ANCA Glomerulonephritis: From Molecules to Man

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Anti-neutrophil cytoplasmic autoantibody (ANCA) glomerulonephritis (GN) is the most common form of rapidly progressive glomerular disease. The objective of this competitive renewal is to understand the pathogenesis and immunopathogenesis of ANCA GN and to translate the discoveries into optimal patient care, and a number of exciting avenues of investigation will be explored in four distinct yet highly synergistic projects that are efficiently supported by two Cores. Project 1 continues to unravel the molecular underpinning of ANCA GN by elucidating genetic variation and epigenetic regulation of transcription, and by clarifying transcriptional profiles of cells, which will drive investigation and discovery of targeted therapies, including repurposing of FDA-approved drugs. Project 2 explores how modulating adaptive and innate immune responses influences the risk and severity of human ANCA GN. Investigations will address specific questions about the nature of immunodominant epitopes, how ANCA glycovariants affect dendritic cells and B cells, will seek clues as to why certain T cells proliferate and are not suppressible, and will determine the function of CD33+ myeloid cells in ANCA GN. Project 3 will use murine models to advance the understanding of alterations in adaptive and innate immune responses and how these alterations influence risk and severity of murine ANCA GN. In parallel with Project 2, Project 3 will explore epitopes and ANCA glycosylation to confirm findings from human studies regarding pathogenicity. The role of innate immunity will be probed from a number of perspectives, including how complement induces disease. Most interestingly, a model of granulomatous inflammation analogous to that seen in human pathology has been produced in these murine models. Project 4 translates what has been learned in Projects 1, 2 and 3 into clinical investigations focusing on biomarkers that distinguish patients who are in remission and no longer require therapy and help determine the duration of immunotherapy. Project 4 will evaluate a prophylactic approach aimed at preventing morbidity and mortality from infections as a consequence of continued immunotherapy. The Administrative Core provides day-to-day logistical support, while the Clinical Core is strategically situated at the center of human investigations. DNA, RNA, serum, plasma, T cells, and B cells are collected through the Clinical Core from patients at disease onset, upon relapse, and at the time of remission, and the proposed studies will have access to a collection of over 20,000 biological samples from 868 ANCA GN patients followed from disease diagnosis until death in an inception cohort started almost three decades ago. The simultaneous collection of biological material permits comprehensive analysis of genetic and epigenetic influences, and the role of adaptive and innate immune responses. Synergistic, hypothesis-driven studies in humans and animals, emanating from multiple perspectives, pave the way toward the ultimate goal of translating discoveries into methods for improving the lives of patients with ANCA GN. These investigations will have the added value of shedding insight into the nature of autoimmunity and autoimmune disease in general.