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- Mechanisms of accelerated atherosclerosis in systemic lupus erythematosus (SLE).
The autoimmune disease SLE is associated with production of antibodies against such self-antigens as double-stranded DNA, histones and phospholipids. A common cause (up to 30%) of mortality in SLE is accelerated atherosclerosis leading to myocardial infarction or stroke. This atherosclerosis, unlike that seen in the general population, is most prevalent in young premenopausal women: a population usually associated with protection from cardiovascular disease. We developed a unique, viable animal model to study the immunological mechanisms of accelerated atherosclerosis in the context of SLE. One of the most important findings of these studies was that the atherosclerotic lesions of lupus-susceptible animals have a three-fold increase in the absolute numbers of T cells and that transfer of these T cells alone is enough to accelerate atherosclerosis. Ongoing projects are focused on understanding this T cell biology and identifying therapeutic targets of lupus and atherosclerosis.
- The role of oxLDL-immune complexes and Fcg receptors in inflammation and atherosclerosis.
Antibody responses to oxidized low density lipoprotein (oxLDL) are a prominent feature of atherosclerosis. One possible mechanism for antibody-mediated modulation of atherosclerosis is through the formation of oxLDL immune complexes (ICs). ICs can regulate inflammation in atherosclerosis by interacting with Fc gamma receptors (FcgRs) expressed on the surface of antigen presenting cells, such as dendritic cells (DCs) and macrophages. Not surprisingly, signaling through FcgRs is tightly regulated and FcgR signaling has been shown to be linked to Toll like receptor-4(TLR-4), a pattern recognition receptor. Both oxLDL-ICs and DCs expressing TLR-4 are present in the atherosclerotic plaque of humans. Therefore, understanding how the FcgRs and TLR-4 signaling pathways interact in the context of atherosclerosis is likely mechanistically important.
- Mechanisms and concequences of HDL small RNA communication in systemic lupus erytematosus (SLE).
In collaboration with the laboratory of Kasey Vickers, Ph.D. we are studying how microRNAs associated with HDL may regulate immune function in SLE. MicroRNAs (miRNAs) are small non-coding RNAs with high gene regulatory potential and function in cell-to-cell communication. Previous work from our laboratory demonstrated that HDL serves as a media to transfer miRNAs between cells in a receptor-dependent manner. We hypothesize that HDL transfers miRNAs between monocytes, macrophages, T cells and B cells and this intercellular communication is altered in SLE. Using established and novel methods, including high-throughput small and long RNA sequencing, PhotoActivatable Ribonucleoside CrossLinking ImmunoPrecipitation (PAR-CLIP), and high-end bioinformatics we will test the hypothesis that changes in cell-to-cell communication networks likely leads to T cell imbalance and B cell activation observed in SLE.