Department of Lead Identification and Optimization Support, Structural Research Group, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach, Germany.
Biochem J. 2012 Oct 15;447(2):205-15. doi: 10.1042/BJ20120884.
Polyclonal autoantibodies against human GM-CSF (granulocyte/macrophage colony-stimulating factor) are a hallmark of PAP (pulmonary alveolar proteinosis) and several other reported autoimmune diseases. MB007 is a high-affinity anti-(human GM-CSF) autoantibody isolated from a patient suffering from PAP which shows only modest neutralization of GM-CSF bioactivity. We describe the first crystal structure of a cytokine-directed human IgG1λ autoantibody-binding fragment (Fab) at 1.9 Å (1 Å=0.1 nm) resolution. Its CDR3-H substantially differs from all VH7 germline IgG1 structures reported previously. We derive a reliable model of the antigen-autoantibody complex by using NMR chemical shift perturbation data in combination with computational methods. Superposition of the modelled complex structure with the human GM-CSF-GM-CSF ternary receptor complex reveals only little overlap between receptor and Fab when bound to GM-CSF. Our model provides a structural basis for understanding the mode of action of the MB007 autoantibody.
针对人 GM-CSF（粒细胞/巨噬细胞集落刺激因子）的多克隆自身抗体是 PAP（肺泡蛋白沉积症）和其他几种报道的自身免疫性疾病的标志。MB007 是一种从患有 PAP 的患者中分离出来的高亲和力抗（人 GM-CSF）自身抗体，仅对 GM-CSF 生物活性具有适度的中和作用。我们描述了第一个针对细胞因子的人 IgG1λ 自身抗体结合片段 (Fab) 的晶体结构，分辨率为 1.9 Å（1 Å=0.1nm）。其 CDR3-H 与以前报道的所有 VH7 胚系 IgG1 结构有很大不同。我们通过使用 NMR 化学位移扰动数据结合计算方法，得出抗原-自身抗体复合物的可靠模型。将建模的复合物结构与人类 GM-CSF-GM-CSF 三元受体复合物叠加，当与 GM-CSF 结合时，受体和 Fab 之间几乎没有重叠。我们的模型为理解 MB007 自身抗体的作用模式提供了结构基础。
