Immune complex-directed cell migration: mechanisms and relevance

免疫球蛋白G （IgG）对抗微生物免疫防御很重要，可引起自身免疫性疾病，并成功地用于治疗目的。了解igg介导的免疫防御具有重要的医学和科学意义。我们研究了IgG免疫复合物（ICs）在诱导和定向非经典单核细胞迁移中的新作用。我们发表了通过低亲和力FcγRIII结合法从血液循环中诱导人slan+非经典单核细胞（slanMo）的局部血管募集，并证明这些细胞在早期ic诱导的狼疮性肾炎中是主要的促炎细胞类型。我们目前的研究表明，ic诱导slanMo迁移，并且ic的梯度诱导了一种强大的定向和定向迁移，相当于趋化因子诱导的细胞迁移。我们提出了一个ic定向细胞迁移的三步模型，首先是ic诱导的非经典单核细胞从血液募集到血管内膜，诱导沿内皮细胞爬行，当组织中ic的斜坡增加时转变为定向迁移。因此，在缺乏趋化因子和补体的情况下，ic似乎单独招募和引导第一波免疫细胞，这可能对控制血清阳性宿主的早期微生物感染或启动igg依赖性自身免疫炎症至关重要。通过我们的研究，我们将解决以下问题：1)ic诱导细胞迁移的分子和功能机制，2)允许ic诱导迁移的细胞及其特定需求，以及3)这些发现的体内相关性。我们将通过迁移细胞的转录组学研究，利用纳米结构表面作为迁移基质，以及研究配体脱离过程中的蛋白质水解机制来实现这些目标。此外，为了进行转化研究，我们将研究ic诱导的骨髓嵌合小鼠皮肤炎症。这些研究探索了IgG- ic在细胞募集中的功能作用，并增加了我们对IgG在免疫防御中的理解。我们的研究结果将为开发针对抑制ic驱动的自身免疫性疾病，刺激病原体特异性或癌症导向的免疫反应的治疗策略提供潜在的知识。

Immunoglobulin G (IgG) is important for the antimicrobial immune defense, can cause autoimmune diseases and is successfully used for therapeutic purposes. Understanding of the IgG-mediated immune defense is of great medical and scientific interest. We study the novel role of IgG immune complexes (ICs) in inducing and orienting the migration of non-classical monocytes. We published on the IC-induced local vascular recruitment of human slan+ nonclassical monocytes (slanMo) from blood circulation via low affinity FcγRIII ligation, and demonstrated that these cells serve as the dominant pro-inflammatory cell type in early IC-induced lupus nephritis. Our current studies demonstrate the induction of migration of slanMo by ICs and that gradients of ICs induce a strong directional and oriented migration equivalent to cell migration induced by chemokines. We propose a three-step model of IC-directed cell migration, starting with IC-induced nonclassical monocyte recruitment from blood to the vascular lining, the induction of crawling along the endothelium, turning into an oriented migration when sensing slopes of ICs ramping up in tissues. Thereby, in the absence of chemokines and complement, ICs alone appear to recruit and direct a first wave of immune cells that may prove essential for controlling early microbial infection in a seropositive host or for initiating IgG-dependent autoimmune inflammation. With our studies we will address the following: 1) the molecular and functional mechanisms of IC-induced cell migration, 2) the cells and their specific requirements to allow for IC-induced migration, and 3) the in vivo relevance of these findings. We will address these objectives by transcriptomic studies of migrating cells, by using nano-structured surfaces to be used as migration matrices and by studying proteolytic mechanisms during ligand disengagement. Furthermore, for translational studies we will investigate IC-induced skin inflammation in bone marrow chimeric mice.These studies explore the functional role of IgG-ICs in cell recruitment and add to our understanding of IgG in immune defense. Results of our studies will provide knowledge with the potential for developing treatment strategies aiming at inhibiting IC-driven autoimmune diseases, stimulating pathogen-specific or cancer-directed immune responses.