Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis.
Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis.
复制标题
DOI：
10.1056/nejmoa052955
复制
发表时间：
2006-06
期刊：
影响因子：
--
通讯作者：
S. Baroni;M. Santillo;F. Bevilacqua;M. Luchetti;T. Spadoni;M. Mancini;P. Fraticelli;P. Sambo;A. Funaro;A. Kazlauskas;E. Avvedimento;A. Gabrielli
中科院分区：
文献类型：
--
作者：
S. Baroni;M. Santillo;F. Bevilacqua;M. Luchetti;T. Spadoni;M. Mancini;P. Fraticelli;P. Sambo;A. Funaro;A. Kazlauskas;E. Avvedimento;A. Gabrielli
系统性硬化症（硬皮病）的特征是免疫异常、内皮细胞损伤和组织纤维化。在硬皮病中已记录了异常氧化应激，并与成纤维细胞活化有关。由于血小板源性生长因子（PDGF）刺激活性氧（ROS）的产生，并且由于硬皮病患者的IgG与人成纤维细胞反应，我们测试了硬皮病患者具有刺激PDGF受体（PDGFR）的血清自身抗体的假设，激活胶原基因表达。方法：我们分析了46例硬皮病患者和75例对照组（包括其他自身免疫性疾病患者）的血清，通过测量纯化IgG与携带PDGFR α或β链失活拷贝的小鼠胚胎成纤维细胞或表达PDGFR α或β的相同细胞孵育产生的ROS的产生来检测PDGFR的刺激性自身抗体。在有和没有特异性PDGFR抑制剂的情况下测定ROS的产生。通过免疫沉淀、免疫印迹和吸收实验表征抗体。结果硬皮病患者均存在PDGFR刺激性抗体。抗体识别天然PDGFR，诱导酪氨酸磷酸化和ROS积累。通过与表达PDGFR α链的细胞或重组PDGFR或PDGFR酪氨酸激酶抑制剂预孵育，消除自身抗体活性。刺激性PDGFR抗体选择性诱导Ha-Ras-ERK 1/2和ROS级联反应，并刺激正常人原代成纤维细胞中I型胶原基因表达和肌成纤维细胞表型转化。结论：抗PDGFR的刺激性自身抗体似乎是硬皮病的一个特异性标志。它们对成纤维细胞的生物活性强烈表明它们在疾病的发病机制中具有因果作用。
BACKGROUND Systemic sclerosis (scleroderma) is characterized by immunologic abnormalities, injury of endothelial cells, and tissue fibrosis. Abnormal oxidative stress has been documented in scleroderma and linked to fibroblast activation. Since platelet-derived growth factor (PDGF) stimulates the production of reactive oxygen species (ROS) and since IgG from patients with scleroderma reacts with human fibroblasts, we tested the hypothesis that patients with scleroderma have serum autoantibodies that stimulate the PDGF receptor (PDGFR), activating collagen-gene expression. METHODS We analyzed serum from 46 patients with scleroderma and 75 controls, including patients with other autoimmune diseases, for stimulatory autoantibodies to PDGFR by measuring the production of ROS produced by the incubation of purified IgG with mouse-embryo fibroblasts carrying inactive copies of PDGFR alpha or beta chains or the same cells expressing PDGFR alpha or beta. Generation of ROS was assayed with and without specific PDGFR inhibitors. Antibodies were characterized by immunoprecipitation, immunoblotting, and absorption experiments. RESULTS Stimulatory antibodies to the PDGFR were found in all the patients with scleroderma. The antibodies recognized native PDGFR, inducing tyrosine phosphorylation and ROS accumulation. Autoantibody activity was abolished by preincubation with cells expressing the PDGFR alpha chain or with recombinant PDGFR or by PDGFR tyrosine kinase inhibitors. Stimulatory PDGFR antibodies selectively induced the Ha-Ras-ERK1/2 and ROS cascades and stimulated type I collagen-gene expression and myofibroblast phenotype conversion in normal human primary fibroblasts. CONCLUSIONS Stimulatory autoantibodies against PDGFR appear to be a specific hallmark of scleroderma. Their biologic activity on fibroblasts strongly suggests that they have a causal role in the pathogenesis of the disease.