Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation.
Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation.
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DOI：
10.4049/jimmunol.1400098
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发表时间：
2014-05-15
期刊：
影响因子：
--
通讯作者：
Rawlings DJ
中科院分区：
文献类型：
--
作者：
Jackson SW;Scharping NE;Kolhatkar NS;Khim S;Schwartz MA;Li QZ;Hudkins KL;Alpers CE;Liggitt D;Rawlings DJ
系统性红斑狼疮（SLE）是一种以自身抗体靶向核酸相关抗原为特征的多系统自身免疫性疾病。内体toll样受体TLR7和TLR9分别对产生靶向RNA或dna相关抗原的抗体至关重要。在小鼠狼疮模型中，TLR7的缺失限制了自身免疫性炎症，而TLR9的缺失则加剧了疾病。究竟是B细胞还是髓细胞TLR7/TLR9信号通路导致了这些影响，目前还没有得到充分的解释。在此，我们利用嵌合策略在平行狼疮模型中评估B细胞内在缺失TLR7和TLR9的影响。我们证明，B细胞固有的TLR7缺失阻止了rna相关的Ab形成，减少了针对非核抗原的类转换抗体的产生，并限制了全身自身免疫。相比之下，B细胞内禀TLR9缺失导致dna反应性抗体减少，但针对广泛的全身自身抗原的抗体增加。此外，我们证明，尽管髓系室中TLR信号完整，但b -内在TLR9缺失导致全身性炎症和免疫复合物（IC）肾小球肾炎增加。这些数据强调了失调的B细胞内在TLR信号在SLE发病机制中的关键重要性。
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by autoantibodies targeting nucleic acid-associated antigens. The endosomal toll-like receptors TLR7 and TLR9 are critical for generation of Abs targeting RNA- or DNA-associated antigens, respectively. In murine lupus models, deletion of TLR7 limits autoimmune inflammation, while deletion of TLR9 exacerbates disease. Whether B cell or myeloid TLR7/TLR9 signaling is responsible for these effects has not been fully addressed. Here, we utilize a chimeric strategy to evaluate the effect of B cell-intrinsic deletion of TLR7 vs. TLR9 in parallel lupus models. We demonstrate that B cell-intrinsic TLR7 deletion prevents RNA-associated Ab formation, decreases production of class-switched Abs targeting non-nuclear antigens and limits systemic autoimmunity. In contrast, B cell-intrinsic TLR9 deletion results in decreased DNA-reactive Ab, but increased Abs targeting a broad range of systemic autoantigens. Further, we demonstrate that B-intrinsic TLR9 deletion results in increased systemic inflammation and immune-complex (IC) glomerulonephritis despite intact TLR signaling within the myeloid compartment. These data stress the critical importance of dysregulated B cell-intrinsic TLR signaling in the pathogenesis of SLE.
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DOI：
10.4049/jimmunol.1202195
发表时间：
2012-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hwang SH;Lee H;Yamamoto M;Jones LA;Dayalan J;Hopkins R;Zhou XJ;Yarovinsky F;Connolly JE;Curotto de Lafaille MA;Wakeland EK;Fairhurst AM
通讯作者：
Fairhurst AM
DOI：
10.4049/jimmunol.1202986
发表时间：
2013-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Koh YT;Scatizzi JC;Gahan JD;Lawson BR;Baccala R;Pollard KM;Beutler BA;Theofilopoulos AN;Kono DH
通讯作者：
Kono DH
影响因子：
7
作者：
Shlomchik MJ
通讯作者：
Shlomchik MJ
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：
20.3
作者：
Hao, Yi;O'Neill, Patrick;Cancro, Michael P.
通讯作者：
Cancro, Michael P.