Apolipoprotein A-I and Its Role in Lymphocyte Cholesterol Homeostasis and Autoimmunity

Abstract

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 ≈1.5-fold increase in T cell proliferation and activation. Plasma antibodies to dsDNA, β2-glycoprotein I, and oxidized LDL were increased in DKO, similar to levels in diet-fed Faslpr/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 gre... Diet-fed DKO mice exhibit accumulation of cholesterol in skin draining LNs. This accumulation was associated with an expansion and activation of T and B lymphocytes and increased concentrations of circulating autoantibodies. Diet-fed DKO mice also showed increased aortic atherosclerosis compared to SKO mice despite having lower levels of plasma cholesterol. These results suggest that apoA-I is important in regulating specific inflammatory pathways as they relate to the development of atherosclerosis.