α1-Antitrypsin deficiency and anti-proteinase 3 antibodies in anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis

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Abstract
SUMMARY: α1-antitrypsin (α1-AT) is a naturally occurring inhibitor of proteinase 3 (PR3) and elastase, two of the target antigens of anti-neutrophil cytoplasmic antibodies (ANCA). An increased incidence of α1-AT phenotypes associated with dysfunctional α1-AT or low serum levels has been reported in patients with anti-PR3 antibodies. We have studied the relationship between ANCA, and phenotypes and serum levels of α1-AT. Phenotypes usually associated with a moderate or severe reduction in α1-AT serum levels or in dysfunctional activity were found more often in individuals with anti-PR3 antibodies than in the general population: four of the 31 patients (13%) with anti-PR3 antibodies had phenotypes MZ (n= 2), S (n= 1) or Z (n= 1) (P < 0·05). However, the corresponding α1-AT serum levels were normal (n= 3) or elevated (n= 1). None of the 31 sera with anti-PR3 antibodies had low levels of α1-AT. No abnormal α1-AT phenotype was demonstrated in seven patients with anti-elastase antibodies, despite a low level of α1-AT in one serum. Anti-myeloperoxidase antibodies are common in patients with ANCA, but no abnormal phenotype or low serum oi-AT level was demonstrated in any of 29 sera containing these antibodies. Finally anti-glomerular basement membrane (GBM) antibodies occur occasionally in patients with ANCA-associated diseases, but again none of 10 sera had an abnormal α1-AT phenotype or low serum level. ANCA were not demonstrated by indirect immunofluorescence in any serum from 73 patients with abnormal α1-AT phenotypes. These results confirm that patients with anti-PR3 antibodies often have α1-AT phenotypes that are usually associated with low serum levels of α1-AT or with dysfunctional protein. Nevertheless, the incidence of anti-PR3 antibodies in patients with abnormal α1-AT phenotypes is very low. This probably reflects the rarity of Wegener's granulomatosis, the major disease associated with anti-PR3 antibodies, and the relative frequency of abnormal α1-AT phenotypes. The mechanism for the development of anti-PR3 antibodies in patients with abnormal α1-AT phenotypes is not clear, but may relate to the increased propensity of unbound and uninhibited PR3 to stimulate autoantibody production.