Fcγ Receptor-Dependent Expansion of a Hyperactive Monocyte Subset in Lupus-Prone Mice
Fcγ Receptor-Dependent Expansion of a Hyperactive Monocyte Subset in Lupus-Prone Mice
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DOI：
10.1002/art.24787
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发表时间：
2009-08-01
影响因子：
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通讯作者：
Izui, Shozo
中科院分区：
文献类型：
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作者：
Santiago-Raber, Marie-Laure;Amano, Hirofumi;Izui, Shozo
目标。易患狼疮的BXSB小鼠出现单核细胞增多症，其特征是Gr-1单核细胞亚群选择性积聚。本研究的目的是探讨激活免疫球蛋白Fc受体(Fc-Gamma R)在单核细胞增多症发生中的可能作用，并对携带抑制Fc-Gamma RIIB的NZB型缺陷Fcgr2b等位基因的狼疮易感小鼠体内聚集的Gr-1亚群的功能表型进行表征。我们分析了BXSB和抗IgG2a类风湿因子转基因C57BL/6小鼠缺乏激活Fc-Gamma R的单核细胞增多症的发生，并检测了激活Fc-Gamma R和抑制Fc-Gamma RIIB对C57BL/6型和NZB型Fcgr2b全基因C57BL/6小鼠Gr-1+和Gr-1-单核细胞亚群的表达水平。我们观察到，在表达IgG2a的抗-IgG2a转基因C57BL/6小鼠中，随着Gr-1亚群的扩大，单核细胞增多，但在那些缺乏IgG2a的小鼠中没有观察到。此外，在缺乏激活FcγR的BXSB和抗IgG2a转基因C57BL/6小鼠中，单核细胞几乎没有发育。在狼疮易感小鼠中积累的Gr-1亚群表现出独特的高活性表型。由于NZB型Fcgr2b等位基因的存在，它表达了非常低水平的抑制性Fc-Gamma RIIB，但表达了高水平的激活Fc-Gamma RIV。这与在Gr-1+亚群上高水平表达Fc-Gamma RIIB和不表达Fc-Gamma RIV相反。我们的结果表明，激活Fc-Gamma R在狼疮易感小鼠单核细胞增多症的发生和Gr-1-Fc Gamma RIIB(Low)Fc Gamma RIV+高活性单核细胞亚群的扩大中起着关键作用。我们的发现进一步强调了NZB型Fcgr2b易感等位基因在小鼠狼疮中的重要性，该等位基因的存在会导致高活性单核细胞的产生增加以及自身反应性B细胞的异常激活。
Objective. Lupus-prone BXSB mice develop monocytosis characterized by selective accumulation of the Gr-1- monocyte subset. The aim of this study was to explore the possible role of activating IgG Fc receptors (Fc gamma R) in the development of monocytosis and to characterize the functional phenotype of the Gr-1- subset that accumulates in lupus-prone mice bearing the NZB-type defective Fcgr2b allele for the inhibitory Fc gamma RIIB.Methods. The development of monocytosis was analyzed in BXSB and anti-IgG2a rheumatoid factor-transgenic C57BL/6 mice deficient in activating Fc gamma R. Moreover, we assessed the expression levels of activating Fc gamma R and inhibitory Fc gamma RIIB on Gr-1+ and Gr-1-monocyte subsets in C57BL/6 mice bearing the C57BL/6-type or the NZB-type Fcgr2b allele.Results. We observed monocytosis with expansion of the Gr-1- subset in anti-IgG2a-transgenic C57BL/6 mice expressing IgG2a, but not in those lacking IgG2a. Moreover, monocytosis barely developed in BXSB and anti-IgG2a-transgenic C57BL/6 mice deficient in activating Fc gamma R. The Gr-1- subset that accumulated in lupus-prone mice displayed a unique hyperactive phenotype. It expressed very low levels of inhibitory Fc gamma RIIB, due to the presence of the NZB-type Fcgr2b allele, but high levels of activating Fc gamma RIV. This was in contrast to high levels of Fc gamma RIIB expression and no Fc gamma RIV expression on the Gr-1+ subset.Conclusion. Our results demonstrated a critical role of activating Fc gamma R in the development of monocytosis and in the expansion of a Gr-1- Fc gamma RIIB(low)Fc gamma RIV+ hyperactive monocyte subset in lupus-prone mice. Our findings further highlight the importance of the NZB-type Fcgr2b susceptibility allele in murine lupus, the presence of which induces increased production of hyperactive monocytes as well as dysregulated activation of autoreactive B cells.