Glomerulonephritis and vasculitis caused by anti-neutrophil cytoplasmic autoantibodies (ANCA) Is the most common form of rapidly progressive glomerular disease. The objective of this competitive renewal is to improve the lives of patients with ANCA disease by elucidating the underlying immunologic and pathogenic mechanisms, and translating this knowledge into improved patient care. During the current Program Project, we have made substantial progress in a number of exciting avenues of exploration that will be pursued in four Projects and two Cores. Project 1 investigates epigenetic regulation of neutrophil genes, and genes that modify the phenotype of ANCA disease. Project 2 explores the biology of relapse and remission in a unique cohort of ANCA disease patients from the perspective of epigenetic regulation of autoantigen genes, B cell autoreactivity and T cell dysregualtion. Project 3 uses animal models of ANCA disease to study Involvement of the alternative complement pathway and Fcy receptors In pathogenesis. Induction of disease by different antigens, and the genetic basis for variations In disease severity. Project 4 provides translation of our more basic research Into clinical investigations to Improve ANCA disease outcomes. We will take advantage of our discoveries of pathogenic roles for epigenetic regulation and complement activation by treating patients with retinoic acid to alter myeloid gene expression and with antl-C5 antibodies to block complement activation. As an extension of the discovery of anti-plamsinogen antibodies while studying autoantigen complementarity, we will determine If venous thrombosis in ANCA disease patients is attributable to these antibodies. The Clinical Core is key to our studies and has allowed us to follow patients with ANCA disease for almost a quarter century. From this valuable patient cohort, we have obtained crucial clinical and pathological Information, and biological specimens. An Administrative Core provides underpinnings of our work. There is substantial synergy among all projects, each projects focus on ANCA disease from different perspectives, and the hypotheses can be tested In human and animal systems. Importantly, the lessons we are learning pertain not only to ANCA disease but also to autoimmunity and Inflammation in general.

Public Health Relevance

Antineutrophil cytoplasmic autoantibodies (ANCA) are antibodies that activate inflammatory cells (neutrophils) In the blood causing them to attack small blood vessels in many organs resulting in vascular Inflammation (vasculitis). This inflammation often involves the small filtering units of the kidney (glomeruli) resulting in glomerulonephritis. The research in this project will study ANCA disease in the test tube, in experimental animals and In patients with the goal of Improving treatment for this severe disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK058335-14
Application #
8512585
Study Section
Special Emphasis Panel (ZDK1-GRB-R (M1))
Program Officer
Flessner, Michael Francis
Project Start
2000-09-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
14
Fiscal Year
2013
Total Cost
$1,454,972
Indirect Cost
$471,883
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Free, Meghan E; Falk, Ronald J (2016) The Search for a Biomarker of Relapse in ANCA-Associated Vasculitis. J Am Soc Nephrol 27:2551-3
Mariani, Laura H; Pendergraft 3rd, William F; Kretzler, Matthias (2016) Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach in Nephrology. Clin J Am Soc Nephrol 11:2054-2060
Yang, Jiajin; Ge, Heng; Poulton, Caroline J et al. (2016) Histone modification signature at myeloperoxidase and proteinase 3 in patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis. Clin Epigenetics 8:85
Zhu, Meng-Lei; Bakhru, Pearl; Conley, Bridget et al. (2016) Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat Commun 7:11350
Rhee, Rennie L; Hogan, Susan L; Poulton, Caroline J et al. (2016) Trends in Long-Term Outcomes Among Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Renal Disease. Arthritis Rheumatol 68:1711-20
Thrasher, Bradly J; Hong, Lee Kyung; Whitmire, Jason K et al. (2016) Epigenetic Dysfunction in Turner Syndrome Immune Cells. Curr Allergy Asthma Rep 16:36
Bakhru, Pearl; Su, Maureen A (2016) Estrogen turns down ""the AIRE"". J Clin Invest 126:1239-41
Jennette, J Charles; Falk, Ronald J (2015) ANCAs are also antimonocyte cytoplasmic autoantibodies. Clin J Am Soc Nephrol 10:4-6
Pendergraft 3rd, William F; Badhwar, Anshul K; Preston, Gloria A (2015) Autoantigen complementarity and its contributions to hallmarks of autoimmune disease. J Theor Biol 375:88-94
Bunch, Donna O; Mendoza, Carmen E; Aybar, Lydia T et al. (2015) Gleaning relapse risk from B cell phenotype: decreased CD5+ B cells portend a shorter time to relapse after B cell depletion in patients with ANCA-associated vasculitis. Ann Rheum Dis 74:1784-6

Showing the most recent 10 out of 75 publications