The increased susceptibility of patients with chronic inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) to the development of atherosclerosis is a major clinical problem. This association is underlied by a synergistic inter-relationship between autoimmune and atherosclerotic diseases which is also observed in experimental animal models of hypercholesterolemia. However, factors common to chronic inflammation and hypercholesterolemia that contribute to this synergism remain poorly characterized. Hypercholesterolemia is associated with the generation of pro-inflammatory phospholipids in the circulation with etiological connections to chronic inflammatory autoimmune disease. One such phospholipid, ysophosphatidylcholine (LPC), is a major pro-atherogenic product of lipoprotein oxidation and phospholipid hydrolysis by pro-inflammatory phospholipases whose over-production is believed to play a pathophysiological role in SLE. LPC stimulates T cell migration via G2A, a G protein-coupled receptor expressed predominantly in ymphocytes and monocyte-derived cells. We recently determined that deletion of G2A in hypercholesterolemic low-density lipoprotein receptor knockout (LDLR-/-) mice suppresses atherosclerosis. Hypercholesterolemia in G2A-deficient (G2A-/-) LDLR-/- mice resulted in significant depletion of lymphocytes from peripheral lymph nodes with concomitant reductions in the numbers of activated and effector CD4+ cells. This suggests that loss of normal G2A-mediated migratory responses of circulating lymphocytes to elevations in blood LPC levels are responsible for the development of lymphopenic lymph nodes. We hypothesize that G2A regulates adaptive immune responses during an inflammatory response by promoting lymphocyte trafficking through lymph nodes in response to transient elevations in circulating LPC levels to ensure efficient antigen surveillance. We propose that the deregulation of this mechanism due to sustained elevations in LPC associated with hypercholesterolemia and chronic inflammation contributes to the synergism between atherosclerotic and autoimmune diseases by promoting T cell-mediated immune responses to auto-antigens. We will test this hypothesis by measuring the impact of G2A deficiency on T cell entry into, and egress from, lymph nodes under normocholesterolemic and hypercholesterolemic conditions. We will also evaluate atherosclerosis and autoimmunity in hypercholesterolemic lupus-prone gld mice in the presence or absence of G2A function;we will determine whether loss of G2A function in hypercholesterolemic gld mice suppresses autoimmune responses to classical lupus antigens, attenuates the development of overt symptoms of autoimmunity, and results in reduced CD4+ T cell-mediated immune responses to atherosclerosis-related auto-antigens. These studies will provide important insight into novel lipidmediated mechanisms underlying the synergistic inter-relationship between autoimmunity and atherosclerosis

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Center Core Grants (P30)
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Special Emphasis Panel (ZAR1)
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University of Alabama Birmingham
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