Deficiency of Type I IFN Receptor in Lupus-Prone New Zealand Mixed 2328 Mice Decreases Dendritic Cell Numbers and Activation and Protects from Disease
Deficiency of Type I IFN Receptor in Lupus-Prone New Zealand Mixed 2328 Mice Decreases Dendritic Cell Numbers and Activation and Protects from Disease
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DOI：
10.4049/jimmunol.0803872
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发表时间：
2009-11-01
影响因子：
4.4
通讯作者：
Jacob, Chaim O.
中科院分区：
文献类型：
--
作者：
Agrawal, Hemant;Jacob, Noam;Jacob, Chaim O.
I型干扰素是天然免疫和获得性免疫的有效调节剂，与系统性红斑狼疮的发病机制有关。在这里，我们报告了新西兰混合型(NZM)2328只缺乏I型干扰素受体(IFNAR)的小鼠的临床和病理狼疮性肾炎和血清抗核抗体水平显著降低。为了确定NZM 2328小鼠体内的炎症环境是否导致IFNAR调节的树突状细胞(DC)的变化，比较了2个月和5个月大(临床健康)的雌性NZM和NZM-IFNAR(-/-)小鼠的DC亚群的数量、激活和功能。2个月龄NZM-IFNAR(-/-)小鼠肾淋巴结CD40(高)活化的浆细胞样树突状细胞(PDC)数量显著增加，提示PDC在发病部位存在早期依赖IFNAR的扩张和激活。与NZM脾相比，5个月龄小鼠的NZM-IFNAR(-/-)脾明显缩小，并含有数量减少的传统DC亚群，但不含PDC。直接体外分析的NZM-IFNAR(-/-)DC较NZM-DC表达CD40、CD86和PDL1显著减少。经合成的TLR9配体体外激活后，NZM-IFNAR(-/-)DC比NZM DC产生更少的IL-12p40/70和TNF-α。在老年小鼠中，IFNAR(-/-)DC对内源性激活刺激的有限反应与脾激活记忆CD4(+)T细胞和CD19(+)B细胞的数量减少有关。因此，IFNAR信号显著增加DC数量、获得抗原提呈能力和在临床上明显的狼疮发病前的促炎功能。免疫学杂志，2009,183：6021-6029。
Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR(-/-) mice. Numbers of activated CD40(high) plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZM-IFNAR(-/-) mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR(-/-) spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR(-/-) DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR(-/-) DC produced less IL-12p40/70 and TNF-alpha than did NZM DC. The limited IFNAR(-/-) DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4(+) T cells and CD19(+) B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease. The Journal of Immunology, 2009, 183: 6021-6029.