title: Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP.
abstract: We have introduced a targeted mutation in SH2D1A/DSHP/SAP, the gene responsible for the human genetic disorder X-linked lymphoproliferative disease (XLP). SLAM-associated protein (SAP)-deficient mice had normal lymphocyte development, but on challenge with infectious agents, recapitulated features of XLP. Infection of SAP- mice with lymphocyte choriomeningitis virus (LCMV) or Toxoplasma gondii was associated with increased T cell activation and IFN-gamma production, as well as a reduction of Ig-secreting cells. Anti-CD3-stimulated splenocytes from uninfected SAP- mice produced increased IFN-gamma and decreased IL-4, findings supported by decreased serum IgE levels in vivo. The Th1 skewing of these animals suggests that cytokine misregulation may contribute to phenotypes associated with mutation of SH2D1A/SAP.
authors.affiliation: National Human Genome Research Institute, National Cancer Institute, and National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Czar
authors.forename: E N
authors.initials: EN
authors.lastname: Kersh
authors.forename: L A
authors.initials: LA
authors.lastname: Mijares
authors.forename: G
authors.initials: G
authors.lastname: Lanier
authors.forename: J
authors.initials: J
authors.lastname: Lewis
authors.forename: G
authors.initials: G
authors.lastname: Yap
authors.forename: A
authors.initials: A
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Sher
authors.forename: C S
authors.initials: CS
authors.lastname: Duckett
authors.forename: R
authors.initials: R
authors.lastname: Ahmed
authors.forename: P L
authors.initials: PL
authors.lastname: Schwartzberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology; D014960:X Chromosome
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; C114953:SH2D1A protein, human; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma