B-cell intrinsic TLR7 signals promote depletion of the marginal zone in a murine model of Wiskott-Aldrich syndrome.
Eur J Immunol
; 45(10): 2773-9, 2015 Oct.
Article
em En
| MEDLINE
| ID: mdl-26256668
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Baço
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Síndrome de Wiskott-Aldrich
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Glicoproteínas de Membrana
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Linfócitos B
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Transdução de Sinais
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Receptor 7 Toll-Like
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Eur J Immunol
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos