Kang SunAh, Rogers Jennifer L, Monteith Andrew J, Jiang Chuancang, Schmitz John, Clarke Stephen H, Tarrant Teresa K, Truong Young K, Diaz Marilyn, Fedoriw Yuri, Vilen Barbara J
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599;
Division of Rheumatology, Allergy, and Immunology, Thurston Arthritis Research Center, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599;
J Immunol. 2016 May 15;196(10):4030-9. doi: 10.4049/jimmunol.1500418. Epub 2016 Apr 8.
Apoptotic debris, autoantibody, and IgG-immune complexes (ICs) have long been implicated in the inflammation associated with systemic lupus erythematosus (SLE); however, it remains unclear whether they initiate immune-mediated events that promote disease. In this study, we show that PBMCs from SLE patients experiencing active disease, and hematopoietic cells from lupus-prone MRL/lpr and NZM2410 mice accumulate markedly elevated levels of surface-bound nuclear self-antigens. On dendritic cells (DCs) and macrophages (MFs), the self-antigens are part of IgG-ICs that promote FcγRI-mediated signal transduction. Accumulation of IgG-ICs is evident on ex vivo myeloid cells from MRL/lpr mice by 10 wk of age and steadily increases prior to lupus nephritis. IgG and FcγRI play a critical role in disease pathology. Passive transfer of pathogenic IgG into IgG-deficient MRL/lpr mice promotes the accumulation of IgG-ICs prior to significant B cell expansion, BAFF secretion, and lupus nephritis. In contrast, diminishing the burden IgG-ICs in MRL/lpr mice through deficiency in FcγRI markedly improves these lupus pathologies. Taken together, our findings reveal a previously unappreciated role for the cell surface accumulation of IgG-ICs in human and murine lupus.
凋亡碎片、自身抗体和IgG免疫复合物（ICs）长期以来一直被认为与系统性红斑狼疮（SLE）相关的炎症有关；然而，它们是否引发促进疾病的免疫介导事件仍不清楚。在本研究中，我们发现，处于疾病活动期的SLE患者的外周血单个核细胞（PBMCs），以及狼疮易感的MRL/lpr和NZM2410小鼠的造血细胞，其表面结合的核自身抗原水平显著升高。在树突状细胞（DCs）和巨噬细胞（MFs）上，自身抗原是促进FcγRI介导的信号转导的IgG-ICs的一部分。在10周龄时，MRL/lpr小鼠的离体髓样细胞上即可明显观察到IgG-ICs的积累，且在狼疮性肾炎发生之前持续增加。IgG和FcγRI在疾病病理过程中起关键作用。将致病性IgG被动转移到IgG缺陷的MRL/lpr小鼠中，可在显著的B细胞扩增、BAFF分泌和狼疮性肾炎发生之前促进IgG-ICs的积累。相反，通过FcγRI缺陷减少MRL/lpr小鼠体内IgG-ICs的负担，可显著改善这些狼疮病理表现。综上所述，我们的研究结果揭示了IgG-ICs在人和小鼠狼疮细胞表面积累中一个前所未有的作用。
