Toll-like receptors in systemic autoimmune disease.
Toll-like receptors in systemic autoimmune disease.
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DOI：
10.1038/nri1957
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发表时间：
2006-11
期刊：
影响因子：
--
通讯作者：
Marshak-Rothstein A
中科院分区：
文献类型：
--
作者：
Marshak-Rothstein A
自体反应性B细胞在体外可被内源性DNA或RNA以及DNA或RNA结合蛋白有效激活，其机制依赖于B细胞受体和toll样受体7 （TLR7）和/或TLR9。I型干扰素（ifn）显著增加b细胞对rna相关自身抗原的反应。同样，TLR7和TLR9似乎在浆细胞样树突状细胞的激活中发挥重要作用，其机制依赖于IgG的低亲和力受体（FcγRIIa，也称为CD32），导致大量I型ifn的产生。遗传y染色体相关自身免疫加速器（Yaa）突变的小鼠表达的TLR7量是正常水平的两倍，并且对TLR7配体高度敏感。TLR7数量的增加可能解释了TLR7在这些小鼠自身免疫性疾病加速中的作用。tlr9缺陷的自身免疫易感性小鼠产生双链DNA或核小体特异性抗体的能力下降，但它们产生正常或增加的rna相关自身抗原特异性抗体的数量。然而，在一些系统性红斑狼疮动物模型中，TLR9缺乏可导致临床疾病恶化。tlr7缺陷的自身免疫易感性小鼠产生rna相关自身抗原特异性抗体的能力下降。与TLR9缺乏相反，TLR7缺乏不会导致临床疾病加重。除DNA和RNA外，其他从死亡或垂死细胞中释放或因组织损伤而释放的内源性TLR配体已被发现可促进或下调慢性炎症。toll样受体是众所周知的微生物传感器，但它们也可以感知内源性分子。本文描述了在全身性自身免疫性疾病中何时可能发生以及如何激活自身反应性B细胞和浆细胞样树突状细胞。toll样受体（TLRs）在病原体相关分子模式的早期检测和随后的适应性免疫反应激活中起着至关重要的作用。tlr是否在内源性配体的识别中也起着重要的作用，这一点一直存在争议。许多体外研究已经证明，哺乳动物TLR配体可以激活自身反应性B细胞和浆细胞样树突状细胞。这些体外观察结果是否转化为TLRs在体内的作用，在全身性自身免疫性疾病的发生或进展是一个激烈研究的主题；开始出现的数据表明情况确实如此。
Autoreactive B cells can be activated effectively in vitro by endogenous DNA or RNA, as well as by DNA- or RNA-binding proteins, through a mechanism that depends on the B-cell receptor and Toll-like receptor 7 (TLR7) and/or TLR9. B-cell responses to RNA-associated autoantigens are markedly increased by type I interferons (IFNs). Similarly, it seems that TLR7 and TLR9 have important roles in the activation of plasmacytoid dendritic cells, through a mechanism that depends on the low-affinity receptor for IgG (FcγRIIa; also known as CD32), leading to the production of large amounts of type I IFNs. Mice that inherit the Y-chromosome-linked autoimmune accelerator (Yaa) mutation express twice the normal amount of TLR7 and are hyper-responsive to TLR7 ligands. The increased amount of TLR7 might account for the role of TLR7 in the acceleration of autoimmune disease in these mice. TLR9-deficient autoimmune-prone mice have a decreased capacity to produce antibodies specific for double-stranded DNA or nucleosomes, but they produce normal or increased amounts of antibodies specific for RNA-associated autoantigens. Nevertheless, TLR9 deficiency can lead to exacerbation of clinical disease in some animal models of systemic lupus erythematosus. TLR7-deficient autoimmune-prone mice have a decreased capacity to produce antibodies specific for RNA-associated autoantigens. In contrast to TLR9 deficiency, TLR7 deficiency does not lead to exacerbated clinical disease. In addition to DNA and RNA, other endogenous TLR ligands that are released from dead or dying cells or are released as a result of tissue injury have been found either to promote or to downregulate chronic inflammatory conditions. Toll-like receptors are well known as sensors of microorganisms, but they can also sense endogenous molecules. This article describes when this might occur and how it might activate autoreactive B cells and plasmacytoid dendritic cells in systemic autoimmune disease. Toll-like receptors (TLRs) have a crucial role in the early detection of pathogen-associated molecular patterns and the subsequent activation of the adaptive immune response. Whether TLRs also have an important role in the recognition of endogenous ligands has been more controversial. Numerous in vitro studies have documented activation of both autoreactive B cells and plasmacytoid dendritic cells by mammalian TLR ligands. The issue of whether these in vitro observations translate to an in vivo role for TLRs in either the initiation or the progression of systemic autoimmune disease is a subject of intense research; data are beginning to emerge showing that this is the case.
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影响因子：
32.4
作者：
Berland, Robert;Fernandez, Luis;Imanishi-Kari, Thereza
通讯作者：
Imanishi-Kari, Thereza
影响因子：
4.4
作者：
Caricchio, R;McPhie, L;Cohen, PL
通讯作者：
Cohen, PL
Toll样受体9控制鼠狼疮中的抗DNA自身抗体产生。
DOI：
10.1084/jem.20050338
发表时间：
2005-07-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Christensen SR;Kashgarian M;Alexopoulou L;Flavell RA;Akira S;Shlomchik MJ
通讯作者：
Shlomchik MJ
DOI：
10.1084/jem.20021553
发表时间：
2003-03-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bennett L;Palucka AK;Arce E;Cantrell V;Borvak J;Banchereau J;Pascual V
通讯作者：
Pascual V
影响因子：
--
作者：
Andrade, F;Casciola-Rosen, LA;Rosen, A
通讯作者：
Rosen, A