Etiology for idiopathic pulmonary alveolar proteinosis : Roles of the autoantibody against GM-CSF in the pathogenesis.

GM-CSF或其受体缺陷的小鼠发生肺泡蛋白沉积症（PAP），其特征在于由磷脂和表面活性剂蛋白组成的过量表面活性剂在肺泡和终末细支气管中积聚，表明GM-CSF在PAP的发病机制中的作用。因此，在该模型中，缺乏GM-CSF信号传导产生AM功能障碍，导致PAP。这一结论得到了以下观察结果的有力支持：受体敲除小鼠中的PAP通过来自野生型小鼠的骨髓移植得到校正，细胞因子敲除小鼠中的PAP通过肺上皮中GM-CSF的转基因表达得到校正。PAP小鼠模型与人类特发性PAP（最常见的获得性形式，病因不明）的关系仍有待阐明。最近，我们在IPAP患者的支气管肺泡灌洗液（BALF）中发现了一种中和GM-CSF生物活性的因子。该因子直接与GM-CSF结合并阻断与细胞上的GM-CSF受体的结合。在这里，我们描述了该因子是一种针对GM-CSF的中和自身抗体，在BALF和IPAP患者的血清中。我们的数据表明，IPAP患者具有类似于PAP小鼠模型的GM-CSF信号传导的破坏。然而，在人类疾病中，GM-CSF信号传导被中和自身抗体消除。这些发现可能促进未来治疗的合理发展，以降低IPAP患者肺中抗GM-CSF自身抗体的水平。

Mice deficient in either GM-CSF or its receptor develop pulmonary alveolar proteinosis (PAP), which is a diseases characterized by accumulation of excessive surfactant composed of phospholipids and surfactant proteins in the alveoli and terminal bronchioli, pointing to a role for GM-CSF in the pathogenesis of PAP. Thus, in this model, lack of GM-CSF signaling produces AM dysfunction leading to PAP. This conclusion is strongly supported by the observation that PAP in the receptor knockout mouse was corrected by bone marrow transplantation from wild type mice and PAP in the cytokine knock out mouse was corrected by transgenic expression of GM-CSF in the pulmonary epithelia. The relationship of the mouse model of PAP to human idiopathic PAP, the most common acquired form of unknown etiology, remains to be elucidated. Recently, we found a factor in the bronchoalveolar lavage fluid (BALF) from IPAP patients that neutralizes the bioactivity of GM-CSF. The factor directly binds to GM-CSF and blocks the binding to GM -CSF receptor on cells. Here, we describe that the factor is a neutralizing auto-antibody directed against GM-CSF in the BALF and sera of patients with IPAP. Our data suggest that IPAP patients have disruption of GM-CSF signaling similar to the mouse model of PAP. In the human disease, however, GM-CSF signaling is abolished by a neutralizing auto-antibody. These findings may promote a rational development of future therapies to lower levels of auto-antibody against GM-CSF in the lung in IPAP patients.