Altered mononuclear phagocyte differentiation associated with genetic defects of the lysosomal acid lipase
Introduction
The early pathogenesis of atherosclerosis is characterized 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]. Furthermore, 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 monocytes in patients with hypercholesterolemia [6]. In comparison to the predominant population of monocytes, small subpopulations of peripheral blood mononuclear phagocytes are characterized by a decreased expression of the 55 kD LPS-receptor (CD14) together with the expression of either the Fc-γ-receptor-III (CD16) correlating to phagocytically active cells or a high expression of surface molecules related to antigen presentation such as HLA-DR and CD40 correlating to cells which are assumed to be the blood precursors of dendritic cells 6, 7, 8, 9, 10. Furthermore, a subset of cells expresses the CD56 (N-CAM) antigen which is also found in less differentiated forms of acute myeloid leukemia suggesting that these cells represent a more immature fraction of monocytes. In our study, patients with hypercholesterolemia had an increased fraction of CD14dimCD16+ monocytes which both correlated with the E4/E4 phenotype of the apolipoprotein E and low plasma levels of HDL cholesterol.
Both the apolipoprotein E phenotype and the level of cellular apolipoprotein E expression are tightly linked to cellular lipoprotein uptake and metabolism. Thus the expression of the more positively charged apolipoprotein E4 is related to higher plasma cholesterol levels through enhanced hepatic internalization of remnants from triglyceride-rich lipoproteins [11]. Furthermore, the uptake of triglyceride-rich lipoprotein particles and intracellular cholesteryl ester hydrolysis are increased by exogenous apolipoprotein E [12]or dependent on cellular apolipoprotein E secretion [13]. Monogenetic defects of lysosomal acid lipase/acid cholesteryl ester hydrolase (LAL/ACEH; EC 3.1.1.13) expression represent a further well characterized determinant of cellular lipoprotein uptake 14, 15.
In this study individuals with a reduced LAL expression served as a further model for the study of the relation of an abnormal cellular lipid metabolism to the phenotype of mononuclear phagocytes. These individuals were identified among the family members of patients with the autosomal recessive infantile-onset Wolman disease (WD) and late-onset cholesteryl ester storage disease (CESD) which both have been attributed to reduced levels of LAL [15]. Compared to controls, WD patients tend to have <1% LAL activity while CESD patients have enzymatic activities <10%. Recently, the genomic organization of the gene for LAL and different mutations leading to CESD and WD have been identified 16, 17, 18, 19, 20, 21. Genotype-phenotype relations in CESD and WD are, however, still poorly understood.
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Patients and controls
Individuals with a partially defective LAL expression were identified among the family members of patients with WD and CESD. The distribution of the individual alleles and mutations of pedigrees A (CESD) [22], B (CESD) [19], and C (WD) [20]are shown in Fig. 1. The study was approved by the Hospital Ethics Committee and informed consent was obtained from all probands. The nine carriers of LAL mutations had a mean age of 28.6 years. With the exception of a 5 and 7 year old child and a 59 year old
Phenotypic and genetic characterization of defective LAL expression in CESD and WD patients and their family members
The goal of this study was the analysis of the relation of abnormal cellular lipid metabolism to the phenotype of mononuclear phagocytes based on well defined defects of LAL expression in members of the families of CESD and WD patients 19, 20, 22. The distribution of individual alleles and mutations of two pedigrees with CESD and a pedigree with WD which were available for the characterization of peripheral blood mononuclear phagocyte subpopulations are shown in Fig. 1.
Two individuals from
Discussion
The characterization of phenotypic alterations of mononuclear phagocytes in relation to defects of LAL expression, which represent well characterized monogenetically determined disorders of cellular lipoprotein metabolism, represents a new approach towards the characterization of potential cellular mechanisms of atherogenesis. Within the wall, phenotypic alterations of mononuclear phagocytes are characteristically associated to lesion progression 1, 2. Increasingly, however, an altered function
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