Thrombopoietin receptor agonists shift the balance of Fcγ receptors toward inhibitory receptor IIb on monocytes in ITP
Thrombopoietin receptor agonists shift the balance of Fcγ receptors toward inhibitory receptor IIb on monocytes in ITP
复制标题
血小板生成素受体激动剂将 ITP 中单核细胞上 Fc γ 受体的平衡转向抑制性受体 IIb
DOI：
10.1182/blood-2016-01-690727
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发表时间：
2016-08-11
期刊：
影响因子：
20.3
通讯作者：
Peng, Jun
中科院分区：
文献类型：
--
作者：
Liu, Xin-guang;Liu, Shuang;Peng, Jun
活化性Fc γ受体（Fc γ R）I和Fc γ RIIa的表达升高以及抑制性Fc γ RIIb的表达降低参与原发性免疫性血小板减少症（ITP）的发病机制。血小板生成素受体激动剂（TPO-RA）已在临床上用于治疗ITP;然而，关于TPO-RA对ITP中Fc γ R调节的影响知之甚少。在这项前瞻性研究中，我们测量了21例接受艾曲泊帕治疗的皮质类固醇耐药/复发慢性ITP患者的单核细胞Fc γ R表达的变化。结果显示，艾曲泊帕治疗6周后，Fc γ RIIb的mRNA和蛋白水平显著升高。同时，Fc γ RI和IIa水平显著降低，而Fc γ RIII表达没有变化。体外吞噬试验表明，单核细胞上Fc γ R向抑制性Fc γ RIIb的平衡转变伴随着单核细胞/巨噬细胞吞噬能力的显著降低。ITP患者对艾曲泊帕治疗的应答与Fc γ R表型和单核细胞/巨噬细胞功能变化相关。此外，艾曲泊帕应答者的血浆转化生长因子-β 1（TGF-β 1）浓度显著升高。在通过将免疫的CD 61敲除小鼠的脾细胞转移到CD 61（+）严重联合免疫缺陷小鼠中建立的ITP小鼠模型中，也发现了TPO-RA对单核细胞Fc γ R平衡的调节。ITP小鼠中罗米司亭给药显著上调抑制性Fc γ RII表达并下调激活性Fc γ RI表达。这些发现表明，ITP患者TPO-RA治疗后血小板计数的恢复与Fc γ R向单核细胞上抑制性Fc γ RIIb平衡的恢复相关，并表明血小板生成剂对ITP的免疫调节具有深远影响。本研究在ClinicalTrials.gov注册为#NCT 01864512。（血。2016;128（6）：852-861）
Elevated expression of the activating Fc gamma receptor (Fc gamma R) I and Fc gamma RIIa together with decreased expression of the inhibitory Fc gamma RIIb are involved in the pathogenesis of primary immune thrombocytopenia (ITP). Thrombopoietin receptor agonists (TPO-RAs) have been used clinically for the management of ITP; however, little is known about the effect of TPO-RAs on Fc gamma R modulation in ITP. In this prospective study, we measured the alteration in monocyte Fc gamma R expression from 21 corticosteroid-resistant/relapsed patients with chronic ITP receiving eltrombopag therapy. Results showed that the mRNA and protein levels of Fc gamma RIIb were significantly elevated after 6-week eltrombopag treatment. Concurrently, Fc gamma RI and IIa levels decreased remarkably, whereas Fc gamma RIII expression did not change. In vitro phagocytosis assays indicated that a shift in the balance of Fc gamma R toward inhibitory Fc gamma RIIb on monocytes was accompanied with a considerable decrease in monocyte/macrophage phagocytic capacity. The response to eltrombopag therapy in patients with ITP was associated with Fc gamma R phenotype and functional changes of monocytes/macrophages. Moreover, the plasma transforming growth factor-beta 1 (TGF-beta 1) concentrations increased significantly in eltrombopag responders. Modulation of monocyte Fc gamma R balance by TPO-RAs was also found in a murine model of ITP established by transferring splenocytes from immunized CD61 knockout mice into CD61(+) severe combined immunodeficient mice. Romiplostim administration in ITP mice significantly upregulated inhibitory Fc gamma RII expression and downregulated activating Fc gamma RI expression. These findings showed that recovery of platelet counts after TPO-RA treatment in ITP is associated with the restoration of Fc gamma R balance toward the inhibitory Fc gamma RIIb on monocytes, and suggested that thrombopoietic agents have a profound effect on immune modulation in ITP. This study is registered at ClinicalTrials.gov as #NCT01864512. (Blood. 2016;128(6):852-861)