Liver and bile duct pathology following Cryptosporidium parvum infection of immunodeficient mice.
Liver and bile duct pathology following Cryptosporidium parvum infection of immunodeficient mice.
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免疫缺陷小鼠感染小隐孢子虫后的肝脏和胆管病理学。
DOI：
10.1002/hep.510300138
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Hayward,A
中科院分区：
文献类型：
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作者：
Stephens,J;Cosyns,M;Jones,M;Hayward,A
获得性免疫缺陷综合征（AIDS）患者和CD 154基因突变的男孩（导致先天性X连锁免疫缺陷伴高IgM [XHIM]）易患微小隐孢子虫（CP）慢性胆道感染，可能导致胆道硬化并最终导致胆管癌。为了确定CP感染和随后的免疫应答是否独立地导致这种发病率，我们用CP感染了严重联合免疫缺陷（SCID）或CD 154、CD 40或干扰素γ（IFN-γ）基因受损的小鼠。即使CP感染持续16周，SCID小鼠也仅出现轻度三合会炎，没有出现胆汁上皮细胞（BEC）凋亡。50%的CD 154基因敲除小鼠发生小叶性肝炎，伴有急性和慢性三裂性肠炎。CD 40敲除小鼠发生了明显的三裂炎，IFN-γ敲除小鼠死于肠炎或存活，发生了明显的三裂炎、门静脉纤维化、胆管硬化、坏死伴肝门内导管样结构扩张和发育不良变化。用来自IFN-γ敲除供体的T细胞重建的CP感染的SCID小鼠要么发展成严重的肠炎，要么存活下来发展成三裂性肠炎、胆管炎、小叶性肝炎伴导管周围硬化和瘢痕形成。同时破坏CD 40和IFN-γ基因的小鼠仍然被CP感染，并发生胆管和肝脏疾病，但没有肠炎。我们的研究结果表明，T细胞细胞因子是免疫缺陷动物对CP感染的炎症和硬化反应所必需的。免疫缺陷小鼠对CP感染的反应至少可以模拟XHIM患者发生硬化性胆管炎或胆管癌的最初步骤。
Patients with acquired immune deficiency syndrome (AIDS) and boys with mutations of the CD154 gene (causing congenital X‐linked immunodeficiency with hyper‐IgM [XHIM]) are susceptible to chronic infections of the biliary tract withCryptosporidium parvum(CP) that may lead to biliary sclerosis and ultimately to cholangiocarcinoma. To determine whether the CP infection and the consequent immune response contribute independently to this morbidity, we infected mice with severe combined immunodeficiency (SCID) or with disrupted genes for CD154, CD40, or interferon gamma (IFN‐γ) with CP. Even when CP infection persisted for 16 weeks, the SCID mice developed only mild triaditis, without apoptosis of biliary epithelial cells (BEC). Fifty percent of the CD154 knockout mice developed lobular hepatitis with acute and chronic triaditis. The CD40 knockout mice developed marked triaditis, and the IFN‐γ knockouts either succumbed to enteritis or survived to develop marked triaditis, portal fibrosis, biliary sclerosis, necrosis with dilation of duct‐like structures within the porta hepatis, and dysplastic changes. CP‐infected SCID mice reconstituted with T cells from IFN‐γ knockout donors either developed severe enteritis or survived to develop triaditis, cholangitis, lobular hepatitis with periductular sclerosis, and scarring. Mice with disruptions of both the CD40 and IFN‐γ genes remained infected by CP and developed bile duct and liver disease, but not enteritis. Our results suggest that T‐cell cytokines are required for the inflammatory and sclerosing responses to CP infection in immunodeficient animals. The response of immunodeficient mice to CP infection may model at least the initial steps toward the development of sclerosing cholangitis or bile duct cancers in XHIM patients.