Lysosome Defects and the Accumulation of Immune Complexes in Human Lupus

尽管系统性红斑狼疮（SLE）涉及多个基因、分子事件和细胞类型， 细胞凋亡碎片及其形成免疫复合物（IgG-IC）被认为是重要的发病和/或 疾病的延续。我们已发表的研究表明，高水平的IgG-IC积累在表面上， SLE中人和鼠造血细胞。在小鼠骨髓细胞上，这是由于 溶酶体酸化防止FcgR结合的IgG-1C降解。未降解的IgG-IC再循环至 细胞表面，在那里它们积累并促进慢性FcgR信号传导。未降解IgG-IC的蓄积 在吞噬体中，诱导吞噬体膜通透性，这使得IgG和核抗原泄漏 进入胞质溶胶，随后激活胞质溶胶传感器并诱导IFNa产生。使用FcgRI缺陷型 我们发现MRL/lpr小鼠的核自身抗原积累减少，信号效应物的激活减少， 自身抗体产生减少（95%），BAFF水平降低（90%），FcgRI-/-/MRL/lpr小鼠未发生 肾脏疾病这些发现暗示溶酶体缺陷和FcgRI信号失调是重要的事件 在SLE中位于多种病理的上游。 初步数据显示，减少的溶酶体酸化是由PI 3 k/mTOR或其上游的事件诱导的。 识别慢性PI 3 k激活和溶酶体酸化减少之间的前馈回路。我们表明 SHIP 1在溶酶体功能障碍中是不可或缺的，并且FcgRI与FcgRIIb的交联（SHIP 1偶联的 受体）恢复溶酶体酸化并减少PI 3 k信号传导。初步 对单核细胞和B细胞的人体研究表明，溶酶体功能障碍在活性的，但不是非活性的， SLE。我们假设，溶酶体功能障碍和涉及FcgRI/RIIa激活的前馈环是 人SLE，其中溶酶体降解水平反映疾病活性。因此，我们建议， 溶酶体功能导致表面IgG-IC的积累，其触发活动性疾病。在目标1和2中， 横断面研究将评估溶酶体功能状态是否反映疾病活动，以及是否 人SLE中溶酶体缺陷的潜在机制与小鼠中的机制相似。在目标3中，纵向 研究将通过活动性和非活动性疾病分析个体SLE患者，以评估溶酶体是否 功能障碍随着疾病复发和缓解而增加和减少。如果成功，这项研究将确定是否 溶酶体缺陷是人类SLE的基础，减弱前馈环是否能恢复溶酶体功能 在活动性疾病患者的细胞中。

Although multiple genes, molecular events, and cell types are implicated in systemic lupus erythematosus (SLE), apoptotic debris and its formation into immune complexes (IgG-ICs) is thought to be important in onset and/or perpetuation of disease. Our published studies show that high levels of IgG-ICs accumulate on the surface of human and murine hematopoietic cells in SLE. On murine myeloid cells, this is a consequence of diminished lysosome acidification that prevents degradation of FcgR-bound IgG-ICs. Undegraded IgG-ICs recycle to the cell surface where they accumulate and promote chronic FcgR signaling. Accumulation of undegraded IgG-ICs in the phagosome induces phagosomal membrane permeability, which allows IgG and nuclear antigens to leak into the cytosol, subsequently activating cytosolic sensors and inducing IFNa production. Using FcgRI-deficient MRL/lpr mice we found reduced accumulation of nuclear self-antigen, reduced activation of signaling effectors, reduced autoantibody production (95%), reduced BAFF levels (90%), and FcgRI-/-/MRL/lpr mice do not develop renal disease. These findings implicate lysosome defects and dysregulated FcgRI signaling as important events in SLE that lie upstream of multiple pathologies. Preliminary data show that diminished lysosome acidification is induced by events at, or upstream of, PI3k/mTOR identifying a feedforward loop between chronic PI3k activation and diminished lysosome acidification. We show that SHIP1 is integral in lysosome dysfunction, and that crosslinking FcgRI with FcgRIIb (a SHIP1 coupled receptor) on murine macrophages restores lysosome acidification and diminishes PI3k signaling. Preliminary human studies of monocytes and B cells show that lysosome dysfunction is evident in active, but not inactive, SLE. We hypothesize that lysosome dysfunction and a feedforward loop involving FcgRI/RIIa activation underlie human SLE, with the level of lysosome degradation reflecting disease activity. Thus, we propose that defects in lysosome function lead to the accumulation of surface IgG-ICs, which triggers active disease. In aims 1 and 2, cross-sectional studies will assess whether the state of lysosome function reflects disease activity, and whether the mechanisms underlying lysosome defects in human SLE are similar to those in mice. In aim 3, a longitudinal study will analyze individual SLE patients through active and inactive disease to assess whether lysosome dysfunction increases and decreases as disease relapses and remits. If successful, this study will define whether lysosome defects underlie human SLE, and whether attenuating the feedforward loop restores lysosome function in cells from patients with active disease.