Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers.
Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers.
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DOI：
10.4049/jimmunol.1700354
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发表时间：
2017-07-15
期刊：
影响因子：
--
通讯作者：
Anolik JH
中科院分区：
文献类型：
--
作者：
Bird AK;Chang M;Barnard J;Goldman BI;Meednu N;Rangel-Moreno J;Anolik JH
中性粒细胞被充分表征为狼疮周围组织损伤的介质，但仍不清楚它们是否影响适应性免疫区室的自我耐受性丧失。狼疮中性粒细胞会产生高水平的已知可促进自身抗体产生的因子，包括白细胞介素 6 和 B 细胞存活因子，以及可抑制淋巴细胞增殖的活性氧中间体。为了评估中性粒细胞是否直接影响次级淋巴器官（SLO）自身反应性的进展，我们在 NZB/W 狼疮小鼠模型中描述了脾中性粒细胞在疾病进展的几个阶段的定位和细胞间接触。在狼疮进展过程中，中性粒细胞在 SLO 中积累，在疾病早期优先定位于 T 淋巴细胞附近，在疾病晚期优先定位于 B 细胞附近。 RNA测序显示，脾脏中性粒细胞转录程序在疾病过程中发生显着变化，中性粒细胞抗炎介质的表达在疾病早期和中期达到峰值，并且有证据表明中性粒细胞在疾病晚期激活。为了评估中性粒细胞对体内 B 细胞自我耐受性的丧失是否主要发挥保护性或有害作用，我们在疾病的不同阶段耗尽了中性粒细胞。狼疮早期的中性粒细胞耗竭导致肾脏疾病的发病、SLO生发中心的形成和自身反应性浆细胞的产生显着加速。相比之下，中性粒细胞耗竭并导致更严重的疾病并没有改变 SLE 的进展。这些结果表明，中性粒细胞在抑制狼疮中自身反应性 B 细胞激活方面具有令人惊讶的时间和环境依赖性作用。
Neutrophils are well characterized as mediators of peripheral tissue damage in lupus, but it remains unclear whether they influence loss of self-tolerance in the adaptive immune compartment. Lupus neutrophils produce elevated levels of factors known to fuel autoantibody production, including interleukin-6 and B cell survival factors, but also reactive oxygen intermediates, which can suppress lymphocyte proliferation. In order to assess whether neutrophils directly influence the progression of auto-reactivity in secondary lymphoid organs (SLO), we characterized the localization and cell-cell contacts of splenic neutrophils at several stages in the progression of disease in the NZB/W murine model of lupus. Neutrophils accumulate in SLO over the course of lupus progression, preferentially localizing near T lymphocytes early in disease and B cells with advanced disease. RNA sequencing reveals that the splenic neutrophil transcriptional program changes significantly over the course of disease, with neutrophil expression of anti-inflammatory mediators peaking during early- and mid-stage disease, and evidence of neutrophil activation with advanced disease. To assess whether neutrophils exert predominantly protective or deleterious effects on loss of B cell self-tolerance in vivo, we depleted neutrophils at different stages of disease. Neutrophil depletion early in lupus resulted in a striking acceleration in the onset of renal disease, SLO germinal center formation, and auto-reactive plasma cell production. In contrast, neutrophil depletion with more advanced disease did not alter SLE progression. These results demonstrate a surprising temporal and context dependent role for neutrophils in restraining auto-reactive B cell activation in lupus.
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DOI：
10.1084/jem.20151724
发表时间：
2016-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jackson SW;Jacobs HM;Arkatkar T;Dam EM;Scharping NE;Kolhatkar NS;Hou B;Buckner JH;Rawlings DJ
通讯作者：
Rawlings DJ
影响因子：
27.4
作者：
Knight JS;Subramanian V;O'Dell AA;Yalavarthi S;Zhao W;Smith CK;Hodgin JB;Thompson PR;Kaplan MJ
通讯作者：
Kaplan MJ
影响因子：
4.4
作者：
Kasagi, Shimpei;Kawano, Seiji;Kumagai, Shunichi
通讯作者：
Kumagai, Shunichi
影响因子：
4.4
作者：
Der, Evan;Dimo, Joana;Jorgensen, Trine N.
通讯作者：
Jorgensen, Trine N.
影响因子：
19.6
作者：
Dessing, Mark C.;Tammaro, Alessandra;Leemans, Jaklien C.
通讯作者：
Leemans, Jaklien C.