title: B-cell intrinsic TLR7 signals promote depletion of the marginal zone in a murine model of Wiskott-Aldrich syndrome.
abstract: Patients with Wiskott-Aldrich syndrome (WAS) exhibit prominent defects in splenic marginal zone (MZ), resulting in abnormal T-cell-independent antibody responses and increased bacterial infections. B-cell-intrinsic deletion of the affected gene WAS protein (WASp) markedly reduces splenic MZ B cells, without impacting the rate of MZ B-cell development, suggesting that abnormal B-cell retention within the MZ accounts for MZ defects in WAS. Since WASp regulates integrin-dependent actin cytoskeletal rearrangement, we previously hypothesized that defective B-cell integrin function promotes MZ depletion. In contrast, we now report that B-cell-intrinsic deletion of the TLR signaling adaptor MyD88 is sufficient to restore the MZ in WAS. We further identify TLR7, an endosomal single-stranded RNA (ssRNA) receptor, as the MyD88-dependent receptor responsible for WAS MZ depletion. These findings implicate spontaneous activation of MZ B cells by ssRNA-containing self-ligands (likely derived from circulating apoptotic material) as the mechanism underlying MZ depletion in WAS. Together, these data suggest a previously unappreciated role for B-cell intrinsic TLR signals in MZ homeostasis, of relevance to both pathogen responses and to the development of systemic autoimmunity.
authors.affiliation: Seattle Children's Research Institute, Seattle, WA, USA.|Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Nikita S
authors.initials: NS
authors.lastname: Kolhatkar
authors.affiliation: Seattle Children's Research Institute, Seattle, WA, USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Scharping
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Sullivan
authors.affiliation: Seattle Children's Research Institute, Seattle, WA, USA.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Jacobs
authors.affiliation: Seattle Children's Research Institute, Seattle, WA, USA.|Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Schwartz
authors.affiliation: Seattle Children's Research Institute, Seattle, WA, USA.
authors.forename: Socheath
authors.initials: S
authors.lastname: Khim
authors.affiliation: Division of Immunology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Centre for Immunodeficiency, Molecular and Cellular Immunology, Institute of Child Health, University College London, London, UK.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.affiliation: Seattle Children's Research Institute, Seattle, WA, USA.|Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.|Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.affiliation: Seattle Children's Research Institute, Seattle, WA, USA.|Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Shaun W
authors.initials: SW
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003599:Cytoskeleton / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D016023:Integrins / Q000235:genetics / Q000276:immunology; D008212:Lymphocyte Depletion; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology*; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: D016023:Integrins; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7
keywords: B cells; Cell trafficking; Marginal zone; Toll-like receptors; Wiskott-Aldrich syndrome