TLR9 promotes tolerance by restricting survival of anergic anti-DNA B cells, yet is also required for their activation.
TLR9 promotes tolerance by restricting survival of anergic anti-DNA B cells, yet is also required for their activation.
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DOI：
10.4049/jimmunol.1202115
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发表时间：
2013-02-15
期刊：
影响因子：
--
通讯作者：
Shlomchik MJ
中科院分区：
文献类型：
--
作者：
Nickerson KM;Christensen SR;Cullen JL;Meng W;Luning Prak ET;Shlomchik MJ
核酸反应性B细胞经常出现在骨髓中，但通过包括受体编辑、功能性无反应性和/或缺失的机制耐受。TLR 9是一种内体dsDNA的传感器，在体内既促进又调节全身性自身免疫，但其在自身免疫中明显矛盾的作用的确切性质仍不清楚。在此，我们在系统性红斑狼疮的自身免疫易感性MRL.Faslpr小鼠模型中使用3 H9抗DNA BCR转基因，确定了TLR 9有助于建立和破坏B细胞耐受的阶段。尽管TLR 9在骨髓中的B细胞发育期间被用于轻链编辑，但TLR 9限制外周中的抗DNA B细胞寿命，因此是致耐受性的。在缺乏TLR 9的情况下，抗DNA B细胞具有更长的寿命并在卵泡中积累，既不被激活也不被删除。这些细胞保留了无反应性细胞的一些特征，即它们具有升高的基础BCR信号传导，但受损的诱导反应并下调其细胞表面BCR表达。相反，当TLR 9-完整的无反应性B细胞聚集在T/B边界附近时，TLR 9-缺陷的抗DNA B细胞在整个卵泡中更加分散。尽管如此，在老年自身免疫易感动物中，抗DNA B细胞的自发外周活化及其通过滤泡外途径分化为AFC需要特异性在B细胞区室中的TLR 9表达。因此，TLR 9在调节抗DNA B细胞中具有自相矛盾的作用：它有助于清除自身反应性细胞的外周库，但也是其激活所必需的。
Nucleic acid reactive B cells frequently arise in the bone marrow but are tolerized by mechanisms including receptor editing, functional anergy, and/or deletion. TLR9, a sensor of endosomal dsDNA, both promotes and regulates systemic autoimmunity in vivo, but the precise nature of its apparently contradictory roles in autoimmunity remained unclear. Here, using the 3H9 anti-DNA BCR transgene in the autoimmune-prone MRL.Faslpr mouse model of systemic lupus erythematosus, we identify the stages at which TLR9 contributes to establishing and breaking B cell tolerance. Although TLR9 is dispensable for light chain editing during B cell development in the bone marrow, TLR9 limits anti-DNA B cell lifespan in the periphery and is thus tolerogenic. In the absence of TLR9, anti-DNA B cells have much longer lifespans and accumulate in the follicle, neither activated nor deleted. These cells retain some characteristics of anergic cells, in that they have elevated basal BCR signaling but impaired induced responses and downregulate their cell surface BCR expression. In contrast, while TLR9-intact anergic B cells accumulate near the T/B border, TLR9-deficient anti-DNA B cells are somewhat more dispersed throughout the follicle. Nonetheless, in older autoimmune-prone animals, TLR9 expression specifically within the B cell compartment is required for spontaneous peripheral activation of anti-DNA B cells and their differentiation into AFCs via an extrafollicular pathway. Thus, TLR9 has paradoxical roles in regulating anti-DNA B cells: it helps purge the peripheral repertoire of autoreactive cells yet is also required for their activation.
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影响因子：
32.4
作者：
Herlands, Robin A.;Christensen, Sean R.;Sweet, Rebecca A.;Hershberg, Uri;Shlomchik, Mark J.
通讯作者：
Shlomchik, Mark J.
通过VlambDax编辑抗DNA B细胞。
DOI：
10.1084/jem.20031712
发表时间：
2004-02-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li Y;Louzoun Y;Weigert M
通讯作者：
Weigert M
影响因子：
32.4
作者：
Isnardi I;Ng YS;Srdanovic I;Motaghedi R;Rudchenko S;von Bernuth H;Zhang SY;Puel A;Jouanguy E;Picard C;Garty BZ;Camcioglu Y;Doffinger R;Kumararatne D;Davies G;Gallin JI;Haraguchi S;Day NK;Casanova JL;Meffre E
通讯作者：
Meffre E
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
15.3
作者：
Mandik-Nayak, L;Seo, SJ;Erikson, J
通讯作者：
Erikson, J