title: Exacerbated experimental arthritis in Wiskott-Aldrich syndrome protein deficiency: modulatory role of regulatory B cells.
abstract: Patients deficient in the cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASp) are predisposed to varied autoimmunity, suggesting it has an important controlling role in participating cells. IL-10-producing regulatory B (Breg) cells are emerging as important mediators of immunosuppressive activity. In experimental, antigen-induced arthritis WASp-deficient (WASp knockout [WAS KO]) mice developed exacerbated disease associated with decreased Breg cells and regulatory T (Treg) cells, but increased Th17 cells in knee-draining LNs. Arthritic WAS KO mice showed increased serum levels of B-cell-activating factor, while their B cells were unresponsive in terms of B-cell-activating factor induced survival and IL-10 production. Adoptive transfer of WT Breg cells ameliorated arthritis in WAS KO recipients and restored a normal balance of Treg and Th17 cells. Mice with B-cell-restricted WASp deficiency, however, did not develop exacerbated arthritis, despite exhibiting reduced Breg- and Treg-cell numbers during active disease, and Th17 cells were not increased over equivalent WT levels. These findings support a contributory role for defective Breg cells in the development of WAS-related autoimmunity, but demonstrate that functional competence in other regulatory populations can be compensatory. A properly regulated cytoskeleton is therefore important for normal Breg-cell activity and complementation of defects in this lineage is likely to have important therapeutic benefits.
authors.affiliation: Molecular Immunology Unit, UCL Institute of Child Health, London, UK.
authors.forename: Gerben
authors.initials: G
authors.lastname: Bouma
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Carter
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.forename: Dessislava
authors.initials: D
authors.lastname: Malinova
authors.forename: Marsilio
authors.initials: M
authors.lastname: Adriani
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Siobhan O
authors.initials: SO
authors.lastname: Burns
authors.forename: Claudia
authors.initials: C
authors.lastname: Mauri
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000276:immunology*
chemical_list: C508609:IL10 protein, human; C556062:IL10 protein, mouse; C495767:WAS protein, human; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D016753:Interleukin-10
keywords: Arthritis; Immune regulation; Regulatory B cells; Regulatory T cell; Th17 cells; Wiskott-Aldrich syndrome protein