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T-lymphocytes and monocytes in atherogenesis

T-Lymphozyten und Monozyten in der Pathogenese der Arteriosklerose

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Abstract

Atherosclerosis is characterized as a chronic inflammatory-fibroproliferative disease of the vessel wall. The attachment of monocytes and T-lymphocytes to the injured endothelium followed by their migration into the intima is one of the first and most crucial steps in lesion development. The co-localization of CD4+T-cells and macrophages in the lesion, the abundant expression of HLA Class II molecules and the co-stimulatory molecule CD40 and its ligand (CD40L) indicate a contribution of cell-mediated immunity to atherogenesis. Transgenic mouse models revealed that dependent on the model T- and B-cells may promote lesion progression, monocytes and macrophages are in contrast essential for the development of atherosclerotic lesions. Apart from the local process in the vessel wall, systemic signs of an inflammatory reaction are also associated with lesion development. Thus plasma levels of C-reactive protein and fibrinogen and the white blood cell count are positively correlated to the risk of cardiovascular disease. Recently, an inflammatory phenotype of circulating peripheral blood monocytes could be demonstrated as a specific cellular correlate to lipid and lipoprotein risk factors. Thus the pool size of LPS receptor (CD14)dim and FcγIIIa receptor (CD16a)+ monocytes positively correlates to plasma cholesterol levels, to triglycerides levels and to the apolipoprotein E4 (apo E4) phenotype in contrast to a negative correlation to the high density lipoprotein (HDL) cholesterol concentration. This CD14dim CD16a+ monocytes are further characterized by a high expression of β1- and β2-integrins, suggesting a higher capacity for attachment at sites of inflammation. A proinflammatory cytokine pattern and an expansion of these cells in other inflammatory diseases are indicating that these cells promore the inflammatory process during atherogenesis. Surface expression of the activation antigen CD45RA on monocytes in correlation to plasma LDL cholesterol and Lp(a) levels further indicates an inflammatory reaction. Regarding the potential mechanisms of the phenotypic changes of peripheral blood monocytes, in a serum free in vitro differentiation model supplemented with M-CSF monocytes from probands which are homozygous for apo E4 showed a significantly higher increase of CD16a expression compared to apo E3/E3 cells indicating that a genetic polymorphism of a single apolipoprotiin gene locus may affect monocyte differentiation. The further characterization of the cellular immunology of monocytes and T-lymphocytes in lesion development will provide new specific diagnostic and therapeutic targets in atherogenesis.

Zusammenfassung

Die Arteriosklerose läßt sich als chronische, inflammatorisch-fibroproliferative Erkrankung der Gefäßwand charakterisieren. Als Antwort auf unterschiedliche Ursachen einer Endothelschädigung adhärieren zirkulierende Monozyten und T-Lymphozyten an das Endothel und wandern in die Gefäßintima. Die Kolokalisation von CD4+-T-Zellen und Makrophagen in der Läsion, die zahlreiche Expression von HLA-Klasse-II-Molekülen und des kostimulatorischen Moleküls CD40 und seines Liganden weisen darauf him, daß neben einer unspezifischen Inflammation auch eine spezifische zellvermittelte Immunantwort einen Beitrag zur Atherogenese leistet. Transgene Mausmodelle zeigen, daß in Abhängikeit des Modells T- und B-Lymphozyten die Entwicklung der arteriosklerotischen Läsionen verstärken können, im Unterschied zu Monozyten/Makrophagen aber nicht unbedingt notwending für deren Entwicklung sind. Neben dem lokal inflammatorischen Prozeß in der Gefäßwand sind auch systemische Zeichen einer entzündlichen Reaktion mit der Entwicklung der Arteriosklerose verbunden. So korrelieren Plasmaspiegel des C-reaktiven Proteins, des Fibrinogens und die Höhe der Leukozytenkonzentration positiv mit dem Risiko einer kardiovaskulären Erkrankung. Kärzlich konnte gezeigt werden, daß mit Lipid- und Lipoproteinrisikofaktoren der Atherogenese ein inflammatorischer Phänotyp der zirkulierenden Monozyten als spezifisches zelluläres Korrelat assoziiert ist. So zeigt die Populationsgröße der Monozyten, die den LPS-Rezeptor CD14 schwach und den FcγIIIa-Rezeptor CD16a stärker exprimieren, eine positive Korrelation mit der Plasmacholesterinkonzentration sowie mit dem Apolipoprotein-E4-Phänotyp und eine negative Korrelation zu HDL-Cholesterinwerten. Diese CD14schwach-CD16a+-Monozyten sind ferner durch eine hohe Expression von β1-and β2-Integrinen charakterisiert, was ein Hinweis auf eine stärkere Fähigkeit dieser Monozyten zur Adhärenz an entzündetes Gewebe sein könnte. Ein proinflammatorisches Zytokinmuster und eine Expansion dieser Zellen auch bei anderen entzündlichen Erkrankungen lassen vermuten, daß diese Zellen den entzündlichen Prozeß der Atherogenese weiter vorantreiben könnten. Ferner zeigt sich sowohl zum LDL-Cholesterin-als auch zum Lp(a)-Spiegel des Plasmas eine positive Korrelation der Expression des Aktivierungsantigens CD45RA auf allen Monozyten als Ausdruck einer entzündlichen Reaktion. Um potentielle Mechanismen dieser phänotypischen Veränderungen der Monozyten des peripheren Blutes weiter aufzudecken, wurde die Monozytendifferenzierung in einem serumfreien In-vitro-Differenzierungsmodell unter Zugabe von M-CSF analysiert. Hierbei war bei Monozyten von für das Apolipoprotein E4 homozygoten Spendern ein signifikant höherer Anstieg der CD16a-Expression im Vergleich zu Apo-E3/E3-Zellen zu beobachten, ein Zeichen, daß ein genetischer Polymorphismus eines einzelnen Apolipoprotein-Genlokus die Monozytendifferenzierung beiinflussen kann. Die weitere Charakterisierung der zellulären Immunologie von Monozyten und T-Lymphozyten in der Entwicklung von arteriosklerotischen Läsionen sollte neue spezifische Ansatzpunkte für die Diagnostik und Therapie der Arteriosklerose eröffnen.

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  1. Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Deutschland

    Gerd Schmitz & Gregor Rothe

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  1. Gerd Schmitz
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  2. Alexandra S. Herr
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  3. Gregor Rothe
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Correspondence to Gerd Schmitz.

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Schmitz, G., Herr, A.S. & Rothe, G. T-lymphocytes and monocytes in atherogenesis. Herz 23, 168–177 (1998). https://doi.org/10.1007/BF03044602

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