Circulating polymers in a1-antitrypsin deficiency

Most individuals carry two wild-type M alleles of the SERPINA1 gene which encodes a1-antitrypsin. 95% of severe deficiency of a1-antitrypsin is associated with the Z allele (Glu342Lys; denoted PiZZ in the homozygote), and with the retention and polymerisation of a1-antitrypsin within hepatocytes [1]. These polymers are contained within periodic acid–Schiff-positive, diastase-resistant inclusions that are associated with neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The concomitant lack of circulating a1-antitrypsin predisposes the Z a1-antitrypsin homozygote to early-onset emphysema. Polymers of a1-antitrypsin form within the lung as a result of local inflammation and exposure to cigarette smoke [2]. They have also been identified in the skin of an individual with a1-antitrypsin deficiency and panniculitis [3] and in a renal biopsy from an individual with a1-antitrypsin deficiency and vasculitis [4]. It is unknown whether these polymers form locally or are deposited in these tissues from a circulating source, and whether extrahepatic polymers are associated with any disease phenotypes. We have assessed whether polymers of a1-antitrypsin are present within serum, from where they originate, and whether they are associated with clinical features in individuals with PiZZ a1-antitrypsin deficiency. In this investigation we used ELISA with the anti-a1-antitrypsin polymer monoclonal antibody (2C1) [5] to assess the presence of polymers in the plasma of 1) 518 individuals with PiZZ a1-antitrypsin deficiency; 2) an individual with a1-antitrypsin deficiency who underwent liver transplantation; and 3) 293 individuals with a mixture of a1-antitrypsin phenotypes. The specificity of the 2C1 antibody was confirmed by using it to immunoprecipitate polymers from the plasma of individuals with and without a positive signal on ELISA (fig. 1a).