原发性胆汁性肝硬化的细胞免疫学发病机制

王寅虎; 杨微; M.Eric Gershwin; 廉哲雄

原发性胆汁性肝硬化的细胞免疫学发病机制

1. 中国科学技术大学生命科学学院肝脏免疫学实验室
2. 加利福尼亚大学戴维斯分校

详细信息

中图分类号: R575.2
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出版历程
- 出版日期: 2011-06-20

Cellular mechanism of immunopathogenesis of primary biliary cirrhosis

摘要

摘要: 原发性胆汁性肝硬化（PBC）是一种器官特异性的进行性自身免疫疾病,常见于女性,以肝脏门脉周围的淋巴细胞浸润,胆管上皮细胞特异性损伤以及血清中高滴度抗线粒体抗体（AMA）为主要特征。最新的PBC研究采用了CD4启动子控制下的TGFβ受体2显性失活（dnTGFβRⅡ）小鼠模型,这种小鼠模型很好地模拟了PBC患者的典型特征。在这种小鼠的基因背景下,通过分别敲除Rag1,μ以及CD1d基因建立了多种双基因缺陷鼠,通过研究发现T细胞,B细胞以及CD1d限制的NKT细胞等对肝脏淋巴细胞浸润,胆管上皮细胞损伤以及AMA的产生发挥着重要的作用。一系列的细胞免疫学实验结果显示,是CD8+T细胞而非CD4+T细胞在肝脏损伤过程中起着决定性的作用,而B细胞除分泌抗自身抗体之外,还具有抑制PBC发生的免疫调节作用。这些机制的研究为揭示人类PBC疾病的细胞免疫学致病机理提供了有力的证据和依托。
- 肝硬化,胆汁性 /
- 疾病模型,动物 /
- 杀伤细胞,天然 /
- B淋巴细胞 /
- T淋巴细胞
Abstract: Primary biliary cirrhosis (PBC) is a progressive, organ-specific autoimmune disease that predominantly affects woman and is characterized by lymphocytic infiltration in portal tracts, immune-mediated destruction of small intrahepatic small bile ducts, and the presence of high titers of serum anti-mitochondrial Abs (AMAs) .A murine model of PBC, generated by expressing a dominant-negative form of TGFβ receptor type Ⅱ (dnTGFβRⅡ) under the direction of the CD4 promoter, demonstrates several key features of human PBC and has been applied in previous PBC studies.Experimental data from Rag1-/-, μ-/-and CD1d-/-mice on a dnTGFβRⅡ background indicated that T cells, B cells and CD1d-restricted NKT cells plays critical roles in liver injury.Moreover, based on a rigorous series of cellular immunological studies, it is concluded that CD8+, but not CD4+ T cells, play a prominent role in mediating pathogenesis, and that B cells can have a suppressive regulatory effect on the infiammatory response besides just secreting auto-antibodies.These studies provide substantial evidence for a cellular mechanism in human primary biliary cirrhosis pathogenesis.
- liver cirrhosis /
- biliary /
- disease models /
- animal /
- killer cells

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参考文献(21)

[1]Talwalkar JA, Souto E, Jorgensen RA, et al.Natural historyof pruritus in primary biliary cirrhosis[J].Clin GastroenterolHepatol, 2003, 1 (4) :297-302.

[2]Kita H, Imawari M, Gershwin ME.Cellular immune response inprimary biliary cirrhosis[J].Hepatol Res, 2004, 28 (1) :12-17.

[3]Gershwin ME, Mackay IR.The causes of primary biliary cirrhosis:Convenient and inconvenient truths[J].Hepatology, 2008, 47 (2) :737-745.

[4]Gershwin ME, Mackay IR.Sturgess A, et al.Identification andspecificity of a cDNA encoding the 70 kd mitochondrial antigenrecognized in primary biliary cirrhosis[J].J Immunol, 1987, 138 (10) :3525-3531.

[5]Shindo M, Mullin GE, Braun-Elwert L, et al.Cytokine mRNAexpression in the liver of patients with primary biliary cirrhosis (PBC) and chronic hepatitis B (CHB) [J].Clin Exp Immunol, 1996, 105 (2) :254-259.

[6]Yasoshima M, Kono N, Sugawara H, et al.Increased expressionof interleukin-6 and tumor necrosis factor-alpha in pathologicbiliary epithelial cells:in situ and culture study[J].Lab Invest, 1998, 78 (1) :89-100.

[7]Van de Water J, Ansari AA, Surh CD, et al.Evidence for the targetingby 2-oxo-dehydrogenase enzymes in the T cell response of primarybiliary cirrhosis[J].J Immunol, 1991, 146 (1) :89-94.

[8]Kita H, Matsumura S, He XS, et al.Quantitative and functionalanalysis of PDC-E2-specific autoreactive cytotoxic Tlymphocytes in primary biliary cirrhosis[J].J Clin Invest, 2002, 109 (9) :1231-1240.

[9]Kita H, Naidenko OV, Kronenberg M, et al.Quantitation andphenotypic analysis of natural killer T cells in primary biliarycirrhosis using a human CD1d tetramer[J].Gastroenterology, 2002, 123 (4) :1031-1043.

[10]Moritoki Y, Lian ZX, Wulff H, et al.AMA production in primarybiliary cirrhosis is promoted by the TLR9 ligand CpG andsuppressed by potassium channel blockers[J].Hepatology, 2007, 45 (2) :314-322.

[11]Kikuchi K, Lian ZX, Yang GX, et al.Bacterial CpG induceshyper-IgM production in CD27 (+) memory B cells in primarybiliary cirrhosis[J].Gastroenterology, 2005, 128 (2) :304-312.

[12]Chuang YH, Lian ZX, Tsuneyama K, et al.Increased killing activityand decreased cytokine production in NK cells in patients withprimary biliary cirrhosis[J].J Autoimmun, 2006, 26 (4) :232-240.

[13]Mao TK, Lian ZX, Selmi C, et al.Altered monocyte responses todefined TLR ligands in patients with primary biliary cirrhosis[J].Hepatology, 2005, 42 (4) :802-808.

[14]Lan RY, Lian ZX, Yang GX, et al.Decreased frequency ofCD4+CD25high regulatory T cells in patients with primary biliarycirrhosis and their first-degree relatives[J].Hepatology, 2005, 42 (Suppl 1) :469A-469A.

[15]Lan RY, Cheng C, Lian ZX, et al.Liver-targeted and peripheralblood alterations of regulatory T cells in primary biliarycirrhosis[J].Hepatology, 2006, 43 (4) :729-737.

[16]Gorelik L, Flavell RA.Abrogation of TGF beta signaling in T cellsleads to spontaneous T cell differentiation and autoimmunedisease[J].Immunity, 2000, 12 (2) :171-181.

[17]Oertelt S, Lian ZX, Cheng CM, et al.Anti-mitochondrial antibodiesand primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice[J].J Immunol, 2006, 177 (3) :1655-1660.

[18]Yang GX, Lian ZX, Chuang YH, et al.Adoptive transfer of CD8 (+) T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis inmice[J].Hepatology, 2008, 47 (6) :1974-1982.

[19]Moritoki Y, Zhang WC, Tsuneyama K, et al.B Cells Suppressthe Inflammatory Response in a Mouse Model of Primary BiliaryCirrhosis[J].Gastroenterology, 2009, 136 (3) :1037-1047.

[20]Moritoki Y, Lian ZX, Lindor K, et al.B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbatescolitis in transforming growth factor-beta receptor II dominantnegative mice[J].Hepatology, 2009, 50 (6) :1893-1903.

[21]Chuang YH, Lian ZX, Yang GX, et al.Natural killer T cellsexacerbate liver injury in a transforming growth factor betareceptor II dominant-negative mouse model of primary biliarycirrhosis[J].Hepatology, 2008, 47 (2) :571-580.

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