Systemic Autoimmunity

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications & trials

Abstract

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), inflammatory myopathies and systemic vasculitides (AAV) as well as various autoinflammatory syndromes. During this year, our group focused on understanding modulation of innate immune pathways by altering immunometabolism, including modulation of the NAD pathway and the itaconate pathway. We also reported new advances on how NETs damage cartilage in rheumatoid arthritis, through a process that involves distinct post-translational modifications of NET autoantigens through carbamylation. Carbamylated NETs appear to display a distinct pathogenic effect on osteoclastogenesis, with implications for bone erosions and joint damage in RA and periodontitis. Studies have also focused on better understanding neutrophil heterogeneity in health and disease using single cell RNA sequencing analysis and other single cell methodology. The branch uses sophisticated gene expression approaches including RNA sequencing, ATAC sequencing and single cell RNA sequencing to better understand cellular heterogeneity in autoimmune diseases and the role of specific cell subsets in mediating pathogenesis. The branch is also exploring how sex differences modulate neutrophil biology using similar techniques. We continue to use sophisticated imaging and functional vascular assays to quantify blood vessel abnormalities in lupus patients. We reported the results of a clinical trial to assess the role of PPAR-gamma agonists in modulating vascular function and disease activity in lupus patients and found that pioglitazone favorably modulated vascular dysfunction and aberrant metabolic responses in SLE. In recent studies, we are expanding our expertise in neutrophil biology to understand how neutrophil dysregulation is implicated in the pathogenesis of COVID-19. We recently reported the results of a multicenter study in pediatric and adult populations and show COVID-19 promotes NET dysregulation and impairments in NET clearance in association with disease activity. We also found that different variants of the virus differently influence NET dysregulation.