title: Systemic autoimmunity and defective Fas ligand secretion in the absence of the Wiskott-Aldrich syndrome protein.
abstract: Autoimmunity is a surprisingly common complication of primary immunodeficiencies, yet the molecular mechanisms underlying this clinical observation are not well understood. One widely known example is provided by Wiskott-Aldrich syndrome (WAS), an X-linked primary immunodeficiency disorder caused by mutations in the gene encoding the WAS protein (WASp) with a high incidence of autoimmunity in affected patients. WASp deficiency affects T-cell antigen receptor (TCR) signaling and T-cell cytokine production, but its role in TCR-induced apoptosis, one of the mechanisms of peripheral immunologic tolerance, has not been investigated. We find that WASp-deficient mice produce autoantibodies and develop proliferative glomerulonephritis with immune complex deposition as they age. We also find that CD4(+) T lymphocytes from WASp-deficient mice undergo reduced apoptosis after restimulation through the TCR. While Fas-induced cell death is normal, WASp deficiency affects TCR-induced secretion of Fas ligand (FasL) and other components of secretory granules by CD4(+) T cells. These results describe a novel role of WASp in regulating TCR-induced apoptosis and FasL secretion and suggest that WASp-deficient mice provide a good model for the study of autoimmune manifestations of WAS and the development of more specific therapies for these complications.
authors.affiliation: Office of the Clinical Director and.
authors.forename: Nikolay P
authors.initials: NP
authors.lastname: Nikolov
authors.forename: Masaki
authors.initials: M
authors.lastname: Shimizu
authors.forename: Sophia
authors.initials: S
authors.lastname: Cleland
authors.forename: Daniel
authors.initials: D
authors.lastname: Bailey
authors.forename: Joseph
authors.initials: J
authors.lastname: Aoki
authors.forename: Ted
authors.initials: T
authors.lastname: Strom
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Schwartzberg
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
authors.forename: Richard M
authors.initials: RM
authors.lastname: Siegel
mesh_terms: D000375:Aging / Q000276:immunology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000097:blood; D017209:Apoptosis / Q000276:immunology*; D001327:Autoimmune Diseases / Q000209:etiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003433:Crosses, Genetic; D003594:Cytoplasmic Granules / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism*; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology*; D007105:Immune Complex Diseases / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D000974:Antibodies, Antinuclear; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D011948:Receptors, Antigen, T-Cell; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein
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