Autoantibodies specific to a peptide of β2-glycoprotein I cross-react with TLR4, inducing a proinflammatory phenotype in endothelial cells and monocytes
Autoantibodies specific to a peptide of β2-glycoprotein I cross-react with TLR4, inducing a proinflammatory phenotype in endothelial cells and monocytes
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DOI：
10.1182/blood-2011-09-378851
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发表时间：
2012-10-18
期刊：
影响因子：
20.3
通讯作者：
Margutti, Paola
中科院分区：
文献类型：
--
作者：
Colasanti, Tania;Alessandri, Cristiano;Margutti, Paola
β（2）-糖蛋白I（β（2）GPI）是抗磷脂抗体的主要抗原靶标。抗β（2）GPI Ab是靶向分子的所有结构域的Ig的异质群体。β 2 GPI结构域I特异性抗体与血栓形成和产科并发症密切相关。在本研究中，我们试图了解该抗β（2）GPI抗体子集可能的致病机制，研究它们与参与炎症或凝血事件的其他自身蛋白的潜在交叉反应性。我们在蛋白质数据库中将β（2）GPI结构域I的氨基酸序列与人蛋白质进行比较，并鉴定出与人TLR 4的表位具有88%同一性的肽。抗磷脂综合征（41%）和系统性红斑狼疮（50%）患者的高比例，提出了血清IgG特异性这种肽。结合TLR 4的抗β（2）GPI肽Ab能够在用TLR 4基因稳定转染的HEK 293细胞中诱导NF-κ B活化。抗β（2）GPI肽Ab诱导TLR 4活化并触发白细胞介素-1受体相关激酶磷酸化和NF-κ B易位，促进内皮细胞上VCAM表达和单核细胞释放TNF-α。总之，我们的观察结果表明，在TLR 4的刺激抗β（2）GPI肽抗体，连接获得性免疫反应与先天免疫抗磷脂综合征和系统性红斑狼疮的一种新的致病机制。（血。2012;120（16）：3360-3370）
beta(2)-glycoprotein I (beta(2)GPI) is the major antigenic target for antiphospholipid Abs. Anti-beta(2)GPI Abs are a heterogeneous population of Igs targeting all domains of the molecule. Abs specific to beta(2)GPI domain I are strongly associated with thrombosis and obstetric complications. In the present study, we sought to understand the possible pathogenic mechanism for this subset of anti-beta(2)GPI Abs, investigating their potential cross-reactivity with other self-proteins involved in inflammatory or coagulant events. We compared the amino acid sequence of the beta(2)GPI domain I with human proteins in a protein databank and identified a peptide sharing 88% identity with an epitope of human TLR4. A high percentage of patients with antiphospholipid syndrome (41%) and systemic lupus erythematosus (50%) presented serum IgG specific to this peptide. Anti-beta(2)GPI peptide Abs binding the TLR4 were able to induce NF-kappa B activation in HEK293 cells that were stably transfected with the TLR4 gene. Anti-beta(2)GPI peptide Abs induced activation of TLR4 and triggered interleukin-1 receptor-associated kinase phosphorylation and NF-kappa B translocation, promoting VCAM expression on endothelial cells and TNF-alpha release by monocytes. In conclusion, our observations suggest a novel pathogenic mechanism in the TLR4 stimulation by anti-beta(2)GPI peptide Abs that links adaptive immune responses with innate immunity in antiphospholipid syndrome and systemic lupus erythematosus. (Blood. 2012;120(16):3360-3370)