title: Molecular pathogenesis of EBV susceptibility in XLP as revealed by analysis of female carriers with heterozygous expression of SAP.
abstract: X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency caused by mutations in SH2D1A which encodes SAP. SAP functions in signalling pathways elicited by the SLAM family of leukocyte receptors. A defining feature of XLP is exquisite sensitivity to infection with EBV, a B-lymphotropic virus, but not other viruses. Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved. We describe a novel approach to this question using female XLP carriers who, due to random X-inactivation, contain both SAP(+) and SAP(-) cells. This represents the human equivalent of a mixed bone marrow chimera in mice. While memory CD8(+) T cells specific for CMV and influenza were distributed across SAP(+) and SAP(-) populations, EBV-specific cells were exclusively SAP(+). The preferential recruitment of SAP(+) cells by EBV reflected the tropism of EBV for B cells, and the requirement for SAP expression in CD8(+) T cells for them to respond to Ag-presentation by B cells, but not other cell types. The inability of SAP(-) clones to respond to Ag-presenting B cells was overcome by blocking the SLAM receptors NTB-A and 2B4, while ectopic expression of NTB-A on fibroblasts inhibited cytotoxicity of SAP(-) CD8(+) T cells, thereby demonstrating that SLAM receptors acquire inhibitory function in the absence of SAP. The innovative XLP carrier model allowed us to unravel the mechanisms underlying the unique susceptibility of XLP patients to EBV infection in the absence of a relevant animal model. We found that this reflected the nature of the Ag-presenting cell, rather than EBV itself. Our data also identified a pathological signalling pathway that could be targeted to treat patients with severe EBV infection. This system may allow the study of other human diseases where heterozygous gene expression from random X-chromosome inactivation can be exploited.
authors: Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors: Umaimainthan
authors: U
authors: Palendira
authors: Carol
authors: C
authors: Low
authors: Anna
authors: A
authors: Chan
authors: Andrew D
authors: AD
authors: Hislop
authors: Edwin
authors: E
authors: Ho
authors: Tri Giang
authors: TG
authors: Phan
authors: Elissa
authors: E
authors: Deenick
authors: Matthew C
authors: MC
authors: Cook
authors: D Sean
authors: DS
authors: Riminton
authors: Sharon
authors: S
authors: Choo
authors: Richard
authors: R
authors: Loh
authors: Frank
authors: F
authors: Alvaro
authors: Claire
authors: C
authors: Booth
authors: H Bobby
authors: HB
authors: Gaspar
authors: Alessandro
authors: A
authors: Moretta
authors: Rajiv
authors: R
authors: Khanna
authors: Alan B
authors: AB
authors: Rickinson
authors: Stuart G
authors: SG
authors: Tangye
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D001402:B-Lymphocytes / Q000473:pathology / Q000821:virology; D000071178:CD48 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D005260:Female; D005838:Genotype; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D017578:Immunoglobulin Class Switching; D007251:Influenza, Human / Q000276:immunology / Q000821:virology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000821:virology; D009975:Orthomyxoviridae / Q000276:immunology / Q000472:pathogenicity; D011956:Receptors, Cell Surface / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D049951:X Chromosome Inactivation
chemical_list: D015703:Antigens, CD; C084093:CD244 protein, human; D000071178:CD48 Antigen; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C114953:SH2D1A protein, human; C000604060:SLAMF6 protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; C000604063:Slamf6 protein, mouse; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1