsushita M, Miyakawa H, Tanaka A, et al. Single nucleotide polymorphisms of the mannose-binding lectin are associated with susceptibility to primary biliary cirrhosis. J Autoimmun, 2001;17: 251-257.
50. Rad R, Prinz C, Neu B, et al. Synergistic effect of Helicobacter pylori virulence factors and interleukin-1 polymorphisms for the development of severe histological changes in the gastric mucosa. J Infect Dis, 2003; 188: 272-281.
51. Donaldson P, Agarwal K, Craggs A, et al. HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: association with disease progression and disease susceptibility. Gut, 2001 ;48: 397-402.
52. Jones DE, Watt FE, Grove J, et al. Tumor necrosis factor-alpha promoter polymorphism in primary biliary cirrhosis. J Hepatol, 1999;30:232-236.
53. Matsushita M, Tanaka A, Kikuchi K, er al. Association of single nucleotide polymorphisms of the interleukin-10 promoter gene and susceptibility to primary biliary cirrhosis: immunogenetic differences in Italian and Japanese patients, Autoimmunity, 2002;35: 531-536.
54. Komuro O, Takahashi H, Sato K, et al. Significance of serum oxidative stress related markers and genotype of GST gent in the pathogeneses of primary biliary cirrhosis. Nihon Rinsho Meneki Gakkai Kaishi, 2004;27: 322-329.
55. Leung PS, Iwayama T, Coppel RL, Gershwin ME: Site-directed mutagenesis of lysine within the immunodominant autoepitope of PDC-E2. Hepatology 1990; 12:1321-1328.
56. Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A: Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J Clin Invest 2001; 108:223-232.
57. Amano K, Leung PS, Rieger R, Quan C, Wang X, Marik J, Suen YF, Kurth MJ, Nantz MH, Ansari AA, Lam KS, Zeniya M, Matsuura E, Coppel RL, Gershwin ME: Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid. J Immunol 2005; 174:5874-5883.
58. Kouroumalis E, Notas G. Pathogenesis of primary biliary cirrhosis: a unifying model. World J Gastroenterol. 2006; 12:2320-7.
59. Graham AM, Dollinger MM, Howie SE, Harrison DJ. Bile duct cells in primary biliary cirrhosis are 'primed' for apoptosis. Eur J Gastroenterol Hepatol 1998; 10: 553-557
60. Tinmouth J, Lee M, Wanless IR, Tsui FW, Inman R, Heathcote EJ. Apoptosis of biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis. Liver 2002; 22:228-234
61. Iwata M, Harada K, Kono N, Kaneko S, Kobayashi K, Nakanuma Y: Expression of Bcl-2 familial proteins is reduced in small bile duct lesions of primary biliary cirrhosis. Hum Pathol 2000; 31:179-184.
62. Worman HJ.Nuclear envelope protein autoantigens in primary biliary cirrhosis. Hepatol Res. 2007; 37 Suppl 3:S406-11.
63. Miyachi K, Miyakawa H, Oda M, Horigome T, Fritzler M. Primary biliary cirrhosis and autoantibodies. Nihon Rinsho Meneki Gakkai Kaishi. 2008;31:47-55.
64. Itoh S, Ichida T, Yoshida T, Hayakawa A, Uchida M, Tashiro-Itoh T, Matsuda Y, Ishihara K, Asakura H.Autoantibodies against a 210 kDa glycoprotein of the nuclear pore complex as a prognostic marker in patients with primary biliary cirrhosis. J Gastroenterol Hepatol. 1998; 13:257-65.
65. Nakamura M, Takii Y, Ito M, Komori A, Yokoyama T, Shimizu-Yoshida Y, Koyabu M, Matsuyama M, Mori T, Kamihira T, Daikoku M, Migita K, Yatsuhashi H, Nozaki N, Shimoda S, Ishibashi H: Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis. J Autoimmun 2006; 26:138-145.
66. Nakamura M, Shimizu-Yoshida Y, Takii Y, Komori A, Yokoyama T, Ueki T, Daikoku M, Yano K, Matsumoto T, Migita K, Yatsuhashi H, Ito M, Masaki N, Adachi H, Watanabe Y, Nakamura Y, Saoshiro T, Sodeyama T, Koga M, Shimoda S, Ishibashi H: Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis. J Hepatol 2005; 42:386-392.
67. Muratori P, Muratori L, Ferrari R, Cassani F, Bianchi G, Lenzi M, et al. Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis. Am J Gastroenterol JT -The American journal of gastroenterology 2003;98(2):431-7.
68. Bogdanos DP, Baum H, Butler P, Rigopoulou EI, Davies ET, Ma Y, et al. Association between the primary biliary cirrhosis specific anti-SP100 antibodies and recurrent urinary tract infection. Dig Liver Dis JT-Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2003;35(11):801-5.
69. Xu G, Shi Y. Apoptosis signaling pathways and lymphocyte homeostasis. Cell Research, 2007, 17(9): 759-771.
70. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136:2348-57.
71. Romagnani P, Annunziato F, Piccinni MP, Maggi E, Romagnani S. Cytokines and chemokines in T lymphopoiesis and T-cell effector function. Immunol Today JT - Immunology today 2000;21:416-8.
72. Van de Water, J., et al. The role of T cells in primary biliary cirrhosis. Semin. Liver Dis. 1997; 17:105-113.
73. Colucci, G., Schafmer, F., and Paronetto, F. In situ characterization of the cell-surface antigens of the mononuclear cell infiltrate and bile duct epithelium in primary biliary cirrhosis. Clin. Immunol. Immunopathol. 1986; 41:35-42.
74. Van de Water J, Ansari A, Prindiville T et al. Heterogeneity of autoreactive T-cell clones specific for the E2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis. J Exp Med 1995; 181:723-33.
75. Van de Water J, Ansari AA, Surh CD, Coppel R, Roche T, Donkovsky HB, Kaplan M, Gershwin ME. Evidence for the targeting by 2-oxo-dehydrogenase enzymes in the T-cell response of primary biliary cirrhosis. J Immunol 1991; 146:89-94.
76. Lohr H, Fleischer B, Gerken G, Yeaman SJ, Meyer-zum-Buschenfelds KH, Manns M. Autoreactive liver-infiltrating T cells in primary biliary cirrhosis recognise inner mitochondrial epitopes and the pyruvate dehydrogenase complex. J Hepatol 1993; 18:322-7.
77. Jones DEJ, Palmer JM, Yeaman SJ, James OFW, Bassendine MF, Diamond AG. T-cell responses to the components of pyruvate dehydrogenase complex in primary biliary cirrhosis. Hepatology 1995; 21:995-1002.
78. Shimoda S, Van de Water J, Ansari A et al. Identification and precursor frequency analysis of a common T-cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis. J Clin Invest 1998; 102:1831-40.
79. Palmer JM, Kirby JA, Jones DE. The immunology of primary biliary cirrhosis: the end of the beginning? Clin Exp Immunol. 2002;129(2):191-7.
80. Palmer JM, Diamond AG, Yeaman SJ, Bassendine MF, Jones DE: T cell responses to the putative dominant autoepitope in primary biliary cirrhosis (PBC). Clin Exp Immunol 1999; 116:133-139.
81.Kita H,Matsumura S,He XS,Ansari AA,Lian ZX,Van de Water J,Coppel RL,Kaplan MM,Gershwin ME:Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis.J Clin Invest 2002;109:1231-1240.
82.Jones DE,Palmer JM,James OF,Yeaman SJ,Bassendine MF,Diamond AG.T-cell responses to the components of pyruvate dehydrogenase complex in primary biliary cirrhosis.Hepatology 1995;21:995-1002
83.Kouroumalis E,Notas G.Pathogenesis of primary biliary cirrhosis:a unifying model.World J Gastroenterol.2006;12:2320-7.
84.Irie J,Wu Y,Wicker LS,Rainbow D,Nalesnik MA,Hirsch R,Peterson LB,Leung PS,Cheng C,Mackay IR,Gershwin ME,Ridgway WM:NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis.J Exp Med 2006;203:1209-1219.
85.Wakabayashi K,Lian ZX,Moritoki Y,Lan RY,Tsuneyama K,Chuang YH,Yang GX,Ridgway W,Ueno Y,Ansari AA,Coppel RL,Mackay IR,Gershwin ME:IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis.Hepatology 2006;44:1240-1249.
86.Oertelt S,Lian ZX,Cheng CM,Chuang YH,Padgett KA,He XS,Ridgway WM,Ansari AA,Coppel RL,Li MO,Flavell RA,Kronenberg M,Mackay IR,Gershwin ME:Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominantnegative mice.J Immunol 2006;177:1655-1660.
87.Itoh S,Matsuzaki Y,Kimura T,Ikegami T,Shoda J,Fujiwara M,et al.Cytokine profile of liver-infiltrating CD4+ T cells separated from murine primary biliary cirrhosis-like hepatic lesions induced by graft-versus-host reaction.J Gastroenterol Hepatol JT-Journal of gastroenterology and hepatology 2000;15(4):443-51.
88.Lazaridis KN,Strazzabosco M,Larusso NF:The cholangiopathies:disorders of biliary epithelia.Gastroenterology 2004;127:1565-1577.
89.Dienes HP,Lohse AW,Gerken G,Schirmacher P,Gallati H,Lohr HF,et al.Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis.Virchows Arch JT-Virchows Archiv:an international journal of pathology 1997;431(2):119-24.
90.Bjorkland A,Loof L,Mendel-Hartvig I,Totterman TH.Primary biliary cirrhosis.High proportion of B-cells in blood and liver tissue produce anti-mitochondrial antibodies of several Ig classes.J Immunol 1994;153:2750-7.
91.Leon MP,Spickett G,Jones DEJ,Bassendine MF.CD4+T-cell subsets defined by isoforms of CD45in primary biliary cirrhosis.Clin Exp Immunol 1995;99:233-9.
92.Kita,H.,et al.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.Med.2002;195:113-123.
93.Falcone,M.,Lee,J.,Patstone,G.,Yeung,B.,and Sarvetnick,N.B lymphocytes are crucial antigen-presenting cells in the pathogenic autoimmune response to GAD65 antigen in nonobese diabetic mice.J.Immunol.1998;161:1163-1168.
94.Serreze,D.V.,et al.B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice.J.Immunol.1998;161:3912-3918.
95.Shimoda.S,Nakamura,M.,Ishibashi,H.,Hayashida,K.,and Niho,Y.HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis:evidence of molecular mimicry in human autoimmune diseases.J.Exp.Med.1995;181:1835-1845.
96.Coppel,R.L.,and M.E.Gershwin.Primary biliary cirrhosis:the molecule and the mimic.Immunol.Rev.1995;144:17-49.
97.Ruth YL,Aftab AA,Lian ZX,et al.Regulatory T cells:Development,function and role in autoimmunity.Autoimmun Rev,2005,25(4):351-363.
98.Mills KH.Regulatory T cells:friend or foe in immunity to infection? Nat Rev Immunol.2004;4:841-55.
99.Akdis M,Blaser K,Akdis CA.T regulatory cells in allergy:novel concepts in the pathogenesis,prevention,and treatment of allergic diseases.J Allergy Clin Immunol.2005;116:961-8.
100.Shevach EM,McHugh RS,Piccirillo CA,Thornton AM.Control of T-cell activation by CD4+CD25+ suppressor T cells.Immunol Rev.2001;182:58-67.
101.Von Boehmer H.Mechanisms of suppression by suppressor T cells.Nat Immunol.2005;6:338-44.
102.Kim JY,Kim HJ,Hurt EM,Chen X,Howard OM,Farrar WL.Functional and genomic analyses of FOXP3-transduced Jurkat-T cells as regulatory T(Treg)-like cells.Biochem Biophys Res Commun.2007;362(1):44-50.
103.Fehervari Z,Sakaguchi S.CD4+ Tregs and immune control.J Clin Invest,2004,114(9):1209-1217.
104.Wakabayashi K,Lian ZX,Moritoki Y,Lan RY,Tsuneyama K,Chuang YH,Yang GX,Ridgway W,Ueno Y,Ansari AA,Coppel RL,Mackay IR,Gershwin ME.IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis.Hepatology.2006;44(5):1240-9.
105.Tang Q,Henriksen K J,Boden EK,Tooley AJ,Ye J,Subudhi SK,et al.Cutting edge:CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells.J Immunol.2003;171:3348-52
106.Longhi MS,Hussain MJ,Mitry RR,Arora SK,Mieli-Vergani G.Vergani D,Ma Y.Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis.J Immunol.2006;176(7):4484-91.
107.Lan RY,Cheng C,Lian ZX,Tsuneyama K,Yang GX,Moritoki Y,Chuang YH,Nakamura T,Saito S,Shimoda S,Tanaka A,Bowlus CL,Takano Y,Ansari AA,Coppel RL,Gershwin ME.Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis.Hepatology. 2006;43(4):729-37..
108.Dejaco C,Duftner C,Grubeck-Loebenstein B,Schirmer M.Imbalance of regulatory T cells in human autoimmune diseases.Immunology.2005:289-300.
109.Sasaki M,Ikeda H,Sawada S,Sato Y,Nakanuma Y.Naturally-occurring regulatory T cells are increased in inflamed portal tracts with cholangiopathy in primary biliary cirrhosis.J Clin Pathol.2007;60:1102-1107.
110.Harada K,Van de Water J,Leung PS,Coppel RL,Ansari A,Nakanuma Y,et al.In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis:predominance of the Th1 subset.Hepatology 1997;25:791-796.
111.Keir ME,Sharpe AH.The B7/CD28 costimulatory family in autoimmunity.Immunol Rev.2005;204:128-43.
112.Nurieva RI.Regulation of immune and autoimmune responses by ICOS-B7h interaction.Clin Immunol.2005 Apr;115(1):19-25.
113.Wang S,Chen L.Co-signaling molecules of the B7-CD28 family in positive and negative regulation of T lymphocyte responses.Microbes Infect.2004 Jul;6(8):759-66.
114.Gao JX,Chang X,Zheng X,et al。A new role for CD28 in the survival of autoreactive T cells in the periphery after chronic exposure to autoantigen.Int Immunol.2004 Oct;16(10):1403-9.
115.Yutaka Arimura,Hidehito Kat,Umberto Dianzani et al.A co-stimulatory molecule on activated T cells,H4/ICOS,delivers specific signals in T_h cells and regulates their responses.Intl Immunol,200214(6),555-566.
116.Watts TH.TNF/TNFR family members in costimulation of T cell responses.Annu Rev Immunol.2005;23:23-68..
117.Richter G,Burdach S.ICOS:a new costimulatory ligand/receptor pair and its role in T-cell activion.Onkologie.2004 Feb;27(1):91-5
118.Mocellin S,Panelli MC,Wang E,et al.The dual role of IL-10.Trends Immunol.2003,24(1):36-43.
119.Gesser B,Leffers H,Jinquan T,et al.Identification of functional domains on human interleukin 10.Proc.Natl.Acad.Sci.USA.1997,94:14620- 14625.
120.Nakahata T,Tsuji K.[Function,molecular structure and gene expression regulation of interleukin-10(IL-10)]Nippon Rinsho.1992,50(8):1827-1832.
121.Moore KW,O'Garra A,de Waal Malefyt R,et al.Interleukin 10.Annual Review of Immunology.1993,11:165-190.
122.Conti P,Kempuraj D,Kandere K,et al.IL-10,an inflammatory/inhibitory cytokine,but not always.Immunol Lett.2003,86(2):123-129.
123.Spits H,de Waal Malefyt R.Functional characterization of human IL-10.Int Arch Allergy Immunol.1992,99(1):8-15.
124.Rousset F,Garcia E,Defrance T,et al.Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes.Proceedings of the National Academy of Sciences of the United States of America.1992,89(5):1890-1893.
125.Ishida H.[Clinical implication of IL-10 in patients with immune and inflammatory diseases].Rinsho Byori.1994,42(8):843-852.
126.Bromberg JS.IL-10 immunosuppression in transplantation.Curr Opin Immunol.1995,7(5):639-643.
127.Trinchieri G.Cytokines acting on or secreted by macrophages during intracellular infection(IL-10,IL-12,IFN-gamma).Curr Opin Immunol.1997,9(1):17-23.
128.Moore KW,de Waal Malefyt R,Coffman RL,et al.Interleukin-10 and the interleukin-10 receptor.Annu Rev Immunol.2001,19:683-765.)
129.Nagano T,Yamamoto K,Matsumoto S,Okamato R,Tagashira M,Ibuki N,et al.Cytokine profile in the liver of primary biliary cirrhosis.J Clin Immunol.1999;19:422-7.
130.Golovanova EV,Il'chenko LIu,Tsaregorodtseva TM,Serova TI,Gudkova RB.Cytokines in primary biliary cirrhosis(diagnostic and prognostic value).Ter Arkh.2004;76:8-11.
131.Kakumu S,Yoshioka K,Tsutsumi Y,Wakita T,Arao M.Production of tumor necrosis factor,interleukin 1,and interferon-gamma by peripheral blood mononuclear cells from patients with primary biliary cirrhosis.Clin Immunol Immunopathol.1990;56:54-65.
132.Yamano T,Higashi T,Nouso K,Nakatsukasa H,Kariyama K,Yumoto E,Kobayashi Y,Yamamoto K,Iwagaki H,Yagi T,Tanimoto T,Kurimoto M,Tanaka N,Tsuji T.Serum interferon-gamma-inducing factor/IL-18 levels in primary biliary cirrhosis.Clin Exp Immunol.2000;122:227-31.
133.Tsutsui H,Adachi K,Seki E,Nakanishi K.Cytokine-induced inflammatory liver injuries.Curr Mol Med.2003;3:545-59.
134.Yan HP,Zhuang H,Liu YM,Feng X,Tan YF,Liu Y,Zhang X,Zhao CH.Immunological characteristics of primary biliary cirrhosis patients.Zhonghua Gan Zang Bing Za Zhi.2005;13:12-6.
135.Harada K,Isse K,Kamihira T,Shimoda S,Nakanuma Y.Th1 cytokine-induced downregnlation of PPARgamma in human biliary cells relates to cholangitis in primary biliary cirrhosis.Hepatology.2005;41:1329-38.
136.Tjandra K,Sharkey KA,Swain MG.Progressive development of a Th1-type hepatic cytokine profile in rats with experimental cholangitis.Hepatology.2000;31:280-90.
137.Harada K,Isse K,Tsuneyama K,Ohta H,Nakanuma Y.Accumulating CD57+CD3+natural killer T cells are related to intrahepatic bile duct lesions in primary biliary cirrhosis.Liver Int 2003;23:94-100
138.Miller LC,Kaplan MM.Serum interleukin-2 and tumor necrosis factor-alpha in primary biliary cirrhosis:decrease by colchicine and relationship to HLA-DR4.Am J Gastroenterol.1992;87:465-70.
139.Sekiya H,Komatsu T,Isono E,Furukawa M,Matsushima S,Yamaguchi N,Yamauchi K,Hayashi N.Decrease in the prevalence of IL-4-producing CD4+T cells in patients with advanced stage od primary biliary cirrhosis.Am J Gastroenterol.1999;94:3589-3594.
140.Tsikrikoni A,Kyriakou DS,Rigopoulou El,Alexandrakis MG,Zachoul K,Passam F,Dalekos GN.Markers of cell activation and apoptosis in bone marrow mononuclear cells of patients with autoimmune hepatitis type Ⅰ and primary biliary cirrhosis.Journal of Hepatology.2005;42:393-399.
141.Hanada S,Harada M,Koga H,Kawaguchi T,Taniguchi E,Kumashiro R,et al.Tumor necrosis factor-alpha and interferon-gamma directly impair epithelial barrier function in cultured mouse cholangiocytes.Liver international.2003;23:3-11.
142.Nakanuma Y,Harada K.Molecular mechanisms of cholangiopathy in primary biliary cirrhosis.Med Mol Morphol.2006;39:55-61.