Follicular Dendritic Cell Activation by TLR Ligands Promotes Autoreactive B Cell Responses.
Follicular Dendritic Cell Activation by TLR Ligands Promotes Autoreactive B Cell Responses.
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DOI：
10.1016/j.immuni.2016.12.014
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发表时间：
2017-01-17
期刊：
影响因子：
32.4
通讯作者：
Carroll MC
中科院分区：
文献类型：
--
作者：
Das A;Heesters BA;Bialas A;O'Flynn J;Rifkin IR;Ochando J;Mittereder N;Carlesso G;Herbst R;Carroll MC
狼疮鼠模型中自身免疫的标志是在淋巴组织中形成生发中心（GC），其中自身反应性B细胞扩增和分化。在宿主对外源抗原的应答中，滤泡树突状细胞（FDC）通过其补体调理免疫复合物的摄取和循环对GC的维持至关重要。然而，FDCs是否保留自身抗原并为自身反应性GC维持和自身抗体分泌所需尚不清楚。在这里，我们确定是否FDCs所需的成熟的自我反应B细胞的生存和分化的GC使用狼疮易感小鼠。我们发现，FDCs采取和保留的核糖核苷酸蛋白（RNP），自身抗体和补体组成的自身免疫复合物（称为RNP-IC）。这种通过CD 21介导的摄取触发了内体TLR 7，导致IFNα通过IRF 5依赖性途径分泌。阻断狼疮小鼠FDC分泌IFNα可恢复B细胞耐受性，并显著减少GC和致病性自身抗体的数量。因此，在该狼疮模型中，FDC是IFNα驱动自身免疫的关键功能来源。该途径在人类中是保守的，这表明它可能是人类狼疮的可行治疗靶点。
A hallmark of autoimmunity in murine models of lupus is the formation of germinal centers (GC) in lymphoid tissues where self-reactive B cells expand and differentiate. In the host response to foreign antigens, follicular dendritic cells (FDCs) are essential for the maintenance of GCs through their uptake and cycling of complement-opsonized immune complexes. Yet, whether FDCs retain self-antigens and are required for self-reactive GC maintenance and autoantibody secretion is not well understood. Here, we determined if FDCs were required for the survival of mature self-reactive B cells and their differentiation in the GC using lupus-prone mice. We found that FDCs took up and retained self-immune complexes composed of ribonucleotide proteins (RNP), autoantibody, and complement (referred to as RNP-IC). This uptake, which was mediated through CD21, triggered endosomal TLR7, leading to the secretion of IFNα via an IRF5-dependent pathway. Blocking of FDC secretion of IFNα in lupus mice restored B cell tolerance, with a significant reduction in the amount of GCs and pathogenic autoantibody. Thus, FDCs are a critical functional source of the IFNα driving autoimmunity in this lupus model. This pathway is conserved in humans, suggesting that it may be a viable therapeutic target in human lupus.
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