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Published ahead of print on January 26, 2006, doi:10.1164/rccm.200511-1797PP

Am. J. Respir. Crit. Care Med., Volume 173, Number 10, May 2006, 1072-1077

A more recent version of this article appeared on May 15, 2006
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Submitted on November 23, 2005
Accepted on January 26, 2006

The Selective Advantage of Alpha-1-antitrypsin Deficiency

David A Lomas1*

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

* To whom correspondence should be addressed. E-mail: dal16{at}cam.ac.uk.

The S and Z deficiency alleles of {alpha}1-antitrypsin are found in over 20% of some Caucasian populations. This high gene frequency suggests that these mutations confer a selective advantage but the biological mechanism of this has remained obscure. It is now well recognised 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 pre-antibiotic 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, pro-inflammatory 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, serpins, serpinopathies, polymers, inflammation




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