Apolipoprotein A-I and its role in lymphocyte cholesterol homeostasis and autoimmunity.

Wilhelm AJ, Zabalawi M, Grayson JM, Weant AE, Major AS, Owen J, Bharadwaj M, Walzem R, Chan L, Oka K, Thomas MJ, Sorci-Thomas MG
Arterioscler Thromb Vasc Biol. 2009 29 (6): 843-9

PMID: 19286630 · PMCID: PMC2761013 · DOI:10.1161/ATVBAHA.108.183442

OBJECTIVE - The purpose of this study was to determine the effects of an atherogenic diet on immune function in LDLr(-/-), ApoA-I(-/-) mice.

METHODS AND RESULTS - When LDLr(-/-), ApoA-I(-/-) (DKO), and LDLr(-/-) (SKO) mice were fed an atherogenic diet, DKO had larger peripheral lymph nodes (LNs) and spleens compared to SKO mice. LNs were enriched in cholesterol and contain expanded populations of T, B, dendritic cells, and macrophages. Expansion of all classes of LN cells was accompanied by a approximately 1.5-fold increase in T cell proliferation and activation. Plasma antibodies to dsDNA, beta2-glycoprotein I, and oxidized LDL were increased in DKO, similar to levels in diet-fed Fas(lpr/lpr) mice, suggesting the development of an autoimmune phenotype. Both LN enlargement and cellular cholesterol expansion were "prevented" when diet-fed DKO mice were treated with helper dependent adenovirus expressing apoA-I. Independent of the amount of dietary cholesterol, DKO mice consistently showed lower plasma cholesterol than SKO mice, yet greater aortic cholesterol deposition and inflammation.

CONCLUSIONS - ApoA-I prevented cholesterol-associated lymphocyte activation and proliferation in peripheral LN of diet-fed DKO mice. A approximately 1.5-fold increase in T cell activation and proliferation was associated with a approximately 3-fold increase in concentrations of circulating autoantibodies and approximately 2-fold increase in the severity of atherosclerosis suggesting a common link between plasma apoA-I, inflammation, and atherosclerosis.

MeSH Terms (25)

Animals Aorta Aortic Diseases Apolipoprotein A-I Atherosclerosis Autoantibodies Autoimmunity beta 2-Glycoprotein I Cell Proliferation Cholesterol Diet, Atherogenic Disease Models, Animal DNA Homeostasis Lipoproteins, LDL Lymph Nodes Lymphocyte Activation Male Mice Mice, Inbred C57BL Mice, Knockout Receptors, LDL Spleen T-Lymphocytes Time Factors

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