Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency.
Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency.
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DOI：
10.4049/jimmunol.1201594
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发表时间：
2012-10-01
期刊：
影响因子：
--
通讯作者：
Mayadas TN
中科院分区：
文献类型：
--
作者：
Rosetti F;Tsuboi N;Chen K;Nishi H;Ernandez T;Sethi S;Croce K;Stavrakis G;Alcocer-Varela J;Gómez-Martin D;van Rooijen N;Kyttaris VC;Lichtman AH;Tsokos GC;Mayadas TN
系统性红斑狼疮（SLE）是一种慢性、多器官炎症性自身免疫性疾病，与高水平的循环自身抗体和免疫复合物相关。我们报告称，将人SLE血清被动转移至中性粒细胞上表达独特的人FcγRIIA和FcγRIIIB的小鼠中，仅当小鼠额外缺乏CD 18整联蛋白Mac-1时，才会诱导狼疮性肾炎和关节炎。流行的观点是巨噬细胞上的Mac-1负责免疫复合物的清除。然而，Mac-1的情况下允许的疾病是不相关的增强肾免疫复合物沉积或原位C1 q/C3补体激活，甚至在巨噬细胞的情况下进行。相反，疾病与Fcγ RIIA诱导的中性粒细胞蓄积增加相关，这是Mac-1缺乏所致。提睾肌脉管系统中的活体显微镜检查显示Mac-1减轻FcγRIIA依赖性中性粒细胞对沉积的免疫复合物的募集。我们的研究结果提供了人类SLE免疫复合物具有致病性的直接证据，证明中性粒细胞是新型人源化狼疮小鼠模型中终末器官损伤的主要介质，并确定Mac-1对Fcγ RIIA介导的中性粒细胞募集的调节是靶器官损伤发展的关键步骤。
Systemic lupus erythematosus (SLE) is a chronic, multi-organ inflammatory autoimmune disorder associated with high levels of circulating autoantibodies and immune complexes. We report that passive transfer of human SLE sera into mice expressing the uniquely human FcγRIIA and FcγRIIIB on neutrophils induces lupus nephritis and in some cases arthritis only when the mice additionally lack the CD18 integrin, Mac-1. The prevailing view is that Mac-1 on macrophages is responsible for immune complex clearance. However, disease permitted by the absence of Mac-1 is not related to enhanced renal immune-complex deposition or in situ C1q/C3 complement activation and proceeds even in the absence of macrophages. Instead, disease is associated with increased FcγRIIA-induced neutrophil accumulation that is enabled by Mac-1 deficiency. Intravital microscopy in the cremasteric vasculature reveals that Mac-1 mitigates FcγRIIA dependent neutrophil recruitment in response to deposited immune complexes. Our results provide direct evidence that human SLE immune-complexes are pathogenic, demonstrate that neutrophils are primary mediators of end organ damage in a novel humanized lupus mouse model, and identify Mac-1 regulation of FcγRIIA-mediated neutrophil recruitment as a key step in development of target organ damage.
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影响因子：
13.6
作者：
Mayadas TN;Rosetti F;Ernandez T;Sethi S
通讯作者：
Sethi S
影响因子：
13.6
作者：
Crispín JC;Liossis SN;Kis-Toth K;Lieberman LA;Kyttaris VC;Juang YT;Tsokos GC
通讯作者：
Tsokos GC
影响因子：
5.1
作者：
Bagavant H;Fu SM
通讯作者：
Fu SM
影响因子：
30.5
作者：
Mocsai, Attila;Abram, Clare L.;Lowell, Clifford A.
通讯作者：
Lowell, Clifford A.
影响因子：
--
作者：
Chen, Mei;Boilard, Eric;Lee, David M.
通讯作者：
Lee, David M.