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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cytokines / biosynthesis*
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Humans
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Immunoglobulin E / blood
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Interferon-gamma / biosynthesis
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Interleukin-4 / biosynthesis
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Intracellular Signaling Peptides and Proteins*
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Lymphocytic Choriomeningitis / immunology
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Lymphocytic choriomeningitis virus
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Lymphoproliferative Disorders / genetics*
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Lymphoproliferative Disorders / immunology*
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Mice
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Mice, Inbred Strains
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Mice, Knockout
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Molecular Sequence Data
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Peptide Fragments / chemistry
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Peptide Fragments / immunology
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Signaling Lymphocytic Activation Molecule Associated Protein
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Spleen / immunology
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T-Lymphocytes / immunology*
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Toxoplasmosis / immunology
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X Chromosome
Substances
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Carrier Proteins
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Cytokines
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Intracellular Signaling Peptides and Proteins
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Peptide Fragments
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SH2D1A protein, human
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Sh2d1a protein, mouse
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Signaling Lymphocytic Activation Molecule Associated Protein
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Interleukin-4
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Immunoglobulin E
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Interferon-gamma