title: Hypogammaglobulinemia and exacerbated CD8 T-cell-mediated immunopathology in SAP-deficient mice with chronic LCMV infection mimics human XLP disease.
abstract: The human genetic disease X-linked lymphoproliferative disease (XLP), which is caused by mutations in SH2D1A/SAP that encode SLAM-associated protein (SAP), is characterized by an inability to control Epstein-Barr virus (EBV) and hypogammaglobulinemia. It is unclear which aspects of XLP disease are specific to herpesvirus infection and which reflect general immunologic functions performed by SAP. We examined SAP- mice during a chronic LCMV infection, specifically to address the following question: Which SAP deficiency immunologic problems are general, and which are EBV specific? Illness, weight loss, and prolonged viral replication were much more severe in SAP- mice. Aggressive immunopathology was observed. This inability to control chronic LCMV was associated with both CD8 T-cell and B-cell response defects. Importantly, we demonstrate that SAP- CD8 T cells are the primary cause of the immunopathology and clinical illness, because depletion of CD8 T cells blocked disease. This is the first direct demonstration of SAP- CD8 T-cell-mediated immunopathology, confirming 30 years of XLP clinical observations and indirect experimentation. In addition, germinal center formation was extremely defective in chronically infected SAP- animals, and hypogammaglobulinemia was observed. These findings in a chronic viral infection mouse model recapitulate key features of human XLP and clarify SAP's critical role regulating both cellular and humoral immunity.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA. shane@liai.org
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
authors.forename: Megan M
authors.initials: MM
authors.lastname: McCausland
authors.forename: Rachael D
authors.initials: RD
authors.lastname: Aubert
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000361:Agammaglobulinemia / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D007239:Infections / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013601:T-Lymphocytes / Q000276:immunology; D019562:Viral Load
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein