ALPHA(1)-ANTITRYPSIN DEFICIENCY AND ANTIPROTEINASE 3 ANTIBODIES IN ANTINEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-ASSOCIATED SYSTEMIC VASCULITIS

alpha(1)-antitrypsin (alpha(1)-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 alpha(1)-AT phenotypes associated with dysfunctional alpha(1)-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 alpha(1)-AT. Phenotypes usually associated with a moderate or severe reduction in alpha(1)-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 alpha(1)-AT serum levels were normal (n = 3) or elevated (n = 1). None of the 31 sera with anti-PR3 antibodies had low levels of alpha(1)-AT. No abnormal alpha(1)-AT phenotype was demonstrated in seven patients with anti-elastase antibodies, despite a low level of alpha(1)-AT in one serum. Anti-myeloperoxidase antibodies are common in patients with ANCA, but no abnormal phenotype or low serum alpha(1)-AT level was demonstrated in any of 29 sera containing these antibodies. Finally anti-glomerular basement membrane (GEM) antibodies occur occasionally in patients with ANCA-associated diseases, but again none of 10 sera had an abnormal alpha(1)-AT phenotype or low serum level. ANCA were not demonstrated by indirect immunofluorescence in any serum from 73 patients with abnormal alpha(1)-AT phenotypes. These results confirm that patients with anti-PR3 antibodies often have alpha(1)-AT phenotypes that are usually associated with low serum levels of alpha(1)-AT or with dysfunctional protein. Nevertheless, the incidence of anti-PR3 antibodies in patients with abnormal alpha(1)-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 alpha(1)-AT phenotypes. The mechanism for the development of anti-PR3 antibodies in patients with abnormal alpha(1)-AT phenotypes is not clear, but may relate to the increased propensity of unbound and uninhibited PR3 to stimulate autoantibody production.