The branch is focusing on identifying the role of aberrant neutrophils and neutrophil extracellular traps in the development of autoimmune responses and end-organ damage in systemic diseases including lupus (SLE), rheumatoid arthritis (RA) and systemic vasculitides (AAV). During this year, our group has identified specific components of NETs that may be involved in inducing vascular damage and is also investigating the mechanisms of oxidant production by neutrophils that may promote immune-mediated damage in lupus and other diseases. We have also reported that NETs are a source of citrullinated autoantigens and this phenomenon may be important in the initiation and perpetuation of aberrant inflammatory responses in rheumatoid arthritis. We found that NET formation is enhanced in RA both in blood and synovium, NETs externalize citrullinated proteins that are known to be important autoantigens in RA. Autoantibodies to citrullinate proteins in turn enhance NET formation. NETs promote synovial fibroblast inflammation. Ongoing work is attempting to further elucidate the interplay between NETs and synovial fibroblasts as an amplification mechanism in inflammatory arthritides in human and murine models. Lupus patients have evidence of aberrant HDL, which is highly oxidized and displays abnormal function, as measured by reverse cholesterol transport. We have studied during this year how this HDL may modify myeloid cell function and promote inflammation leading to premature vascular disease. Following a bench to bedside approach we are actively studying a well-characterized cardiovascular lupus cohort which is being followed prospectively for identification of novel biomarkers that predict progression of vascular inflammation, endothelial dysfunction and premature vascular events. We are using sophisticated imaging and functional vascular assays to quantify these abnormalities in lupus patients. We have initiated a clinical trial to assess the role of PPAR-gamma agonists in modulating vascular function and disease activity in lupus patients, at the NIH Clinical Center. In collaboration with other investigators at NIAMS, we are investigating how JAK inhibitors may modulate autoimmunity and vascular damage in lupus using murine systems in vivo and human systems in vitro. Finally, in collaboration with Dr. Peter Grayson, we are focusing on better understanding how medications that are known to induce autoimmunity modulate immunogenicity of neutrophils as a mechanism leading to immune dysregulation. This applies to diseases like ANCA-vasculitis and lupus.
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