Human pulmonary alveolar proteinosis associated with a defect in GM- CSF/IL-3/IL-5 receptor common β chain expression

Pulmonary alveolar proteinosis (PAP) is a heterogenous disorder of genetic or acquired etiologies. In some cases congenital PAP is associated with hereditary surfactant protein (SP)-B deficiency. To date, the molecular defect in the majority of patients with PAP has not been identified. In mice, PAP has been generated by targeted deletion of the genes for either the GM- CSF/IL-3/IL-5 receptor common β chain (βc) or GM-CSF. Here, we describe an expression defect of βc in three of seven pediatric patients with PAP and in one patient with severe lung disease suspected to be PAP. The patients failed to express normal levels of βc as shown by flow cytometry. Strikingly reduced or absent function of βc was demonstrated by ligand binding studies and progenitor clonogenic assays. Analysis of βc DNA revealed a point mutation from proline to threonine at codon 602 in one patient. Our findings provide evidence that a defect in the expression of a hematopoietic cytokine receptor is associated with human PAP.