DESCRIPTION OVERALL (provided by applicant): Our Program Project focuses on the study of anti-neutrophil cytoplasmic autoantibody (ANCA) glomerulonephritis. The objective of this competitive renewal remains the elucidation of the causes and pathogenic mechanisms of ANCA necrotizing and crescentic glomerulonephritis. During the last four years of our current Program Project, we have made substantial progress in our understanding of this disease. This progress has opened a number of exciting avenues of exploration that we have divided into four projects and two cores. Project 1 is an immunopathogenesis study centered on our most recent observation that a complementary peptide to proteinase 3 may stimulate the autoimmune response. This most intriguing study has broad implications for all autoimmunity. In Project 2, we explore the role of ANCA-antigens (proteinase 3 and myeloperoxidase) and their interaction with autoantibodies, B cells and T cells;and their participation in the induction of. vascular injury. Project 3 focuses on the molecular genetics of ANCA glomerulonephritis and explores genes that are permissive for or that modify the phenotype and course of ANCA glomerulonephritis. During the current Program Project, we elucidated an animal model in which antimyeloperoxidase antibodies or lymphocytes were passively transferred into na[unreadable]ve recipient mice and induced a human-like pauci-immune necrotizing and crescentic glomerulonephritis. Project 4 will take advantage of this novel animal model to elucidate pathogenic mechanisms. The Clinical Core is key to all of our studies and allows us to follow patients with ANCA glomerulonephritis for almost 20 years. From these patients, we have been able to obtain crucial clinical and pathological information and biological specimens for all of our studies. There is substantial synergy among all of these projects for three reasons: (1) because all of the projects focus on ANCA glomerulonephritis, (2) ideas gleaned from one project have direct bearing on studies performed in another project, and (3) the same hypotheses can be tested in different projects in human and animal systems both in vivo and in vitro. During our current Program Project interval, we have made a number of seminal observations pertaining not only specifically to ANCA glomerulonephritis but also to autoimmunity and inflammation in general. Substantial progress has been made, however, we have much yet to learn about "ANCA glomerulonephritis: from molecules to man".