Apolipoprotein A-I and its role in lymphocyte cholesterol homeostasis and autoimmunity.
OBJECTIVE
The purpose of this study was to determine the effects of an atherogenic diet on immune function in LDLr(-/-), ApoA-I(-/-) mice.


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.
Wilhelm
Ashley J
AJ
Department of Pathology, Lipid Sciences Research Center, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA.
Zabalawi
Manal
M
Grayson
Jason M
JM
Weant
Ashley E
AE
Major
Amy S
AS
Owen
John
J
Bharadwaj
Manish
M
Walzem
Rosemary
R
Chan
Lawrence
L
Oka
Kazuhiro
K
Thomas
Michael J
MJ
Sorci-Thomas
Mary G
MG
D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism; D001018:Aortic Diseases / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016632:Apolipoprotein A-I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D049109:Cell Proliferation; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D004247:DNA / Q000276:immunology; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D006706:Homeostasis; D008077:Lipoproteins, LDL / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D053482:beta 2-Glycoprotein I / Q000276:immunology
D016632:Apolipoprotein A-I; D001323:Autoantibodies; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D053482:beta 2-Glycoprotein I; C099252:oxidized low density lipoprotein; D004247:DNA; D002784:Cholesterol