DNA graphic

Barbara Vilen, PhD

Associate Professor

The University of North Carolina at Chapel Hill

Microbiology and Immunology

http://vilenlab.wixsite.com/vilenlab/about

The role of immune complexes and BAFF in promoting atherosclerosis in lupus

SLE is characterized by immune dysregulation and inflammation, and is associated with cardiovascular disease, diabetes, and obesity. This suggests a connection between immune-mediated inflammation, defects in metabolism, and cardiovascular disease. In this application we propose to use a model of lupus to investigate the potential interplay between the immune, endocrine, and cardiovascular systems. Our goal is to define whether the immune regulators that contribute to lupus nephritis are linked to the dysregulation of cellular metabolic processes during the development of atherosclerosis. Heightened BAFF is associated with lupus and our recent findings in MRL/lpr mice show that one source of BAFF arises from constitutive binding and recycling of FcgammaR1 (FcgR1) bound by IgG immune complexes formed from apoptotic debris (IgG-apop ICs). We postulate that the elevated BAFF chronically activates PI3K/mTOR leading to the activation and maturation of adipocytes thereby augmenting adipocyte-mediated inflammation. To address this, we will use a previously characterized passive autoantibody transfer model wherein we inject anti-nucleosome into MRL/lpr mice lacking IgG (AID-/-/MRL/lpr). This induces the accumulation of IgG-apop ICs on hematopoietic cells and leads to heightened serum BAFF. Using this model, we will address whether mTOR-mediated lipid synthesis is augmented as BAFF levels rise, whether myeloid cells accumulate lipid bodies, whether adipocytes are activated, and whether atherosclerosis is evident. Also, we will delineate the in vivo contributions of BAFF receptor (BR3), FcgR1, and mTOR through neutralization, blocking, or gene deletion of BR3 or FcgR1. Overall, this proposal is significant because the preliminary studies identify one pathway that leads to heightened BAFF secretion in lupus, and proposes to identify how that pathway may lead to atherosclerosis. If successful, this study will advance our understanding of cardiovascular disease in SLE and potentially identify targets for effective therapeutics.

Together, ManyOne Can make a difference!
Stay informed about events, research developments, and ways you can help. Sign up for updates