Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake.
Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake.
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DOI：
10.1084/jem.20072413
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发表时间：
2008-07-07
期刊：
影响因子：
--
通讯作者：
Smith KG
中科院分区：
文献类型：
--
作者：
Willcocks LC;Lyons PA;Clatworthy MR;Robinson JI;Yang W;Newland SA;Plagnol V;McGovern NN;Condliffe AM;Chilvers ER;Adu D;Jolly EC;Watts R;Lau YL;Morgan AW;Nash G;Smith KG
拷贝数（CN）变异（CNV）已被证明是常见的基因组区域编码的免疫相关基因，从而影响多基因自身免疫。FCGR3B的低CN最近与系统性红斑狼疮（SLE）相关。FcγRIIIb是一种糖基磷脂酰肌醇连接的IgG低亲和力受体，主要存在于人中性粒细胞上。我们提供的新数据表明，在Fcγ RIIIb缺陷家族和正常人群中，FCGR3B CNV与蛋白质表达、中性粒细胞对免疫复合物的摄取和粘附以及可溶性血清FcγRIIIb相关。因此，FcγRIIIb表达降低可能导致免疫复合物清除受损，这是SLE的一个特征，解释了我们在高加索人群中证实的低FCGR3B CNV与SLE之间的相关性。与此相反，抗神经元胞质抗体相关性系统性血管炎（AASV），一种与免疫复合物沉积无关的疾病，与高FCGR3B CN相关。因此，我们确定了FCGR3B CNV在免疫复合物清除中的作用，这一功能可以解释为什么低FCGR3B CNV与SLE相关，而与AASV无关。这是第一个报告的疾病相关基因CNV和蛋白质表达和功能的变化，可能有助于自身免疫性疾病的易感性之间的关联。
Copy number (CN) variation (CNV) has been shown to be common in regions of the genome coding for immune-related genes, and thus impacts upon polygenic autoimmunity. Low CN of FCGR3B has recently been associated with systemic lupus erythematosus (SLE). FcγRIIIb is a glycosylphosphatidylinositol-linked, low affinity receptor for IgG found predominantly on human neutrophils. We present novel data demonstrating that both in a family with FcγRIIIb-deficiency and in the normal population, FCGR3B CNV correlates with protein expression, with neutrophil uptake of and adherence to immune complexes, and with soluble serum FcγRIIIb. Reduced FcγRIIIb expression is thus likely to contribute to the impaired clearance of immune complexes, which is a feature of SLE, explaining the association between low FCGR3B CNV and SLE that we have confirmed in a Caucasian population. In contrast, antineutrophil cytoplasmic antibody–associated systemic vasculitis (AASV), a disease not associated with immune complex deposition, is associated with high FCGR3B CN. Thus, we define a role for FCGR3B CNV in immune complex clearance, a function that may explain why low FCGR3B CNV is associated with SLE, but not AASV. This is the first report of an association between disease-related gene CNV and variation in protein expression and function that may contribute to autoimmune disease susceptibility.
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