ALTERED MONONUCLEAR PHAGOCYTE DIFFERENTIATION-ASSOCIATED WITH GENETIC-DEFECTS OF THE LYSOSOMAL ACID LIPASE

Multiparameter flow cytometry reveals a complex heterogeneity of monon uclear phagocyte differentiation within the peripheral blood compartme nt. In this study, the relation of abnormal cellular lipid metabolism to the phenotype of peripheral blood mononuclear phagocytes, which fin ally may be related to atherogenesis, was analyzed using recently char acterized autosomal recessive defects of lysosomal acid lipase (LAL) e xpression as model system. The reduction of LAL activity in nine heter ozygote, disease free carriers of mutations from two cholesteryl ester storage disease (CESD) pedigrees and the family of a patient with Wol man disease was associated with an increased fraction of monocytes whi ch expressed CD56 (N-CAM) (4.1 +/- 2.7% of monocytes, compared to 2.2 +/- 0.5% in ten controls, P < 0.05), an antigen characteristic of imma ture myeloid cells, suggesting an increased turnover of monocytes. Fur thermore, a trend was observed towards an enhanced blood pool of more mature mononuclear phagocytes which show decreased expression of the 5 5 kD lipopolysaccharide receptor (CD14) together with either expressio n of the Fc-gamma-receptor III (CD16) or a high expression of CD33. A similar phenotype of peripheral mononuclear phagocytes was observed in the two CESD patients analyzed. In conclusion, our data suggest that these monogenetic defects of lysosomal lipoprotein metabolism are asso ciated with complex alterations of mononuclear phagocyte differentiati on and extravasation. (C) 1997 Elsevier Science Ireland Ltd.