MODIFIED LDL, AUTOIMMUNITY AND VASCULAR DISEASE IN DIABETES

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DESCRIPTION: (provided by applicant) High levels of immune complexes (IC) containing oxLDL predict the development of macrovascular complications in type 1 diabetes (DM) and are associated with coronary artery disease (CAD) in type 2 DM. Data obtained during the on-going funding period shows that the levels of oxLDL-IC are significantly associated with internal carotid intima-medial thickness (p<0.001, n=853) and are significantly increased in type 1 DM with micro/macroalbuminuria and moderate/severe retinopathy, compared with levels of LDL-IC in patients with normalalbuminuria or mild retinopathy (p<0.013 and 0.0006, respectively). The levels of LDL-IC are strongly correlated with serum Apo B levels, serum Lp(a) levels and serum triglycerides (p<0.0001, n=853) and have also a significant direct correlation (p<0.0001, n=854) with C-reactive protein and with soluble ICAM-1 (p<0.02, n=455). LDL-IC correlate as well with Hb A1c (p<0.005, n=888), suggesting that glycemic control will impact the formation of LDL-IC. We have also demonstrated in patients with micro or macroalbuminuria that antibodies (Ab) against ox-LDL isolated from oxLDL-IC have a higher affinity than the free Ab present in sera of the same patients. This suggests that one critical factor determining the pathogenicity of oxLDL-IC is the synthesis of oxLDL Ab of moderate affinity, able to form stable IC with pro-inflammatory potential. Because Chlamydia pneumonia has been shown to have a strong epidemiological correlation with CAD and one of its major antigens is a cell wall lipopolysaccharide (LPS), that when released into circulation is transported by lipoproteins, we plan to investigate whether chlamydia LPS is present in IC purified from sera of diabetic patients. The main goal of this proposal is to compare the levels of soluble adhesion molecules (sCAM) and the levels and characteristics of LDL-IC isolated from the sera of a type 2 DM cohort (Prospective VA Cooperative Trial) under intensive or standard glycemic control. We hypothesize that, similarly to type 1 DM, LDL-IC in type 2 DM have pro-inflammatory characteristics and are associated with micro and macrovascular complications. We further hypothesize that intensive glycemic control will impact the formation of IC and the release of CAMs into the circulation. We also propose to determine whether or not patients from the DCCT/EDIC cohort (type 1 DM) and VA cohort 2 (type 2 DM) that develop macrovascular disease, retinopathy and micro/macro-albuminuria have a higher incidence of chronic C. pneumoniae infection and to characterize the IC present in the serum of patients from both cohort 1 and 2 that develop macrovascular disease/nephropathy/retinopathy for oxLDL, oxLDL-Lp(a), AGE-LDL, Chlamdial-LPS or DNA, as well as Ab against these antigens. We will also determine the affinity and isotype distribution of Ab isolated from IC, to evaluate their pro-inflammatory potential. Finally, we will assess possible pathogenic mechanisms triggered by these IC by investigating their ability to induce accumulation of cholesterol in macrophages, kidney mesangial cells and retinal pericytes and to activate these cells leading to the expression of cytokines, sCAM and metalloproteinases. Incorporation of our study into the Program allows us to compare LDL-IC levels with the inflammatory markers and endothelial cell dysfunction markers measured in other projects and that will result in a better understanding of the significance of auto-immune responses to modified forms of LDL to the pathogenesis of atherosclerosis in diabetes.