Pawar Rahul D, Ramanjaneyulu Allam, Kulkarni Onkar P, Lech Maciej, Segerer Stephan, Anders Hans-Joachim
Medizinische Poliklinik, University of Munich, Pettenkoferstrasse 8a, 80336 Munich, Germany.
J Am Soc Nephrol. 2007 Jun;18(6):1721-31. doi: 10.1681/ASN.2006101162. Epub 2007 Apr 25.
Small nuclear RNA and associated lupus autoantigens activate B cells and dendritic cells via Toll-like receptor-7 (TLR-7); therefore, TLR-7 may represent a potential therapeutic target in lupus. MRL lpr mice were administered an injection of either saline or synthetic oligodeoxynucleotides with immunoregulatory sequences (IRS) that specifically block signaling via TLR-7 (IRS 661) or via TLR-7 and TLR-9 (IRS 954, which uses a active sequence from IRS 661 along with a TLR-9 inhibitory sequence) from weeks 11 to 24 of age. IRS 661 and IRS 954 both significantly reduced the weight of spleen and lymph nodes as well as serum levels of TNF as compared with saline-treated MRL lpr mice. Only IRS 661 but not IRS 954 significantly reduced serum levels of IL-12p40, anti-dsDNA IgG(2a), IgG(2b), and anti-Smith IgG. Both IRS localized to the kidney after intraperitoneal injection and significantly improved the activity index and chronicity index for lupus nephritis in MRL lpr mice. This was associated with significant reduction of renal glomerular and interstitial macrophage infiltrates and the number of interstitial T cells. Autoimmune lung injury was also attenuated with IRS 661 and IRS 954. These data demonstrate that TLR-7 antagonism, initiated after the onset of autoimmunity, can prevent autoimmune kidney and lung injury in MRL lpr mice. Concomitant blockade of TLR-9 with IRS 954 neutralized the effect of TLR-7 blockade on dsDNA IgG(2a), dsDNA IgG(2b), and Smith antigen autoantibodies but had neither additive nor opposing effects on autoimmune lung and kidney injury. Hence, TLR-7 is proposed as a novel and potential therapeutic target in systemic lupus erythematosus.
小核RNA及相关狼疮自身抗原通过Toll样受体7（TLR-7）激活B细胞和树突状细胞；因此，TLR-7可能是狼疮潜在的治疗靶点。在11至24周龄期间，给MRL lpr小鼠注射生理盐水或具有免疫调节序列（IRS）的合成寡脱氧核苷酸，该序列可特异性阻断通过TLR-7（IRS 661）或通过TLR-7和TLR-9（IRS 954，其使用来自IRS 661的活性序列以及TLR-9抑制序列）的信号传导。与生理盐水处理的MRL lpr小鼠相比，IRS 661和IRS 954均显著降低了脾脏和淋巴结的重量以及血清TNF水平。只有IRS 661而非IRS 954显著降低了血清IL-12p40、抗双链DNA IgG（2a）、IgG（2b）和抗史密斯IgG水平。腹腔注射后，两种IRS均定位于肾脏，并显著改善了MRL lpr小鼠狼疮性肾炎的活动指数和慢性指数。这与肾小球和间质巨噬细胞浸润以及间质T细胞数量的显著减少有关。IRS 661和IRS 954也减轻了自身免疫性肺损伤。这些数据表明，自身免疫发病后启动的TLR-7拮抗作用可预防MRL lpr小鼠的自身免疫性肾和肺损伤。用IRS 954同时阻断TLR-9可中和TLR-7阻断对双链DNA IgG（2a）、双链DNA IgG（2b）和史密斯抗原自身抗体的作用，但对自身免疫性肺和肾损伤既无相加作用也无拮抗作用。因此，TLR-7被认为是系统性红斑狼疮的一个新的潜在治疗靶点。
