Mice deficient in the X-linked lymphoproliferative disease gene sap exhibit increased susceptibility to murine gammaherpesvirus-68 and hypo-gammaglobulinemia
Mice deficient in the X-linked lymphoproliferative disease gene sap exhibit increased susceptibility to murine gammaherpesvirus-68 and hypo-gammaglobulinemia
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DOI：
10.1002/jmv.10504
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发表时间：
2003-11-01
影响因子：
12.7
通讯作者：
Romeo, G
中科院分区：
文献类型：
--
作者：
Yin, L;Al-Alem, U;Romeo, G
X-连锁淋巴组织增生性疾病的特征是暴露于EB病毒（EBV）时免疫失调和不受控制的淋巴组织增生。这种疾病归因于SAP基因（也称为SH 2D 1A或DSHP）的突变。为了阐明SAP在X连锁淋巴组织增生性疾病的病理生理学中的作用，通过删除该基因的外显子2产生了SAP缺陷小鼠品系。在感染与EBV同源的鼠γ疱疹病毒-68后，突变小鼠与野生型同窝小鼠相比表现出更活跃的CD 8（+）T细胞增殖和更多的播散性淋巴细胞浸润。慢性组织损伤和噬血作用在sap缺陷小鼠中明显，但在其野生型同窝出生的小鼠中不明显。一致地，在SAP缺陷小鼠中观察到鼠γ疱疹病毒-68再活化，表明病毒控制受损。值得注意的是，在小鼠γ疱疹病毒-68感染之前和之后，在突变小鼠中观察到IgE缺乏和血清IgG水平降低，其在X连锁淋巴组织增生性疾病患者中再现低丙种球蛋白血症。因此，这种小鼠模型将是一个有用的工具，解剖的各种表型的X-连锁淋巴组织增生性疾病。
X-linked lymphoproliferative disease is characterized by immune dysregulation and uncontrolled lymphoproliferation on exposure to Epstein-Barr virus (EBV). This disease has been attributed to mutations in the SAP gene (also denominated as SH2D1A or DSHP). To delineate the role of SAP in the pathophysiology of X-linked lymphoproliferative disease, a strain of sap-deficient mice has been generated by deleting exon 2 of the gene. After infection with murine gammaherpesvirus-68, which is homologous to EBV, the mutant mice exhibit more vigorous CD8(+) T cell proliferation and more disseminated lymphocyte infiltration compared to their wild-type littermates. Chronic tissue damage and hemophagocytosis were evident in sap-deficient mice but not in their wild-type littermates. Concordantly, murine gammaherpesvirus-68 reactivation was observed in sap-deficient mice, indicating an impaired control of the virus. Notably, IgE deficiency and decreased serum IgG level were observed in mutant mice prior to and after murine gammaherpesvirus-68 infection, which reproduces hypogammaglobulinemia in X-linked lymphoproliferative disease patients. This mouse model will therefore be a useful tool for dissecting the various phenotypes of X-linked lymphoproliferative disease.