Immune complex-directed cell migration: mechanisms and relevance

免疫球蛋白G（IgG）是重要的抗菌免疫防御，可导致自身免疫性疾病，并成功地用于治疗目的。对IgG介导的免疫防御的理解具有极大的医学和科学兴趣。我们研究了IgG免疫复合物（IC）在诱导和定向非经典单核细胞迁移中的新作用。我们发表了关于通过低亲和力FcγRIII连接从血液循环中IC诱导局部血管募集人slan+非经典单核细胞（slanMo）的文章，并证明这些细胞在早期IC诱导的狼疮肾炎中是主要的促炎细胞类型。我们目前的研究表明，诱导的移民slanMo的IC和梯度的IC诱导一个强大的定向和定向迁移相当于细胞迁移诱导的趋化因子。我们提出了一个三步模型的IC导向的细胞迁移，从IC诱导的非经典单核细胞从血液中招募到血管内膜，诱导爬行沿着内皮，变成一个定向迁移时，感应斜坡的IC斜升组织。因此，在不存在趋化因子和补体的情况下，IC单独似乎募集和引导第一波免疫细胞，这可能证明对于控制血清阳性宿主中的早期微生物感染或对于启动IgG依赖性自身免疫炎症是必需的。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）细胞及其特定要求，以允许IC诱导的迁移，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，通过使用纳米结构表面作为迁移基质和通过研究配体脱离过程中的蛋白水解机制来解决这些目标。此外，在翻译研究方面，我们将研究IC诱导的骨髓嵌合小鼠皮肤炎症，这些研究探讨了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旨在抑制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.