HUMAN PULMONARY ALVEOLAR PROTEINOSIS ASSOCIATED WITH A DEFECT IN GM-CSF IL-3/IL-5 RECEPTOR COMMON BETA-CHAIN EXPRESSION/

Pulmonary alveolar proteinosis (PAP) is a heterogenous disorder of gen etic or acquired etiologies. In some cases congenital PAP is associate d with hereditary surfactant protein (SP)-B deficiency. To date, the m olecular defect in the majority of patients with PAP has not been iden tified. In mice, PAP has been generated by targeted deletion of the ge nes for either the GM-CSF/IL3/IL-5 receptor common beta chain (beta c) or GM-CSF. Here, we describe an expression defect of beta c in three of seven pediatric patients with PAP and in one patient with severe lu ng disease suspected to be PAP. The patients failed to express normal levels of beta c as shown by now cytometry. Strikingly reduced or abse nt function of beta c was demonstrated by ligand binding studies and p rogenitor clonogenic assays. Analysis of beta c DNA revealed a point m utation from proline to threonine at codon 602 in one patient. Our fin dings provide evidence that a defect in the expression of a hematopoie tic cytokine receptor is associated with human PAP.