Phagocytosis is the main CR3-mediated function affected by the lupus-associated variant of CD11b in human myeloid cells.
Phagocytosis is the main CR3-mediated function affected by the lupus-associated variant of CD11b in human myeloid cells.
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DOI：
10.1371/journal.pone.0057082
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Botto M
中科院分区：
文献类型：
--
作者：
Fossati-Jimack L;Ling GS;Cortini A;Szajna M;Malik TH;McDonald JU;Pickering MC;Cook HT;Taylor PR;Botto M
CD11b/CD18整合素（补体受体3，CR3）是单核细胞、中性粒细胞、巨噬细胞和树突状细胞的表面受体，在白细胞外渗和吞噬等多种免疫过程中起关键作用。非同义CR3多态性的次要等位基因（rs1143679，精氨酸与组氨酸在77位的对话：R77H）代表了人类系统性红斑狼疮最强的遗传风险因素之一，杂合性（77R/H）是最常见的疾病相关基因型。据报道，77H等位基因的纯合性分别可以减少人单核细胞和单核细胞源性巨噬细胞的粘附和吞噬，而不影响CD11b的表面表达。本文综合评估了R77H对单核细胞、中性粒细胞、巨噬细胞和树突状细胞中不同cr3介导的活性的影响。R77H不改变CD11b的表面表达，包括其在任何这些细胞类型中的活性形式。我们发现，与77R/R细胞相比，杂合的77R/H巨噬细胞、单核细胞和中性粒细胞对两种不同的ic3b包被靶标的摄取明显减少。等位基因特异性转导的永生化巨噬细胞系表明，较小的等位基因77H是导致吞噬功能受损的原因。R77H不影响中性粒细胞粘附、中性粒细胞在体内的转运或toll样受体7/8介导的单核细胞或树突状细胞释放的细胞因子，无论是否有CR3预结合ic3b包被靶标。我们的研究结果表明，与77H CD11b变异相关的cr3介导的吞噬作用的减少不受巨噬细胞的限制，但在其他表达cr3的专业吞噬细胞中也可以证明。77H与系统性红斑狼疮易感性之间的关联很可能与废物处理受损有关，这是狼疮发病机制的关键组成部分。
The CD11b/CD18 integrin (complement receptor 3, CR3) is a surface receptor on monocytes, neutrophils, macrophages and dendritic cells that plays a crucial role in several immunological processes including leukocyte extravasation and phagocytosis. The minor allele of a non-synonymous CR3 polymorphism (rs1143679, conversation of arginine to histidine at position 77: R77H) represents one of the strongest genetic risk factor in human systemic lupus erythematosus, with heterozygosity (77R/H) being the most common disease associated genotype. Homozygosity for the 77H allele has been reported to reduce adhesion and phagocytosis in human monocytes and monocyte-derived macrophages, respectively, without affecting surface expression of CD11b. Herein we comprehensively assessed the influence of R77H on different CR3-mediated activities in monocytes, neutrophils, macrophages and dendritic cells. R77H did not alter surface expression of CD11b including its active form in any of these cell types. Using two different iC3b-coated targets we found that the uptake by heterozygous 77R/H macrophages, monocytes and neutrophils was significantly reduced compared to 77R/R cells. Allele-specific transduced immortalized macrophage cell lines demonstrated that the minor allele, 77H, was responsible for the impaired phagocytosis. R77H did not affect neutrophil adhesion, neutrophil transmigration in vivo or Toll-like receptor 7/8-mediated cytokine release by monocytes or dendritic cells with or without CR3 pre-engagement by iC3b-coated targets. Our findings demonstrate that the reduction in CR3-mediated phagocytosis associated with the 77H CD11b variant is not macrophage-restricted but demonstrable in other CR3-expressing professional phagocytic cells. The association between 77H and susceptibility to systemic lupus erythematosus most likely relates to impaired waste disposal, a key component of lupus pathogenesis.
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DOI：
10.1084/jem.20081648
发表时间：
2009-04-13
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dai Z;Turtle CJ;Booth GC;Riddell SR;Gooley TA;Stevens AM;Spies T;Groh V
通讯作者：
Groh V
影响因子：
--
作者：
Green, Matthew R. J.;Kennell, Amy S. M.;Salaman, Myer R.
通讯作者：
Salaman, Myer R.
中国汉族人群的全基因组关联研究确定了系统性红斑狼疮的九个新易感位点
影响因子：
30.8
作者：
Han, Jian-Wen;Zheng, Hou-Feng;Zhang, Xue-Jun
通讯作者：
Zhang, Xue-Jun
6q23 上 TNFAIP3 附近的遗传变异与系统性红斑狼疮相关。
影响因子：
30.8
作者：
Graham, Robert R.;Cotsapas, Chris;Davies, Leela;Hackett, Rachel;Lessard, Christopher J.;Leon, Joanlise M.;Burtt, Noel P.;Guiducci, Candace;Parkin, Melissa;Gates, Casey;Plenge, Robert M.;Behrens, Timothy W.;Wither, Joan E.;Rioux, John D.;Fortin, Paul R.;Graham, Deborah Cunninghame;Wong, Andrew K.;Vyse, Timothy J.;Daly, Mark J.;Altshuler, David;Moser, Kathy L.;Gaffney, Patrick M.
通讯作者：
Gaffney, Patrick M.
影响因子：
15.9
作者：
Cao, Chunzhang;Gao, Yamei;Zhang, Li
通讯作者：
Zhang, Li