Altered Lymphocyte Responses and Cytokine Production in Mice Deficient in the X-Linked Lymphoproliferative Disease Gene SH2D1A/DSHP/SAP

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 o...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-06, Vol.98 (13), p.7449-7454
Main Authors: Czar, Michael J., Kersh, Ellen N., Mijares, Lilia A., Lanier, Gibson, Lewis, Jennifer, Yap, George, Chen, Amy, Sher, Alan, Duckett, Colin S., Ahmed, Rafi, Schwartzberg, Pamela L.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
B lymphocytes
Biological Sciences
Carrier Proteins - genetics
Carrier Proteins - physiology
Cytokines
Cytokines - biosynthesis
Disease
DSHP gene
g-Interferon
Genes
Genetic mutation
Humans
Immunoglobulin E - blood
Immunology
Infections
Interferon-gamma - biosynthesis
Interleukin-4 - biosynthesis
Intracellular Signaling Peptides and Proteins
Lymphocyte choriomeningitis virus
Lymphocytes
Lymphocytic Choriomeningitis - immunology
Lymphocytic choriomeningitis virus
Lymphoproliferative Disorders - genetics
Lymphoproliferative Disorders - immunology
Mice
Mice, Inbred Strains
Mice, Knockout
Molecular Sequence Data
Natural killer cells
Peptide Fragments - chemistry
Peptide Fragments - immunology
Phenotypes
Rodents
SAP gene
SH2D1A gene
Signaling Lymphocytic Activation Molecule Associated Protein
Spleen - immunology
Splenocytes
T lymphocytes
T-Lymphocytes - immunology
Toxoplasma gondii
Toxoplasmosis - immunology
X Chromosome
X-linked lymphoproliferative disease
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Description
Summary: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-γ production, as well as a reduction of Ig-secreting cells. Anti-CD3-stimulated splenocytes from uninfected SAP-mice produced increased IFN-γ 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.131193098