Sekine Hideharu, Kinser Ting Ting Hsieh, Qiao Fei, Martinez Efrain, Paulling Emily, Ruiz Phillip, Gilkeson Gary S, Tomlinson Stephen
Medical University of South Carolina, Charleston, SC, USA.
Arthritis Rheum. 2011 Apr;63(4):1076-85. doi: 10.1002/art.30222.
Complement has both protective and pathogenic functions in lupus due to a balance between its role in the clearance of immune complexes (ICs) and apoptotic cells and its role in inflammation. The classical pathway contributes to IC and apoptotic cell clearance, whereas the alternative pathway is a key mediator of renal inflammation. The aim of this study was to investigate the effect of a new targeted inhibitor of the alternative pathway, CR2-fH, on lupus-like renal disease in MRL/lpr mice.
Mice were treated with either saline, CR2-fH, CR2-Crry (which inhibits all complement pathways), or soluble CR2 (sCR2; C3d-binding targeting vehicle). Sera were analyzed every 2 weeks for autoantibodies, circulating ICs, and C3. Urinary excretion of albumin was also determined, and kidneys were collected at 23 weeks for histologic evaluation.
Treatment with CR2-fH or CR2-Crry improved survival and significantly reduced proteinuria, glomerular C3 deposition, and the level of circulating ICs. CR2-fH, but not CR2-Crry, also significantly reduced glomerulonephritis, expression of serum anti-double-stranded DNA (anti-dsDNA) antibodies, and glomerular IgG and C1q deposition. Interestingly, sCR2 also significantly reduced the levels of anti-dsDNA antibodies and circulating ICs and reduced glomerular deposition of IgG, C1q, and C3, although there was no significant reduction in glomerulonephritis, proteinuria, or mortality.
Targeted and selective inhibition of the alternative complement pathway is an effective treatment of murine lupus and is more effective than blockade of all pathways. The data demonstrate benefits to leaving the classical/lectin pathways intact and indicate distinct roles for the classical and alternative pathways of complement in disease progression. The sCR2-targeting vehicle contributes to therapeutic activity, possibly via modulation of autoimmunity.
由于补体在免疫复合物（ICs）和凋亡细胞清除中的作用与其在炎症中的作用之间的平衡，补体在狼疮中具有保护和致病双重功能。经典途径有助于ICs和凋亡细胞的清除，而替代途径是肾脏炎症的关键介质。本研究的目的是探讨一种新型替代途径靶向抑制剂CR2-fH对MRL/lpr小鼠狼疮样肾病的影响。
小鼠分别用生理盐水、CR2-fH、CR2-Crry（抑制所有补体途径）或可溶性CR2（sCR2；C3d结合靶向载体）治疗。每2周分析血清中的自身抗体、循环ICs和C3。还测定了尿白蛋白排泄量，并在23周时收集肾脏进行组织学评估。
用CR2-fH或CR2-Crry治疗可提高生存率，并显著降低蛋白尿、肾小球C3沉积和循环ICs水平。CR2-fH而非CR2-Crry还显著减轻了肾小球肾炎、血清抗双链DNA（抗dsDNA）抗体表达以及肾小球IgG和C1q沉积。有趣的是，sCR2也显著降低了抗dsDNA抗体水平和循环ICs，并减少了IgG、C1q和C3的肾小球沉积，尽管肾小球肾炎、蛋白尿或死亡率没有显著降低。
靶向和选择性抑制替代补体途径是治疗小鼠狼疮的有效方法，比阻断所有途径更有效。数据表明保留经典/凝集素途径完整有好处，并表明补体经典途径和替代途径在疾病进展中具有不同作用。sCR2靶向载体可能通过调节自身免疫发挥治疗作用。
