DNA Methylation in Patients with ANCA-associated Vasculitis: Emerging Differences Based on Cell Type, Disease Serotype and Activity



Britta Jones


Research Mentor:

Dr. Ron Falk, MD


Clinical Co-mentor:

Dr. Dominic Ciavatta, PhD

Home Department Pathology & Laboratory Science
Project Description
Systemic small-vessel vasculitis is characterized by circulating anti-neutrophil cytoplasmic autoantibodies (ANCA). ANCA-associated vasculitis is an autoimmune disease in which patients have pathogenic autoantibodies reacting to myeloperoxidase (MPO) or proteinase 3 (PR3) and exhibit glomerulonephritis and systemic vasculitisANCA bind to these antigens on the surface of neutrophils and monocytes and activate the cells, leading to downstream vasculitis. These autoantibodies are only part of what contributes to ANCA-associated vasculitis. 

Normally, MPO and PR3 are silenced, but in patients with ANCA disease these antigens are aberrantly expressed in monocytes and mature neutrophils. Abundant antigen expression on the surface of neutrophils and monocytes, in the presence of ANCA, predispose an individual to ANCA-mediated vasculitis. Additionally, dysregulation of CD4+ T cells contribute to ANCA-associated vasculitis by permitting autoantibody formation. 

Studies within our laboratory have shown that epigenetic status plays a role in the transcriptional activity of MPO and PR3. These studies implicate a failure in normal gene silencing by showing that aberrant expression in patients with ANCA disease can result from decreased histone methylation. Histone modifications and DNA methylation are two epigenetic mechanisms considered to play a role in the etiology of ANCA disease. DNA methylation is known to regulate gene transcription and cellular function through its effect on DNA accessibility state. The ability of the epigenome to be modified in response to environmental factors makes this field particularly promising in the study of immune-mediated conditions, such as ANCA disease. We hypothesize that, regardless of disease phenotype and status, altered DNA methylation profiles exist in ANCA patients and contribute to the etiology of ANCA-associated vasculitis.