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Blood, 1 November 2006, Vol. 108, No. 9, pp. 3085-3093. Prepublished online as a Blood First Edition Paper on June 20, 2006; DOI 10.1182/blood-2006-04-018929. This Article Full Text Full Text (PDF) Supplementary Figure All Versions of this Article: blood-2006-04-018929v1 108/9/3085    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Crotty, S. Articles by Ahmed, R. Search for Related Content PubMed PubMed Citation Articles by Crotty, S. Articles by Ahmed, R. Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Hypogammaglobulinemia and exacerbated CD8 T-cell–mediated immunopathology in SAP-deficient mice with chronic LCMV infection mimics human XLP disease Shane Crotty, Megan M. McCausland, Rachael D. Aubert, E. John Wherry, and Rafi Ahmed From the Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, San Diego, CA; Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA; and The Wistar Institute, Philadelphia, PA. 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. G. Evans, J. M. Moser, L. T. Krug, V. Pozharskaya, A. L. Mora, and S. H. Speck A gammaherpesvirus-secreted activator of V{beta}4+ CD8+ T cells regulates chronic infection and immunopathology J. Exp. Med., March 17, 2008; 205(3): 669 - 684. [Abstract] [Full Text] [PDF] B. R. Mothe, B. S. Stewart, C. Oseroff, H.-H. Bui, S. Stogiera, Z. Garcia, C. Dow, M. P. Rodriguez-Carreno, M. Kotturi, V. Pasquetto, et al. Chronic Lymphocytic Choriomeningitis Virus Infection Actively Down-Regulates CD4+ T Cell Responses Directed against a Broad Range of Epitopes J. Immunol., July 15, 2007; 179(2): 1058 - 1067. [Abstract] [Full Text] [PDF] I.-J. Kim, C. E. Burkum, T. Cookenham, P. L. Schwartzberg, D. L. Woodland, and M. A. Blackman Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs J. Immunol., February 1, 2007; 178(3): 1692 - 1701. [Abstract] [Full Text] [PDF] M. M. McCausland, I. Yusuf, H. Tran, N. Ono, Y. Yanagi, and S. Crotty SAP Regulation of Follicular Helper CD4 T Cell Development and Humoral Immunity Is Independent of SLAM and Fyn Kinase J. Immunol., January 15, 2007; 178(2): 817 - 828. [Abstract] [Full Text] [PDF]

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