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Published ahead of print on January 26, 2006, doi:10.1164/rccm.200511-1797PP
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American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 1072-1077, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200511-1797PP

Pulmonary Perspective

The Selective Advantage of {alpha}1-Antitrypsin Deficiency

David A. Lomas

Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, United Kingdom

Correspondence and requests for reprints should be addressed to Prof. David Lomas, Sc.D., F.R.C.P., Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 2XY UK. E-mail: dal16{at}cam.ac.uk

ABSTRACT

The S- and Z-deficiency alleles of {alpha}1-antitrypsin are found in more than 20% of some white populations. This high gene frequency suggests that these mutations confer a selective advantage, but the biologic mechanism of this has remained obscure. It is now well recognized that the S and Z alleles result in a conformational transition within the {alpha}1-antitrypsin molecule and the formation of polymers that are retained within the endoplasmic reticulum of hepatocytes. Polymers of mutant {alpha}1-antitrypsin can also form within the alveoli and small airways of the lung where they may drive the inflammation that underlies emphysema in individuals with {alpha}1-antitrypsin deficiency. This local production of polymers by mutant S and Z {alpha}1-antitrypsin may have also provided protection against infectious disease in the preantibiotic era by focusing and amplifying the inflammatory response to limit invasive respiratory and gastrointestinal infection. It is only since the discovery of antibiotics, the widespread adoption of smoking, and increased longevity that these protective, proinflammatory properties of {alpha}1-antitrypsin mutants have become detrimental to cause the emphysema and systemic inflammatory diseases associated with {alpha}1-antitrypsin deficiency.

Key Words: {alpha}1-antitrypsin • inflammation • polymers • serpinopathies • serpins




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