The most frequent question that patients ask at the time of diagnosis of antl-neutrophil cytoplasmic autoantibody (ANCA) disease Is "what caused my disease"? Currently, we are studying the Immunopathogenesis of ANCA disease from the perspective of the autoantibody. Now we turn our attention to epigenetic regulation of the autoantigens and to genes that modify disease phenotype.
Aim 1 builds on our discovery that mature, multi-lobed peripheral neutrophils from patients are expressing PR3 and MPO transcripts normally seen only In Immature bone marrow cells. We have shown that loss of RUNX3 suppressor function is linked with loss of methylation status of histone H3K27, a quintessential histone modification involved in epigenetic gene silencing. Further, we know that the environmentally responsive histone demethylase, JumonjI D3, is Increased In patients. We will explore whether there Is an epigenomic signature that predisposes patients to ANCA disease. Genetically modified mice will be used to explore how RUNX3, the histone methyltransferase Enhancer of Zeste 2, and JumonjI D3 regulate neutrophil gene expression. Finally, we will study the fate of aberrant transcripts of the autoantigen including sense and antisense transcripts. The results of this aim will focus attention on epigenetic regulation of the critical autoantigen genes as Important to the etiology of ANCA disease.
In Aim 2 we focus our attention on specific genes that modify the phenotype of ANCA disease. Genes Implicated in modifying phenotype in other autoimmune diseases will be tested for association with subgroups of ANCA disease patients, based on the hypothesis that these genes will modulate the phenotype of ANCA disease. New candidate genes. Identified in a mouse genome wide screen for quantitative trait loci, will be examined for alleles that associate with ANCA disease. Finally, genome wide association studies comparing genotypes of ANCA cases versus healthy controls, and ANCA patients with good versus poor outcomes will uncover genetic loci that govern disease susceptibility and prognosis. Uncovering genetic influences of ANCA disease will make strides towards the ultimate goal of answering the question of what causes ANCA disease.

Public Health Relevance

Autoimmune disease affects -2.5 million Americans. Our studies will impact our understanding of immunopathogenesis of autoimmunity and neutrophil biology in general. We offer a novel concept that Turning off aberrantly expressed genes Is a creditable therapeutic target In ANCA disease, which would dramatically open a therapeutic window for other autoimmune diseases. Identification of autoimmunlty-llnked genes will likely provide clues for the basis of other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK058335-15
Application #
8707431
Study Section
Special Emphasis Panel (ZDK1-GRB-R)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
15
Fiscal Year
2014
Total Cost
$337,293
Indirect Cost
$108,774
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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
Joy, Melanie S; Roberts, Brittney V; Wang, Jinzhao et al. (2014) A pilot study of leukocyte expression patterns for drug metabolizing enzyme and transporter transcripts in autoimmune glomerulonephritis. Int J Clin Pharmacol Ther 52:303-13
Jennette, J Charles; Falk, Ronald J (2014) Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease. Nat Rev Rheumatol 10:463-73
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

Showing the most recent 10 out of 42 publications