Atherosclerosis 130 (1997) 215 – 221 Altered mononuclear phagocyte differentiation associated with genetic defects of the lysosomal acid lipase Gregor Rothe a , Josef Sto ¨hr a , Petra Fehringer a , Christoph Gasche b , Gerd Schmitz a, * a Institute for Clinical Chemistry and Laboratory Medicine, Uniersity of Regensburg, D-93042 Regensburg, Germany b Department of Gastroenterology and Hepatology, Uniersity of Vienna, Vienna, Austria Received 22 August 1996; received in revised form 11 December 1996; accepted 19 December 1996 Abstract Multiparameter flow cytometry reveals a complex heterogeneity of mononuclear phagocyte differentiation within the peripheral blood compartment. In this study, the relation of abnormal cellular lipid metabolism to the phenotype of peripheral blood mononuclear phagocytes, which finally may be related to atherogenesis, was analyzed using recently characterized autosomal recessive defects of lysosomal acid lipase (LAL) expression as model system. The reduction of LAL activity in nine heterozygote, disease free carriers of mutations from two cholesteryl ester storage disease (CESD) pedigrees and the family of a patient with Wolman disease was associated with an increased fraction of monocytes which 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 immature myeloid cells, suggesting an increased turnover of monocytes. Furthermore, a trend was observed towards an enhanced blood pool of more mature mononuclear phagocytes which show decreased expression of the 55 kD lipopolysaccharide receptor (CD14) together with either expression of the Fc- -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 associated with complex alterations of mononuclear phagocyte differentiation and extravasation. © 1997 Elsevier Science Ireland Ltd. Keywords: Monocyte subpopulations; Mononuclear phagocyte differentiation; Wolman disease; Cholesteryl ester storage disease; Lysosomal acid lipase 1. Introduction The early pathogenesis of atherosclerosis is charac- terized already by an increased adhesion of monocytes to the injured endothelium followed by extravasation into the vessel wall [1]. Within the wall, the unregulated cellular lipid accumulation by monocytes leads to foam cell formation and the development of fatty streaks [2]. Furthermore, activated macrophages secrete cytokines and modify lipoproteins at least in part by oxidation. There is increasing evidence that the phenotype of peripheral blood monocytes may be affected dependent on disturbances of cellular lipid or lipoprotein metabolism. Thus, there appears to be an enhanced monocyte progenitor proliferation in animal models of hypercholesterolemia [3]. Functional abnormalities such as impaired monocyte signal transduction have been observed in hypercholesterolemic patients [4]. Further- more, enhanced antigen presentation has been reported upon pre-incubation of monocytes in cholesterol-rich media [5]. Using multiparameter flow cytometry our group has recently been able to demonstrate an altered phenotype of the highly heterogeneous peripheral blood mono- cytes in patients with hypercholesterolemia [6]. In com- parison to the predominant population of monocytes, small subpopulations of peripheral blood mononuclear * Corresponding author. Tel.: +49 941 9446200; fax: +49 941 9446202; e-mail: gerd.schmitz@klinik.uni-regensburg.de 0021-9150/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S0021-9150(97)06065-6