This project explores the biology of remission and relapse in patients with antl-neutrophil cytoplasmic autoantibodies (ANCA) glomerulonephritis and small vessel vasculitis (ANCA disease). The genesis of this exploration stems from the clinical observation that some patients with ANCA disease have 30 years of remission while others have repetitive relapses of significant disease. Ideally, patients destined to relapse should have targeted therapy based on the mechanism responsible for their relapse, and those in remission should be spared immunosuppressive therapy. Although clinical predictors of relapse have been Identified, we have only a rudimentary understanding of the mechanistic basis for relapse and remission. This project takes advantage of our longitudinal ANCA disease cohort to examine relapse and remission from several perspectives.
Aim 1 will consider whether relapse is a consequence of aberrant epigenetic regulation of genes encoding the autoantigens myeloperoxidase (MPO) and proteinase 3 (PR3). Building on our basic science findings that epigenetically controlled gene silencing is absent at PR3 and MPO genomic loci In patients with active disease, whether epigenetic silencing of the autoantigen genes is lost during relapse and re-established during remission will be determined.
Aim 2 examines whether relapse stems from aberrant B cell function. Is there clonal expansion of the same autoreactive B cell cloneiIn disease onset and relapse, or is relapse a consequence of a new B cell population reactive to different epitopes of MPO and PR3? Whether relapse is due to dysregulated B cells, in the circulation or tissue, that permit production of autoantibodies will be Investigated.
In Aim 3, T cell regulation is explored with a focus on T regulatory cells that appear functionally "ineffective" in relapsing disease. Is relapse caused by an Imbalance in T regulatory cells and proinflamatory Th17 cells that is restored during remission? These analyses will be performed simultaneously and repetitively over time in ANCA disease patients allowing us to gain a mechanistic understanding of the biology of remission and relapse. These observations have broad implications for the care of patients with ANCA disease and for relapsing and remitting autoimmune disease of all types.

Public Health Relevance

It Is not known why some patients with ANCA disease are treated and stay In long-term remission while others have relapses. This study will help understand the biology of remission and relapse, so treatments can be tailored to the patient. Those who stay in remission could avoid needless toxic immunosuppressive therapy, while those who relapse could be treated with drugs that suppress the cause of disease activity. Insights into the biology of this disease will help in understanding other autoimmune diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-R)
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University of North Carolina Chapel Hill
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Aybar, L T; McGregor, J G; Hogan, S L et al. (2015) Reduced CD5(+) CD24(hi) CD38(hi) and interleukin-10(+) regulatory B cells in active anti-neutrophil cytoplasmic autoantibody-associated vasculitis permit increased circulating autoantibodies. Clin Exp Immunol 180:178-88
Cao, Yali; Liu, Kuo; Tian, Zhigang et al. (2015) PTPN22 R620W polymorphism and ANCA disease risk in white populations: a metaanalysis. J Rheumatol 42:292-9
Jennette, J Charles; Falk, Ronald J (2014) B cell-mediated pathogenesis of ANCA-mediated vasculitis. Semin Immunopathol 36:327-38
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Xiao, Hong; Dairaghi, Daniel J; Powers, Jay P et al. (2014) C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol 25:225-31
Geetha, Duvuru; Poulton, Caroline J; Hu, Yichun et al. (2014) Clinical characteristics and outcome of pauci-immune glomerulonephritis in African Americans. Semin Arthritis Rheum 43:778-83
Xiao, Hong; Ciavatta, Dominic; Aylor, David L et al. (2013) Genetically determined severity of anti-myeloperoxidase glomerulonephritis. Am J Pathol 182:1219-26
Jennette, J Charles (2013) Overview of the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Clin Exp Nephrol 17:603-6
Free, Meghan E; Bunch, Donna O'Dell; McGregor, Julie Anne et al. (2013) Patients with antineutrophil cytoplasmic antibody-associated vasculitis have defective Treg cell function exacerbated by the presence of a suppression-resistant effector cell population. Arthritis Rheum 65:1922-33

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