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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 24, 2006 Accepted June 9, 2006 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 Division of Vaccine Discovery,La Jolla Institute for Allergy and Immunology (LIAI), CA, USA Emory Vaccine Center and Department of Microbiology and Immunology, Emory University,Atlanta,GA, USA The Wistar Institute, Philadelphia, PA, USA * Corresponding author; email: shane{at}liai.org. The human genetic disease XLP, caused by mutations in SH2D1A/SAP, encoding 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 immunological functions performed by SAP. We examined SAP- mice during a chronic LCMV infection, specifically to address the question: which SAP-deficiency immunological 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, as depletion of CD8 T cells blocked disease. This is the first direct demonstration of SAP- CD8 T cell mediated immunopathology, confirming thirty 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. A. Lin, P. K. Tripathi, A. Sholl, M. B. Jordan, and D. A. Hildeman Gamma Interferon Signaling in Macrophage Lineage Cells Regulates Central Nervous System Inflammation and Chemokine Production J. Virol., September 1, 2009; 83(17): 8604 - 8615. [Abstract] [Full Text] [PDF] N. Nagy, L. Matskova, L. L. Kis, U. Hellman, G. Klein, and E. Klein The proapoptotic function of SAP provides a clue to the clinical picture of X-linked lymphoproliferative disease PNAS, July 21, 2009; 106(29): 11966 - 11971. [Abstract] [Full Text] [PDF] S. Chaganti, C. S. Ma, A. I. Bell, D. Croom-Carter, A. D. Hislop, S. G. Tangye, and A. B. Rickinson Epstein-Barr virus persistence in the absence of conventional memory B cells: IgM+IgD+CD27+ B cells harbor the virus in X-linked lymphoproliferative disease patients Blood, August 1, 2008; 112(3): 672 - 679. [Abstract] [Full Text] [PDF] 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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