B-cell intrinsic TLR7 signals promote depletion of the marginal zone in a murine model of Wiskott-Aldrich syndrome.
B-cell intrinsic TLR7 signals promote depletion of the marginal zone in a murine model of Wiskott-Aldrich syndrome.
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DOI：
10.1002/eji.201545644
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发表时间：
2015-10
影响因子：
5.4
通讯作者：
Jackson SW
中科院分区：
文献类型：
--
作者：
Kolhatkar NS;Scharping NE;Sullivan JM;Jacobs HM;Schwartz MA;Khim S;Notarangelo LD;Thrasher AJ;Rawlings DJ;Jackson SW
患有Wiskott-Aldrich综合征（WAS）的患者表现出脾边缘区（MZ）的显著缺陷，导致异常的T细胞非依赖性抗体应答和增加的细菌感染。受影响基因WAS蛋白（WASp）的B细胞内在缺失显著减少了脾MZ B细胞，而不影响MZ B细胞发育的速率，表明MZ内的异常B细胞滞留导致WAS中的MZ缺陷。由于WASp调节整联蛋白依赖的肌动蛋白细胞骨架重排，我们以前假设有缺陷的B细胞整联蛋白功能促进MZ消耗。相比之下，我们现在报告说，B细胞内在删除的Toll样受体（TLR）信号转导接头MyD 88是足以恢复MZ在WAS。我们进一步确定TLR 7，内体单链RNA（ssRNA）受体，作为MyD 88依赖性受体负责WAS MZ消耗。这些发现表明，含ssRNA的自身配体（可能来源于循环凋亡物质）自发激活MZ B细胞是WAS中MZ耗竭的潜在机制。总之，这些数据表明，以前未被重视的作用，B细胞内在TLR信号在MZ稳态，相关的病原体反应和全身性自身免疫的发展。
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 toll-like receptor (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.