Crow Andrew R, Song Seng, Freedman John, Helgason Cheryl D, Humphries R Keith, Siminovitch Katherine A, Lazarus Alan H
Transfusion Medicine Research, St Michael's Hospital, Toronto, ON, Canada.
Blood. 2003 Jul 15;102(2):558-60. doi: 10.1182/blood-2003-01-0023. Epub 2003 Mar 20.
It has been established that amelioration of murine immune thrombocytopenia purpura (ITP) by IVIg is dependent on the inhibitory receptor FcgammaRIIB. Co-cross-linking of the FcgammaRIIB with the B-cell receptor complex or with FcepsilonRI in mast cells results in cell inhibition, which is mediated by recruitment of the inositol phosphatase SHIP1 to the cytoplasmic tail of the FcgammaR. The FcgammaRIIB can also associate with protein tyrosine phosphatase SHP-1 as a potential secondary target of the receptor. Alternatively, homoaggregation of FcgammaRIIB can induce a proapoptotic state in B cells that is dependent on the presence of Bruton tyrosine kinase (Btk), a kinase also expressed in monocytes. We sought to determine if these signaling pathways may direct IVIg-mediated FcgammaRIIB-dependent regulation of in vivo monocyte function in a murine model of ITP in which IVIg functions in an FcgammaRIIB-dependent manner. We demonstrate that mice deficient in SHIP1, SHP-1, and Btk respond to the ameliorating effects of IVIg with the same kinetics as control mice. We conclude that IVIgmediated inhibitory pathways operating via monocyte FcgammaRIIB may involve a transmembrane signaling pathway different from that of B cells.
已经确定，静脉注射免疫球蛋白（IVIg）改善小鼠免疫性血小板减少性紫癜（ITP）依赖于抑制性受体FcγRIIB。FcγRIIB与B细胞受体复合物或肥大细胞中的FcεRI共交联会导致细胞抑制，这是由肌醇磷酸酶SHIP1募集到FcγR的细胞质尾部介导的。FcγRIIB还可以与蛋白酪氨酸磷酸酶SHP-1结合，作为该受体的潜在次要靶点。另外，FcγRIIB的同源聚集可以在B细胞中诱导促凋亡状态，这取决于布鲁顿酪氨酸激酶（Btk）的存在，Btk也是一种在单核细胞中表达的激酶。我们试图确定在ITP小鼠模型中，这些信号通路是否可能指导IVIg介导的FcγRIIB依赖性体内单核细胞功能调节，在该模型中IVIg以FcγRIIB依赖性方式发挥作用。我们证明，SHIP1、SHP-1和Btk缺陷的小鼠对IVIg改善作用的反应动力学与对照小鼠相同。我们得出结论，通过单核细胞FcγRIIB起作用的IVIg介导的抑制途径可能涉及与B细胞不同的跨膜信号通路。
