Summary
Patients homozygous for the Z allele of alpha-1-antitrypsin (α1AT) have very low serum levels and are predisposed to emphysema. There have also been reports of emphysema being associated with the heterozygous phenotype FZ. To investigate whether Fα1AT was dysfunctional, the inhibitory activity of Fα1AT against human neutrophil elastase (HNE) was compared with that of common α1AT phenotypes. Time-dependent inhibition of HNE by α1AT was used to calculate the association rate constant (k assoc) for M, MZ, FM, FZ, F (partially purified from FZ or FS), Z and S α1AT phenotypes in human sera. The results for k assoc at 25°C were 9.1 (SD 0.9), 9.7 (SD 0.9), 8.0 (SD 0.8), 4.0 (SD 0.4), 4.2 (SD 0.8), 5.1 (SD 0.6) and 8.6 (SD 0.6) × 106 M−1s−1 respectively. F was found to have reduced activity much like that of Z, the α1AT most commonly associated with emphysema. MZ (low risk for disease) and FZ heterozygotes had similar intermediate α1AT levels. However the in vivo inhibition time for FZ was almost three times longer than for MZ, indicating greater exposure to proteolytic damage from free elastase for FZ than MZ individuals.
In conclusion, Fα1AT is expressed in serum at low normal levels but is dysfunctional in its ability to inhibit HNE. Individuals who coinherit the F and a deficiency allele such as Z or Null, are likely to have a high risk for the development of emphysema. The disease risk for F homozygotes remains to be determined.