Copenhagen Lupus and Vasculitis Clinic, Centre for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen University Hospital, Denmark.
Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
Autoimmun Rev. 2016 Jul;15(7):719-25. doi: 10.1016/j.autrev.2016.03.009. Epub 2016 Mar 9.
Immune complex (IC) deposition in the glomerular basement membrane (GBM) is a key early pathogenic event in lupus nephritis (LN). The clarification of the mechanisms behind IC deposition will enable targeted therapy in the future. Circulating cell-derived microparticles (MPs) have been proposed as major sources of extracellular autoantigens and ICs and triggers of autoimmunity in LN. The overabundance of galectin-3-binding protein (G3BP) along with immunoglobulins and a few other proteins specifically distinguish circulating MPs in patients with systemic lupus erythematosus (SLE), and this is most pronounced in patients with active LN. G3BP co-localizes with deposited ICs in renal biopsies from LN patients supporting a significant presence of MPs in the IC deposits. G3BP binds strongly to glomerular basement membrane proteins and integrins. Accordingly, MP surface proteins, especially G3BP, may be essential for the deposition of ICs in kidneys and thus for the ensuing formation of MP-derived electron dense structures in the GBM, and immune activation in LN. This review focuses on the notion of targeting surface molecules on MPs as an entirely novel treatment strategy in LN. By targeting MPs, a double hit may be achieved by attenuating both the autoantigenic fueling of immune complexes and the triggering of the adaptive immune system. Thereby, early pathogenic events may be blocked in contrast to current treatment strategies that primarily target and modulate later events in the cellular and humoral immune response.
免疫复合物（IC）在肾小球基底膜（GBM）中的沉积是狼疮性肾炎（LN）的早期关键致病事件。阐明 IC 沉积背后的机制将使未来能够进行靶向治疗。循环细胞衍生的微颗粒（MPs）已被提议作为细胞外自身抗原和 IC 的主要来源，以及 LN 中自身免疫的触发因素。与全身性红斑狼疮（SLE）患者的循环 MPs 相比，Galectin-3 结合蛋白（G3BP）与免疫球蛋白和其他几种蛋白质的过度表达明显区分开来，在活动性 LN 患者中最为明显。G3BP 与 LN 患者的肾活检中沉积的 IC 共定位，支持 MPs 在 IC 沉积中的大量存在。G3BP 与肾小球基底膜蛋白和整合素强烈结合。因此，MP 表面蛋白，特别是 G3BP，可能是 IC 在肾脏中沉积的必要条件，从而导致 GBM 中 MP 衍生的电子致密结构的形成以及 LN 中的免疫激活。这篇综述重点介绍了将 MPs 表面分子作为 LN 全新治疗策略的概念。通过靶向 MPs，可以通过减轻免疫复合物的自身抗原燃料和适应性免疫系统的触发来实现双重打击。因此，可以阻断早期发病事件，而当前的治疗策略主要针对和调节细胞和体液免疫反应中的后期事件。
