Functions of CD177 as a novel IgG Fc receptor

项目总结 抗体疗法成为治疗感染、癌症和炎症性疾病不可或缺的手段。 然而，抗体治疗的临床反应差异很大，抗体治疗的效果是 在病人身上很难预测。迄今为止，影响抗体治疗效果的遗传因素仍然存在。 不完全理解。几乎所有成功的治疗性抗体都是免疫球蛋白，这需要免疫球蛋白Fc受体。 (或FcγR)免疫细胞以诱导有效的免疫功能。FCγR是目标小区之间必不可少的链路 由治疗性抗体和效应器免疫细胞调理，负责杀死感染者和 免疫治疗中的异常细胞。人类使用许多Fcγ受体来调节独特的免疫细胞 功能和功能性FcγR基因变异显著影响免疫反应。在初步研究中， 我们发现人CD177与IgA特异性结合，提示CD177是一种免疫球蛋白Fc受体。 CD177在骨髓细胞中选择性表达，在骨髓细胞的增殖和分化中起作用 髓系细胞包括中性粒细胞、髓细胞、早幼粒细胞、巨核细胞和早期 红血球。CD177在循环白细胞中中性粒细胞上唯一表达，其百分比为 个体CD177+中性粒细胞百分率为0%~100%。值得注意的是，CD177缺乏是一种常见的疾病 表型为3-5%的人群完全缺乏CD177的表达。我们小组是第一个 阐明CD177缺乏的遗传机制和表达变异。CD177能够调解 中性粒细胞激活，但CD177的生理配体和免疫功能仍然知之甚少。 我们推测CD177是一种新的免疫球蛋白Fc受体，CD177的遗传变异显著 影响免疫球蛋白介导的免疫功能。拟议研究的理由/前提是 CD177作为新的功能性免疫球蛋白Fc受体，将填补有关人类全谱的关键知识空白 Fcγ受体，它们对抗体介导的反应是必不可少的。我们将通过以下方式测试我们的假设： 具体目标如下：1)检验CD177是一种新的免疫球蛋白Fc受体(FcγR)的假设；2)检验CD177是一种新的Ig G Fc受体 假设CD177基因变异影响人类免疫球蛋白和CD177之间的相互作用；以及3)测试 CD177影响免疫球蛋白免疫功能的假说。我们的研究将为 CD177介导的免疫功能及其反应变异性的遗传机制 抗体疗法。CD177在抗体治疗和疫苗接种中可能是有价值的生物标志物。

PROJECT SUMMARY Antibody therapy becomes indispensable for the treatment of infection, cancer, and inflammatory disease. Nevertheless, clinical responses to antibody therapy vary markedly and efficacies of antibody therapy are largely unpredictable in patients. To date, the genetic factors affecting the efficacy of antibody therapy remain incompletely understood. Almost all successful therapeutic antibodies are IgGs, which require IgG Fc receptors (or FcγRs) on immune cells to elicit effective immune functions. FcγRs are essential links between target cells opsonized by therapeutic antibodies and effector immune cells that are responsible for killing the infected and abnormal cells in immunotherapy. Humans use a number of FcγRs to mediate distinctive immune cellular functions and functional FcγR genetic variants significantly impact immune responses. In preliminary studies, we found that human CD177 specifically binds IgG but to IgA, suggesting that CD177 is an IgG Fc receptor. CD177 is selectively expressed in bone marrow cells and has a role in the proliferation and differentiation of myeloid lineage cells including neutrophils, myelocytes, promyelocytes, megakaryocytes, and early erythroblasts. CD177 is exclusive expressed on neutrophils among circulating leukocytes with the percentages of CD177+ neutrophils ranging from 0% to 100% in individuals. Notably, CD177 deficiency is a common phenotype as 3–5% human populations completely lack CD177 expression. Our group was the first to delineate genetic mechanisms of CD177 deficiency and expression variations. CD177 is able to mediate neutrophil activation, but the physiological ligands and immune functions of CD177 remain poorly understood. We hypothesize that CD177 is a novel IgG Fc receptor and that the CD177 genetic variants significantly affect IgG-mediated immune functions. The rationale/premise of the proposed study is that the definition of CD177 as novel functional IgG Fc-receptor will fill the critical knowledge gap about the full repertoire of human FcγRs, which are essential for antibody-mediated responses. We will test our hypothesis by pursuing the following Specific Aims: 1) to test the hypothesis that CD177 is a novel IgG Fc receptor (FcγR); 2) to test the hypothesis that CD177 genetic variants affect the interaction between human IgG and CD177; and 3) to test the hypothesis that CD177 affects IgG-mediated immune functions. Our study will provide novel insights into CD177-mediated immune functions and into the genetic mechanisms underlying response variability of antibody therapy. CD177 may serve as valuable biomarkers in antibody therapy and vaccinations.