Ae2a,b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis
Ae2a,b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis
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DOI：
10.1053/j.gastro.2008.02.020
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发表时间：
2008-05-01
期刊：
影响因子：
29.4
通讯作者：
Medina, Juan F.
中科院分区：
文献类型：
--
作者：
Salas, January T.;Banales, Jesus M.;Medina, Juan F.
背景和目标：Cl-/HCO 3（-）阴离子交换器2（AE 2）参与细胞内pH（pH（i））调节和跨上皮酸碱转运，包括促分泌素刺激的胆汁碳酸氢盐排泄。原发性胆汁性肝硬化（PBC）患者的肝活检标本和血液单核细胞中发现AE 2基因表达减少，PBC是一种以慢性非化脓性胆管炎为特征的疾病，与抗线粒体抗体（AMA）和其他自身免疫现象相关。在广泛Ae 2基因破坏的小鼠中，我们以前报道过精子发生改变和胃酸分泌减少。我们现在描述在这些Ae 2（a，B）缺陷小鼠中观察到的肝胆和免疫学变化。方法：采用流式细胞术检测小鼠脾细胞pHi和T细胞亚群。使用细胞因子阵列估计CD 3刺激的细胞因子分泌。免疫印迹法和蛋白质组学检测AMA。通过免疫组织病理学、流式细胞术和血清生化学评估肝胆变化。用实时荧光定量聚合酶链反应分析胆管细胞基因表达。结果如下：Ae 2（a，B）（-/-）小鼠表现出脾肿大、脾细胞中pHi升高、白细胞介素-12 p70和干扰素γ的产生增加、CD 8（+）T细胞群扩增和CD 4（+）FoxP 3（+）/调节性T细胞代表不足。大多数Ae 2（a，B）（-/-）小鼠AMA检测呈阳性，显示免疫球蛋白M和G以及肝脏特异性碱性磷酸酶的血清水平升高。大约三分之一的Ae 2（a，B）（-/-）小鼠具有广泛的门静脉炎症，CD 8（+）和CD 4（+）T淋巴细胞围绕受损的胆管。从Ae 2（a，B）（-/-）小鼠分离的胆管细胞显示出与氧化应激相容的基因表达变化和抗原呈递增加。结论：Ae 2缺陷改变免疫细胞中的pHi稳态和胆管细胞中的基因表达谱，导致类似PBC的免疫和肝胆变化。
Background & Aims: Cl-/HCO3(-) anion exchanger 2 (AE2) is involved in intracellular pH (pH(i)) regulation and transepithelial acid-base transport, including secretin-stimulated biliary bicarbonate excretion. AE2 gene expression was found to be reduced in liver biopsy specimens and blood mononuclear cells from patients with primary biliary cirrhosis (PBC), a disease characterized by chronic nonsuppurative cholangitis associated with antimitochondrial antibodies (AMA) and other autoimmune phenomena. In mice with widespread Ae2 gene disruption, we previously reported altered spermiogenesis and reduced gastric acid secretion. We now describe the hepatobiliary and immunologic changes observed in these Ae2(a,b)-deficient mice. Methods: In this murine model, splenocyte pHi and T-cell populations were studied by flow cytometry. CD3-stimulated cytokine secretion was estimated using cytokine arrays. AMA were evaluated by immunoblotting and proteomics. Hepatobiliary changes were assessed by immunohistopathology, flow cytometry, and serum biochemistry. Cholangiocyte gene expression was analyzed by real-time polymerase chain reaction. Results: Ae2(a,b)(-/-) mice exhibit splenomegaly, elevated pHi in splenocytes, increased production of interleukin-12p70 and interferon gamma, expanded CD8(+) T-cell population, and under represented CD4(+)FoxP3(+)/regulatory T cells. Most Ae2(a,b)(-/-) mice tested positively for AMA, showing increased serum levels of immunoglobulin M and G, and tiver-specific alkaline phosphatase. About one third of Ae2(a,b)(-/-) mice had extensive portal inflammation with CD8(+) and CD4(+) T lymphocytes surrounding damaged bile ducts. Cholangiocytes isolated from Ae2(a,b)(-/-) mice showed gene expression changes compatible with oxidative stress and increased antigen presentation. Conclusions: Ae2 deficiency alters pHi homeostasis in immunocytes and gene expression profile in cholangiocytes, leading to immunologic and hepatobiliary changes that resemble PBC.