Sanquin Research and Landsteiner Laboratory, Department of Experimental Immunohematology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Front Immunol. 2021 Mar 15;12:594773. doi: 10.3389/fimmu.2021.594773. eCollection 2021.
Antibody-mediated blood disorders ensue after auto- or alloimmunization against blood cell antigens, resulting in cytopenia. Although the mechanisms of cell destruction are the same as in immunotherapies targeting tumor cells, many factors are still unknown. Antibody titers, for example, often do not strictly correlate with clinical outcome. Previously, we found C-reactive protein (CRP) levels to be elevated in thrombocytopenic patients, correlating with thrombocyte counts, and bleeding severity. Functionally, CRP amplified antibody-mediated phagocytosis of thrombocytes by phagocytes. To investigate whether CRP is a general enhancer of IgG-mediated target cell destruction, we extensively studied the effect of CRP on IgG-Fc receptor (FcγR)-mediated cell destruction: through respiratory burst, phagocytosis, and cellular cytotoxicity by a variety of effector cells. We now demonstrate that CRP also enhances IgG-mediated effector functions toward opsonized erythrocytes, in particular by activated neutrophils. We performed a first-of-a-kind profiling of CRP binding to all human FcγRs and IgA-Fc receptor I (FcαRI) using a surface plasmon resonance array. CRP bound these receptors with relative affinities of FcγRIa = FcγRIIa/b = FcγRIIIa > FcγRIIIb = FcαRI. Furthermore, FcγR blocking (in particular FcγRIa) abrogated CRP's ability to amplify IgG-mediated neutrophil effector functions toward opsonized erythrocytes. Finally, we observed that CRP also amplified killing of breast-cancer tumor cell line SKBR3 by neutrophils through anti-Her2 (trastuzumab). Altogether, we provide for the first time evidence for the involvement of specific CRP-FcγR interactions in the exacerbation of IgG-mediated cellular destruction; a trait that should be further evaluated as potential therapeutic target e.g., for tumor eradication.
抗体介导的血液疾病继发于针对血细胞抗原的自身或同种免疫，导致细胞减少症。虽然细胞破坏的机制与针对肿瘤细胞的免疫疗法相同，但仍有许多因素未知。例如，抗体滴度通常与临床结果并不严格相关。以前，我们发现血小板减少症患者的 C 反应蛋白 (CRP) 水平升高，与血小板计数和出血严重程度相关。功能上，CRP 增强了吞噬细胞对血小板的抗体介导的吞噬作用。为了研究 CRP 是否是 IgG 介导的靶细胞破坏的一般增强剂，我们广泛研究了 CRP 对 IgG-Fc 受体 (FcγR) 介导的细胞破坏的影响：通过呼吸爆发、吞噬作用和各种效应细胞的细胞毒性。我们现在证明 CRP 还增强了 IgG 介导的针对调理红细胞的效应功能，特别是通过活化的中性粒细胞。我们使用表面等离子体共振阵列首次对 CRP 与人所有 FcγR 和 IgA-Fc 受体 I (FcαRI) 的结合进行了分析。CRP 与这些受体的相对亲和力为 FcγRIa = FcγRIIa/b = FcγRIIIa > FcγRIIIb = FcαRI。此外，FcγR 阻断（特别是 FcγRIa）消除了 CRP 增强 IgG 介导的中性粒细胞对调理红细胞的效应功能的能力。最后，我们观察到 CRP 还通过抗 Her2（曲妥珠单抗）增强了中性粒细胞对乳腺癌肿瘤细胞系 SKBR3 的杀伤作用。总的来说，我们首次提供了证据，证明特定的 CRP-FcγR 相互作用参与了 IgG 介导的细胞破坏的加剧；这一特征应进一步评估为潜在的治疗靶点，例如用于肿瘤消除。
