Complexes between proteinase 3, α1-antitrypsin and proteinase 3 anti-neutrophil cytoplasm autoantibodies: a comparison between α1-antitrypsin PiZ allele carriers and non-carriers with Wegener's granulomatosis

To test the hypothesis that anti-neutrophil cytoplasm autoantibodies (ANCAs) interfere with the functions of proteinase 3 (PR3) (the Wegener autoantigen) and α₁-antitrypsin (α₁AT), complexes of PR3/α₁AT and PR3/PR3-ANCA-IgG were assayed. Plasma samples were obtained from 44 patients with Wegener's granulomatosis (WG): 34 had active disease (88% ANCA positive) whereas 10 patients were in remission (20% ANCA positive). Plasma samples from 14 of the patients with active disease were also available at the time of remission. The complexes of PR3/α₁AT and PR3/PR3-ANCA-IgG were detected by capture enzyme-linked immunoassays (ELISAs). α₁AT deficiency was evaluated by determining PiZ alleles by ELISA. Eight (18%) of the patients were PiZ positive. The frequency of this α₁-antitrypsin phenotype in the Scandinavian population is 4.7% (P < 0.001). The median PR3/α₁AT complex level in the PiZ-positive group with active disease (n = 5) was similar to the level in the PiZ-negative group with active disease. During remission the median level for the PR3/α₁AT complex was significantly higher than in the acute group (P < 0.001) including both PiZ-positive and PiZ-negative patients. No difference between PiZ positivity and PiZ negativity could be found in the remission group. PR3/PR3-ANCA-IgG complexes were found in patients with acute disease as well as in patients in remission, in almost equal frequency. This complex was also present in 13/18 ANCA-negative samples from patients in remission. Finally, purified IgG fractions from WG patients were examined for their capacity to inhibit binding between PR3 and α₁AT. An effect on the binding between PR3 and α₁AT by PR3-ANCA could not be demonstrated. Thus, our results do not support the hypothesis that PR3-ANCA interferes with the binding between PR3 and α₁AT. However, the high prevalence of the PiZ alleles among WG patients suggests that an imbalance between proteinases and α₁AT may be of importance in this disease. The clinical usefulness of both the PR3/α₁AT and the PR3/PR3-ANCA-IgG complexes and the possible influence on ANCA detection need to be examined in prospective longitudinal studies.