Pathogenesis of vascular inflammation by anti-neutrophil cytoplasmic antibodies
Pathogenesis of vascular inflammation by anti-neutrophil cytoplasmic antibodies
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DOI：
10.1681/asn.2005101048
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发表时间：
2006-05-01
影响因子：
13.6
通讯作者：
Falk, RJ
中科院分区：
文献类型：
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作者：
Jennette, JC;Xiao, H;Falk, RJ
一名新生儿在经胎盘转移具有髓过氧化物酶 (MPO) 特异性的抗中性粒细胞胞浆抗体 (ANCA) IgG 后出现肾小球肾炎和肺出血的报告是令人信服的临床证据，表明 ANCA 具有致病性。体外研究表明，ANCA 通过直接 Fab'2 结合和 Fc 受体结合激活细胞因子引发的中性粒细胞和单核细胞。被 ANCA 激活的中性粒细胞释放氧自由基、裂解酶和炎性细胞因子，并粘附并杀死内皮细胞。被动施用小鼠抗小鼠 MPO IgG 引起的小鼠模型提供了令人信服的证据，表明在缺乏抗原特异性 T 细胞的情况下单独使用 ANCA IgG 可引起坏死性肾小球肾炎和血管炎。这种致病过程通过协同炎症因子而增强，可能是通过中性粒细胞的启动。用人 MPO 免疫大鼠会诱导产生与大鼠 MPO 交叉反应的抗体，引起肾小球肾炎和血管炎。这些 ANCA 与趋化因子协同作用，导致白细胞粘附在小血管壁上，从而造成随后的损伤。迄今为止，由抗蛋白酶 3 诱导的疾病动物模型的稳健性较差。临床和实验数据表明但并未证明 ANCA 自身免疫反应是由对 ANCA 抗原的反义肽或其模拟物的免疫反应启动的，所述反义肽可能由传染性病原体引入体内。这种抗体反应会引发与 ANCA 抗原发生交叉反应的抗独特型抗体。 ANCA 疾病的发病机制是多因素的，遗传和环境因素影响自身免疫反应的发生、急性损伤的介导以及对损伤的慢性反应的诱导。
The reports of a newborn who developed glomerulortephritis and pulmonary hemorrhage after transplacental transfer of anti-neutrophil cytoplasmic antibody (ANCA) IgG with specificity for myeloperoxidase (MPO) is compelling clinical evidence that ANCA are pathogenic. In vitro studies indicate that ANCA activate cytokine-primed neutrophils and monocytes through both direct Fab'2 binding and Fc receptor engagement. Neutrophils that have been activated by ANCA release oxygen radicals, lytic enzymes, and inflammatory cytokines and adhere to and kill endothelial cells. A murine model caused by passive administration of mouse anti-mouse MPO IgG provides convincing evidence that ANCA IgG alone in the absence of antigen-specific T cells can cause necrotizing glomerulonephritis and vasculitis. This pathogenic process is enhanced by synergistic inflammatory factors, probably through priming of neutrophils. Immunization of rats with human MPO induces antibodies that cross-react with rat MPO and cause glomerulonephritis and vasculitis. These ANCA act in concert with chemokines to cause adherence of leukocytes to the walls of small vessels with subsequent injury. To date, animal models of disease that is induced by anti-proteinase 3 are less robust. Clinical and experimental data suggest but do not prove that the ANCA autoimmune response is initiated by an immune response to an antisense peptide of the ANCA antigen or its mimic that may be introduced into the body by an infectious pathogen. This antibody response elicits anti-idiotypic antibodies that cross-react with ANCA antigens. The pathogenesis of ANCA disease is multifactorial, with genetic and environmental factors influencing onset of the autoimmune response, the mediation of acute injury, and the induction of the chronic response to injury.