High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis
High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis
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DOI：
10.1182/blood-2003-05-1565
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发表时间：
2004-02-01
期刊：
影响因子：
20.3
通讯作者：
Keicho, N
中科院分区：
文献类型：
--
作者：
Uchida, K;Nakata, K;Keicho, N
粒细胞-巨噬细胞集落刺激因子（GM-CSF）缺乏可导致肺泡巨噬细胞（AM）对表面活性物质的吸收功能受损，进而导致肺泡蛋白沉积症（PAP）。最近，我们发现，中和性抗GM-CSF自身抗体在特发性肺泡蛋白沉积症（iPAP）患者中特异性产生。类似于鼠PAP模型，自身抗体降低GM-CSF活性，导致AM功能障碍和表面活性剂蓄积是合理的。为了检验这一假设，我们估计了患者肺部自身抗体的中和活性，并表征了其生物学特性。在iPAP患者的支气管肺泡灌洗液（BALF）中，GM-CSF生物活性完全消失，但在健康受试者中则不然。肺泡中存在高浓度的自身抗体，并与GM-CSF共存。他们以高亲合力（K-AV = 20.0 +/- 7.5 μ M）和高特异性识别人GM-CSF，与其超结构反应，中和GM-CSF活性至肺中正常存在的GM-CSF水平的4000至58000倍。虽然靶表位在患者中不同，但GM-CSF氨基酸78至94被一致识别。因此，自身抗体以高特异性和高亲和力结合GM-CSF，大量存在于肺中，并有效地阻断GM-CSF与其受体的结合，抑制AM分化和功能。我们的数据加强了抗GM-CSF自身抗体与该病发病机制相关的证据。
Deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mice results in pulmonary alveolar proteinosis (PAP) from impaired surfactant catabolism by alveolar macrophages (AMs). Recently, we have shown that neutralizing anti-GM-CSF autoantibodies develop specifically in patients with idiopathic pulmonary alveolar proteinosis (iPAP). Analogous to murine PAP models, it is plausible that the autoantibodies reduce GM-CSF activity, resulting in AM dysfunction and surfactant accumulation. To examine this hypothesis, we estimated the neutralizing activity of the auto-antibodies in the lungs of patients and characterized their biologic properties. GM-CSF bioactivity was completely abrogated in the bronchoalveolar lavage fluid (BALF) of patients with iPAP but not in healthy subjects. Autoantibodies were present in the alveoli in high concentrations and colocalized with GM-CSF. They recognized human GM-CSF with high avidity (K-AV = 20.0 +/- 7.5 muM) and high specificity, reacting with its superstructure and neutralizing GM-CSF activity to a level 4000 to 58 000 times the levels of GM-CSF normally present in the lung. Although target epitopes varied among patients, GM-CSF amino acids 78 to 94 were consistently recognized. Thus, autoantibodies bind GM-CSF with high specificity and high affinity, exist abundantly in the lung, and effectively block GM-CSF binding to its receptor, inhibiting AM differentiation and function. Our data strengthen the evidence associating anti-GM-CSF autoantibodies with the pathogenesis of this disease.