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PMID: 11404475 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 13 ·2001-06-19 ·Pages 7449-54

Czar MJ, Kersh EN, Mijares LA, Lanier G, Lewis J, Yap G, Chen A, Sher A, Duckett CS, Ahmed R, Schwartzberg PL

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.

MeSH Terms
Amino Acid Sequence Animals Carrier Proteins/genetics,physiology Cytokines/biosynthesis Humans Immunoglobulin E/blood Interferon-gamma/biosynthesis Interleukin-4/biosynthesis Intracellular Signaling Peptides and Proteins Lymphocytic Choriomeningitis/immunology Lymphocytic choriomeningitis virus Lymphoproliferative Disorders/genetics,immunology Mice Mice, Inbred Strains Mice, Knockout Molecular Sequence Data Peptide Fragments/chemistry,immunology Signaling Lymphocytic Activation Molecule Associated Protein Spleen/immunology T-Lymphocytes/immunology Toxoplasmosis/immunology X Chromosome
Chemicals
Carrier Proteins Cytokines Intracellular Signaling Peptides and Proteins Peptide Fragments SH2D1A protein, human Sh2d1a protein, mouse Signaling Lymphocytic Activation Molecule Associated Protein Interleukin-4 Immunoglobulin E Interferon-gamma
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Czar M J
National Human Genome Research Institute, National Cancer Institute, and National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.
Kersh E N
Mijares L A
Lanier G
Lewis J
Yap G
Chen A
Sher A
Duckett C S
Ahmed R
Schwartzberg P L
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.131193098
Published
2001-06-19
Epub
2001-00-12
Pages
7449-54
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC34689
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.131193098 PMC Full Text View journal details
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