title: Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production.
abstract: T cells from patients with systemic lupus erythematosus (SLE) display a number of abnormalities, including increased early signaling events following engagement of the TCR. Signaling lymphocytic activation molecule family cell surface receptors and the X-chromosome-defined signaling lymphocytic activation molecule-associated protein (SAP) adaptor are important in the development of several immunocyte lineages and modulating the immune response. We present evidence that SAP protein levels are decreased in T cells and in their main subsets isolated from 32 women and three men with SLE, independent of disease activity. In SLE T cells, SAP protein is also subject to increased degradation by caspase-3. Forced expression of SAP in SLE T cells normalized IL-2 production, calcium (Ca(2+)) responses, and tyrosine phosphorylation of a number of proteins. Exposure of normal T cells to SLE serum IgG, known to contain anti-CD3/TCR Abs, resulted in SAP downregulation. We conclude that SLE T cells display reduced levels of the adaptor protein SAP, probably as a result of continuous T cell activation and degradation by caspase-3. Restoration of SAP levels in SLE T cells corrects the overexcitable lupus T cell phenotype.
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Maria P
authors.initials: MP
authors.lastname: Karampetsou
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; Service d'Immunologie et Allergie, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland; and.
authors.forename: Denis
authors.initials: D
authors.lastname: Comte
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Katalin
authors.initials: K
authors.lastname: Kis-Toth
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; gtsokos@bidmc.harvard.edu.
authors.forename: George C
authors.identifier: 0000-0001-9589-2360
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein / Q000235:genetics / Q000378:metabolism*; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D055815:Young Adult
chemical_list: D007074:Immunoglobulin G; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D014443:Tyrosine; D053148:Caspase 3; D002118:Calcium