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Protective alpha1-antitrypsin effects in autoimmune vasculitis are compromised by methionine oxidation

Item Type:Article
Title:Protective alpha1-antitrypsin effects in autoimmune vasculitis are compromised by methionine oxidation
Creators Name:Ebert, M.J. and Jerke, U. and Eulenberg-Gustavus, C. and Kling, L. and Jenne, D.E. and Kirchner, M. and Mertins, P. and Bieringer, M. and Elitok, S. and Eckardt, K.U. and Schreiber, A. and Salama, A.D. and Kettritz, R.
Abstract:BACKGROUND: Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitidies (AAV) are life-threatening systemic autoimmune conditions. ANCA directed against proteinase 3 (PR3) or myeloperoxidase (MPO) bind their cell surface-presented antigen, activate neutrophils and cause vasculitis. An imbalance between PR3 and its major inhibitor a1-antitrypsin (AAT) was proposed to underlie PR3- but not MPO-AAV. We measured AAT and PR3 in healthies and AAV patients and studied protective AAT effects pertaining to PR3- and MPO-ANCA. METHODS: Plasma and blood neutrophils were assessed for PR3 and AAT. Wild-type, mutant, and oxidation-resistant AAT species were produced to characterize AAT-PR3 interactions by flow cytometry, immunoblotting, FRET assays, and surface plasmon resonance measurements. Neutrophil activation was measured using the ferricytochrome C assay and AAT methionine-oxidation by Parallel Reaction Monitoring. RESULTS: We found significantly increased PR3 and AAT pools in both PR3- and MPO-AAV patients, however, only in PR3-AAV did the PR3 pool correlate with ANCA titer, inflammatory response and disease severity. Mechanistically, AAT prevented PR3 from binding to CD177, thereby reducing neutrophil surface antigen for ligation by PR3-ANCA. Active PR3-AAV patients showed critical methionine-oxidation in plasma AAT that was recapitulated by ANCA-activated neutrophils. The protective PR3-related AAT effects were compromised by methionine-oxidation in the AAT reactive center loop but preserved when two critical methionines were substituted by valine and leucine. CONCLUSION: Pathogenic differences between PR3- and MPO-AAV are related to AAT regulation of membrane-PR3, attenuating neutrophil activation by PR3- rather than MPO-ANCA. Oxidation-resistant AAT could serve as adjunctive therapy in PR3-AAV.
Keywords:Proteinase 3, Alpha1-Antitrypsin, Neutrophils, Anti-Neutrophil Cytoplasmic, Autoantibodies, Vasculitis
Source:Journal of Clinical Investigation
ISSN:0021-9738
Publisher:American Society for Clinical Investigation
Page Range:e160089
Date:20 September 2022
Official Publication:https://doi.org/10.1172/jci160089
PubMed:View item in PubMed

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