The increased susceptibility of patients with chronic inflammatory autoimmune diseases such as systemic lupuserythematosus (SLE) and rheumatoid arthritis (RA) to the development of atherosclerosis is a major clinicalproblem. This association is underlied by a synergistic inter-relationship between autoimmune and atheroscleroticdiseases which is also observed in experimental animal models of hypercholesterolemia. However, factorscommon to chronic inflammation and hypercholesterolemia that contribute to this synergism remain poorlycharacterized. Hypercholesterolemia is associated with the generation of pro-inflammatory phospholipids in thecirculation with etiological connections to chronic inflammatory autoimmune disease. One such phospholipid,ysophosphatidylcholine (LPC), is a major pro-atherogenic product of lipoprotein oxidation and phospholipidhydrolysis by pro-inflammatory phospholipases whose over-production is believed to play a pathophysiologicalrole in SLE. LPC stimulates T cell migration via G2A, a G protein-coupled receptor expressed predominantly inymphocytes and monocyte-derived cells. We recently determined that deletion of G2A in hypercholesterolemiclow-density lipoprotein receptor knockout (LDLR-/-) mice suppresses atherosclerosis. Hypercholesterolemia inG2A-deficient (G2A-/-) LDLR-/- mice resulted in significant depletion of lymphocytes from peripheral lymph nodeswith concomitant reductions in the numbers of activated and effector CD4+ cells. This suggests that loss ofnormal G2A-mediated migratory responses of circulating lymphocytes to elevations in blood LPC levels areresponsible for the development of lymphopenic lymph nodes. We hypothesize that G2A regulates adaptiveimmune responses during an inflammatory response by promoting lymphocyte trafficking through lymph nodes inresponse to transient elevations in circulating LPC levels to ensure efficient antigen surveillance. We propose thatthe deregulation of this mechanism due to sustained elevations in LPC associated with hypercholesterolemia andchronic inflammation contributes to the synergism between atherosclerotic and autoimmune diseases bypromoting T cell-mediated immune responses to auto-antigens. We will test this hypothesis by measuring theimpact of G2A deficiency on T cell entry into, and egress from, lymph nodes under normocholesterolemic andhypercholesterolemic conditions. We will also evaluate atherosclerosis and autoimmunity in hypercholesterolemiclupus-prone gld mice in the presence or absence of G2A function; we will determine whether loss of G2A functionin hypercholesterolemic gld mice suppresses autoimmune responses to classical lupus antigens, attenuates thedevelopment of overt symptoms of autoimmunity, and results in reduced CD4+ T cell-mediated immuneresponses to atherosclerosis-related auto-antigens. These studies will provide important insight into novel lipidmediatedmechanisms underlying the synergistic inter-relationship between autoimmunity and atherosclerosis
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