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

特发性肺泡蛋白沉积症的病因学：GM-CSF 自身抗体在发病机制中的作用。

基本信息

批准号：
13670624
负责人：
NAKATA Koh
金额：
$ 2.5万
依托单位：
Research Institute, International Medical Center of Japan
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

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.

缺乏GM-CSF或其受体缺乏的小鼠会发展出肺肺泡蛋白质病（PAP），该疾病是一种疾病，其特征是由肺泡和末端支气管中的磷脂和表面活性剂蛋白组成的过度表面活性剂的积累，并指向GM-CSF在PAP中的作用。因此，在此模型中，缺乏GM-CSF信号传导会导致PAP的AM功能障碍。这一结论得到了以下观察结果，即受体敲除小鼠中的PAP通过野生型小鼠的骨髓移植来纠正，而细胞因子敲除小鼠的PAP通过肺上皮质体中GM-CSF的转基因表达校正了细胞因子敲除小鼠。 PAP的小鼠模型与人类特发性PAP的关系是最常见的未知病因形式，尚待阐明。最近，我们发现了IPAP患者的支气管肺泡灌洗液（BALF）的一个因素，该因素可以中和GM-CSF的生物活性。该因子直接与GM -CSF结合，并阻止细胞上与GM -CSF受体的结合。在这里，我们描述了该因素是针对IPAP患者的BALF和血清中针对GM-CSF的中和自身抗体。我们的数据表明，IPAP患者的GM-CSF信号与PAP的小鼠模型相似。然而，在人类疾病中，GM-CSF信号被中和自身抗体消除。这些发现可能会促进IPAP患者肺中对GM-CSF的自身抗体较低水平的未来疗法的合理发展。