Faculty Collaboration Database

Apolipoprotein A-I and its role in lymphocyte cholesterol homeostasis and autoimmunity. Arterioscler Thromb Vasc Biol 2009 Jun;29(6):843-9

Date

03/17/2009

Pubmed ID

19286630

Pubmed Central ID

PMC2761013

DOI

10.1161/ATVBAHA.108.183442

Scopus ID

2-s2.0-66349139424 (requires institutional sign-in at Scopus site)   102 Citations

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 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.

Author List

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

Authors

Mary Sorci Thomas PhD Professor in the Medicine department at Medical College of Wisconsin
Michael J. Thomas PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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