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.
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.
|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|
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