All ETDs from UAB

Advisory Committee Chair

Janusz H Kabarowski

Advisory Committee Members

G M Anantharamaiah

Geeta Datta

Hubert M Tse

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Apolipoprotein A-I (ApoA-I), the major lipid-binding protein of high-density lipoprotein (HDL), can suppress inflammation and autoimmunity in hypercholesterolemic mice by modulating cellular cholesterol homeostasis and lipid oxidation. However, the cellular and molecular mechanisms involved are poorly understood, and whether ApoA-I or ApoA-I mimetic peptides can similarly exert immunosuppressive effects or improve inflammatory organ disease in SLE under normolipidemic conditions remains unresolved. We therefore first took a genetic approach in which bone marrow from SLE-prone Sle123 mice was transferred into wild-type, ApoA-I knockout (ApoA-I-/-) and ApoA-I transgenic (ApoA-Itg) mice. Transgenic expression of ApoA-I suppressed CD4+ T and B lymphocyte activation, reduced pathogenic interferon-f× (IFNf×) secreting CD4+ T cells, follicular T helper (Tfh) cells and germinal center (GC) B cells, and lowered anti-DNA autoantibodies. Surprisingly, immunosuppression in ApoA-Itg mice was not caused by alterations in lymphocyte cholesterol levels, and ApoA-I deficiency did not exacerbate autoimmunity. Transgenic ApoA-I expression also improved SLE-mediated glomerulonephritis (GN) and attenuated anti-glomerular basement membrane (anti-GBM) antibody mediated GN, the latter independently of immune suppression. Conversely, treatment of SLE-prone gld mice with D-4F ApoA-I mimetic peptide was not immunosuppressive, as it failed reduce anti-DNA autoantibodies or CD4+ T cell and B cell activation compared to untreated controls. D-4F treatment also did not improve SLE-associated GN or attenuate autoimmune-mediated reductions in HDL cholesterol or paraoxonase activity. Additionally, peptide treatment had no effect on SLE phenotypes in more physiologically relevant SLE-prone Sle123 mice. However, D-4F treated Sle123 mice exhibited reduced aortic endothelial dysfunction, an early marker of cardiovascular disease. We conclude that raising HDL through ApoA-I augmentation mediates immunosuppression by attenuating T and B cell activation independently of lymphocyte cholesterol levels. This involves reducing both CD4+ Tfh cells as well as IFNf× producing CD4+ T helper cells. Furthermore, ApoA-I can improve GN by reducing pathogenic autoantibodies in SLE as well as through direct anti-inflammatory action in the kidney possibly mediated by removal of oxidized lipids. Finally, although current HDL-based therapies do not reproduce the immunosuppressive benefits of transgenic ApoA-I expression, mimetic peptide treatments may prove useful in identifying novel lipid pathways associated with immunosuppression and attenuated complications of autoimmune disease.

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