The Selective Advantage of α1-Antitrypsin Deficiency

DA Lomas - American journal of respiratory and critical care …, 2006 - atsjournals.org
American journal of respiratory and critical care medicine, 2006atsjournals.org
The S-and Z-deficiency alleles of α1-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 α1-
antitrypsin molecule and the formation of polymers that are retained within the endoplasmic
reticulum of hepatocytes. Polymers of mutant α1-antitrypsin can also form within the alveoli …
The S- and Z-deficiency alleles of α1-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 α1-antitrypsin molecule and the formation of polymers that are retained within the endoplasmic reticulum of hepatocytes. Polymers of mutant α1-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 α1-antitrypsin deficiency. This local production of polymers by mutant S and Z α1-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 α1-antitrypsin mutants have become detrimental to cause the emphysema and systemic inflammatory diseases associated with α1-antitrypsin deficiency.
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