title: WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity.
abstract: Patients with the immunodeficiency Wiskott-Aldrich syndrome (WAS) frequently develop systemic autoimmunity. Here, we demonstrate that mutation of the WAS gene results in B cells that are hyperresponsive to B cell receptor and Toll-like receptor (TLR) signals in vitro, thereby promoting a B cell-intrinsic break in tolerance. Whereas this defect leads to autoantibody production in WAS protein-deficient (WASp(-/-)) mice without overt disease, chimeric mice in which only the B cell lineage lacks WASp exhibit severe autoimmunity characterized by spontaneous germinal center formation, class-switched autoantibodies, renal histopathology, and early mortality. Both T cell help and B cell-intrinsic TLR engagement play important roles in promoting disease in this model, as depletion with anti-CD4 antibodies or generation of chimeric mice with B cells deficient in both WASp and MyD88 prevented development of autoimmune disease. These data highlight the potentially harmful role for cell-intrinsic loss of B cell tolerance in the setting of normal T cell function, and may explain why WAS patients with mixed chimerism after stem cell transplantation often develop severe humoral autoimmunity.
authors.affiliation: Department of Pediatrics, University of Washington School of Medicine, Seattle, WA; Seattle Children’s Research Institute, Seattle, WA, USA.
authors.forename: Shirly
authors.initials: S
authors.lastname: Becker-Herman
authors.forename: Almut
authors.initials: A
authors.lastname: Meyer-Bahlburg
authors.forename: Marc A
authors.initials: MA
authors.lastname: Schwartz
authors.forename: Shaun W
authors.initials: SW
authors.lastname: Jackson
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Hudkins
authors.forename: Chaohong
authors.initials: C
authors.lastname: Liu
authors.forename: Blythe D
authors.initials: BD
authors.lastname: Sather
authors.forename: Socheath
authors.initials: S
authors.lastname: Khim
authors.forename: Denny
authors.initials: D
authors.lastname: Liggitt
authors.forename: Wenxia
authors.initials: W
authors.lastname: Song
authors.forename: Gregg J
authors.initials: GJ
authors.lastname: Silverman
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002678:Chimera; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency* / Q000235:genetics
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011947:Receptors, Antigen, B-Cell; D051193:Toll-Like Receptors; D051316:Wiskott-Aldrich Syndrome Protein