title: Mice deficient in the X-linked lymphoproliferative disease gene sap exhibit increased susceptibility to murine gammaherpesvirus-68 and hypo-gammaglobulinemia.
abstract: 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 hypo-gammaglobulinemia 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.
authors.affiliation: Unit of Genetic Cancer Susceptibility, International Agency for Research on Cancer, 150 cours Albert-Thomas, 69372 Lyon Cedex 08, France. yin@iarc.fr
authors.forename: Luo
authors.initials: L
authors.lastname: Yin
authors.forename: Umaima
authors.initials: U
authors.lastname: Al-Alem
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Tong
authors.forename: Cuiling
authors.initials: C
authors.lastname: Li
authors.forename: Manuela
authors.initials: M
authors.lastname: Badiali
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Médard
authors.forename: Janos
authors.initials: J
authors.lastname: Sumegi
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
mesh_terms: D000361:Agammaglobulinemia / Q000235:genetics*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004195:Disease Models, Animal; D018142:Gammaherpesvirinae / Q000472:pathogenicity*; D017353:Gene Deletion; D006566:Herpesviridae Infections / Q000235:genetics / Q000473:pathology / Q000821:virology; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013601:T-Lymphocytes / Q000276:immunology; D014775:Virus Activation
chemical_list: D002352:Carrier Proteins; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; C114953:SH2D1A protein, human; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein