This dissertation focuses on the interaction of antineutrophil cytoplasmic autoantibodies (ANCA) and two of their target autoantigens, myeloperoxidase and lysosomal membrane protein 2. The results of these interactions reveal novel epitopes associated with disease activity in granulomatosis with polyangiitis (GPA). The relationship between lysosomal membrane protein 2 (LAMP-2), a putative 3rd autoantigen, and ANCA disease is described in Chapter 1. In 2008, LAMP-2 was purposed to be a novel autoantigen which predicted relapse in ANCA disease. Exhaustive efforts uncovered that antibodies directed to LAMP-2 were not specific to ANCA disease nor were they relevant to disease activity in two US patient cohorts. Chapter 2 investigates the binding sites of myeloperoxidase (MPO) specific autoantibodies in sera samples from patients with ANCA glomerulonephritis and healthy controls. We proposed to prove the hypothesis that anti-MPO autoantibodies are restricted to a limited number of epitopes on MPO and whether circulating autoantibodies target the same epitopes during relapse and remission. In addition, to identify MPO epitopes of interest, a conformation dependent proteomics assay was used in conjunction with traditional immunologic methods. An ANCA disease associated epitope was uncovered (Chapter 3) with an association with disease activity. The discovery of this epitope has lead to the development of a preclinical test for ANCA disease (patent pending). As a whole, this is a comprehensive body of work which determines the complete profile of MPO specific epitopes found in a patient cohort in the southeastern US.