The Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
Proc Natl Acad Sci U S A. 2013 May 7;110(19):7832-7. doi: 10.1073/pnas.1216011110. Epub 2013 Apr 25.
The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.
致病性自身抗体的起源仍然未知。特发性肺泡蛋白沉积症是由针对粒细胞-巨噬细胞集落刺激因子（GM-CSF）的自身抗体引起的。我们从六名特发性肺泡蛋白沉积症患者中产生了 19 种针对 GM-CSF 的单克隆自身抗体。这些自身抗体使用了多种 V 基因，排除了作为病因的首选 V 基因使用，并针对 GM-CSF 上至少四个非重叠的表位，这表明 GM-CSF 是驱动自身抗体的原因，而不是与 GM-CSF 发生交叉反应的病原体上的 B 细胞表位。自身抗体中的体细胞突变数量表明，记忆 B 细胞已经得到 T 细胞的帮助并重新进入生发中心。所有自身抗体均中和 GM-CSF 的生物活性，与亲和力和离解速率呈普遍相关性。GM-CSF 中的点突变会改变某些自身抗体的结合，从而降低与 GM-CSF 受体的结合。那些能够有效中和 GM-CSF 的单克隆自身抗体可能对治疗炎症性疾病（如类风湿关节炎和多发性硬化症、癌症和疼痛）有用。
