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Comparison of PR3-ANCA and MPO-ANCA Epitope Specificity upon Disease Relapse
Citation:
Roth, A., W. Winnik, J. McGregor, E. Berg, C. Jennette, J. Jennette, G. Preston, AND R. Falk. Comparison of PR3-ANCA and MPO-ANCA Epitope Specificity upon Disease Relapse. Presented at American Society of Nephrology, October 30 - November 04, 2012.
Impact/Purpose:
This manuscript resulted from advising a UNC student Aleeza Roth by Witold Winnik. No laboratory work was performed in EPA. The interaction with the student resulted in a refinement of mass spectrometry methodology that might benefit future EPA projects performed within the RCU Proteomics Research Core.
Description:
BACKGROUND Relapse is a major clinical problem in ANCA vasculitis that causes increased morbidity and mortality. Compared to MPO-ANCA patients, patients with PR3-ANCA run a significantly increased risk of experiencing relapses. We hypothesized that a relapsing patient is producing autoantibodies with epitope specificities differing from those at disease onset. METHODS Epitope mapping entailed immobilizing ANCA to native PR3 or MPO, which protects epitopes from enzymatic digestion. Epitopes were eluted and identified by matrix-assisted laser desorption mass spectrometry (MALDI-MS). 16O-to-18O exchange was used to detect peptide targets of low level autoantibodies from healthy individuals. Autoantibody specificity was determined for 25 patients (active vs. relapse) and 15 healthy individuals. RESULTS A total of 14 PR3 epitopes or 25 MPO epitopes were detected from patients with active disease. Upon reactivation of disease PR3-ANCA patients developed additional unique anti-PR3 autoantibodies whereas MPO-ANCA patients did not. MPO-ANCA target the same MPO epitopes upon reactivation of disease. In contrast, PR3-ANCA patients develop anti-PR3 that do not target the same epitopes. Natural PR3-ANCA (3/14) and MPO-ANCA (12/25) from patients in remission and healthy controls reacted at very low levels with dissimilar epitopes. CONCLUSIONS ANCA titers in clinical assays reflect a combination of both pathogenic and nonpathogenic ANCA. Relapse of disease in patients with PR3-ANCA, un-like MPO-ANCA, develop a different repertoire of B cell clones which target previously unrecognized epitopes. This abstract does not necessarily reflect EPA policy.