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Apolipoprotein A-I modulates regulatory T cells in autoimmune LDLr-/-, ApoA-I-/- mice.

Wilhelm AJ, Zabalawi M, Owen JS, Shah D, Grayson JM, Major AS, Bhat S, Gibbs DP, Thomas MJ, Sorci-Thomas MG
J Biol Chem. 2010 285 (46): 36158-69

PMID: 20833724 · PMCID: PMC2975238 · DOI:10.1074/jbc.M110.134130

The immune system is complex, with multiple layers of regulation that serve to prevent the production of self-antigens. One layer of regulation involves regulatory T cells (Tregs) that play an essential role in maintaining peripheral self-tolerance. Patients with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis have decreased levels of HDL, suggesting that apoA-I concentrations may be important in preventing autoimmunity and the loss of self-tolerance. In published studies, hypercholesterolemic mice lacking HDL apoA-I or LDLr(-/-), apoA-I(-/-) (DKO), exhibit characteristics of autoimmunity in response to an atherogenic diet. This phenotype is characterized by enlarged cholesterol-enriched lymph nodes (LNs), as well as increased T cell activation, proliferation, and the production of autoantibodies in plasma. In this study, we investigated whether treatment of mice with lipid-free apoA-I could attenuate the autoimmune phenotype. To do this, DKO mice were first fed an atherogenic diet containing 0.1% cholesterol, 10% fat for 6 weeks, after which treatment with apoA-I was begun. Subcutaneous injections of 500 μg of lipid-free apoA-I was administered every 48 h during the treatment phase. These and control mice were maintained for an additional 6 weeks on the diet. At the end of the 12-week study, DKO mice showed decreased numbers of LN immune cells, whereas Tregs were proportionately increased. Accompanying this increase in Tregs was a decrease in the percentage of effector/effector memory T cells. Furthermore, lipid accumulation in LN and skin was reduced. These results suggest that treatment with apoA-I reduces inflammation in DKO mice by augmenting the effectiveness of the LN Treg response.

MeSH Terms (25)

Animals Apolipoprotein A-I Autoimmunity CD3 Complex CD11c Antigen Cell Proliferation Cholesterol, HDL Dendritic Cells Diet, Atherogenic Female Flow Cytometry Humans Injections, Subcutaneous Lipids Lymph Nodes Lymphocyte Activation Lymphocyte Count Macrophages Male Mice Mice, Inbred C57BL Microscopy, Fluorescence Receptors, LDL Skin T-Lymphocytes, Regulatory

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