54-OR: Nucleolin Autoantibody Accelerates Atherosclerosis in Type 1 Diabetes

Abstract

Hyperglycemia has been evaluated extensively as risk factors for cardiovascular disease (CVD) in people with type 1 diabetes (T1DM). However, the effects of the autoantibody on atherosclerosis and immunogenic trigger are not well understood in T1D. Using the generated several mice models of atherosclerosis including NOD, congenic ApoE-/-/NOD (NDM and no- autoimmune), ApoE-/-/NOD (autoimmunity with insulitis, NDM) and ApoE-/-/NOD autoimmune DM mice, we analyzed immune cells composition of aorta and have observed the increasing numbers of CD3+(CD3+/CD25-), Th1 and Th17 subset of T cells and B cells and decreased Treg (CD3+/CD25+/Foxp3+) in the ApoE-/-/NOD and ApoE-/-/NOD-DM mice vs. control. In addition, we postulate that the identification of specific autoantibody(s) which induce dysregulaton of T-cells, resulting in enhancing its infiltration and accumulation at the plaques could aid new immunotherapies for atherosclerosis. Here we performed autoantigen microarrays to profile and identify specific autoantibodies, enhancing the severe atherosclerosis in subgroups of Medalist patients with chronic duration of T1D due to autoimmunity with positive HLA DR3/4 risk alleles and autoantibodies and compared to the people with monogenic diabetes lacking HLA DR3/4 risk alleles for T1D and autoantibodies. Autoantigen microarrays from the plasma of T1D patients with positive DR3/4 risk and CVD identified 8 autoantibodies changed in the context of atherosclerosis, compared to the people with monogenic diabetes. To confirm the autoantibody profiling data from the patients, we analyzed the autoantibody profiles in the T1D mice models of atherosclerosis described above. Autoantigen microarrays analysis of the plasma of T1D patients and mice showed several common findings that reached significance anti-Nucleolin Ab, p=0.005. These findings indicate autoimmunity may contribute to the progression of atherosclerosis in T1D. Further studies are in progress to replicate these findings in other cohorts of T1D. Disclosure K. Park: None. Q. Li: None. H. Park: None. J. Fu: None. S. Kissler: None. E. Maddaloni: Research Support; Self; European Foundation for the Study of Diabetes, Speaker's Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck KGaA. I. Wu: None. A. H. Lichtman: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc. Funding DK036836, DK036836, EY026080