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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

{alpha}1-Antitrypsin deficiency is one of the most common genetic disorders to affect the white population. Indeed, 7.7% of the northern European population and 25% of individuals in the Iberian Peninsula carry either the S- or Z-deficiency alleles (1). There have been significant advances during the past 40 years in our understanding of the pathobiology of {alpha}1-antitrypsin deficiency, but many questions remain unanswered. Perhaps one of the most perplexing questions is "Why have these mutations been retained during evolution?" More specifically, "What is the selective advantage provided by a mutation that causes liver and lung disease in affected individuals?" Recent developments in understanding the molecular mechanisms that underlie {alpha}1-antitrypsin deficiency now allow us to address this question. This perspective will review our understanding of {alpha}1-antitrypsin deficiency and then address the issue of the selective advantage provided by the S and Z mutations.

EPIDEMIOLOGY AND EVOLUTION OF {alpha}1-ANTITRYPSIN DEFICIENCY

{alpha}1-Antitrypsin deficiency was first described by Carl-Bertil Laurell and Sten Eriksson in 1963 (2). Since that time, two point mutations have been shown to explain the vast majority of cases of {alpha}1-antitrypsin deficiency. The Z allele (Glu342Lys) causes the most severe plasma deficiency and is most prevalent in southern Scandinavia and the northwest European seaboard, with gene frequencies reducing toward the south and east of the continent (1). In contrast, the S allele (Glu264Val) causes only mild plasma deficiency and is most common in southern Europe and becomes less frequent as one moves northeast. The frequencies of the Z allele in the United States are similar to the lowest frequencies in Europe, but the S allele is more common than in northern Europeans. {alpha}1-Antitrypsin deficiency is infrequent in the Asian, African, and Middle Eastern populations (3). It is also rare in Japan, but, when present, it is usually the result of the Siiyama mutation (Ser53Phe) (4). In the genetically isolated island of Sardinia, the most common cause of severe {alpha}1-antitrypsin deficiency is the Mmalton mutation (deletion of residue 52) (5).

The Z allele is believed to have arisen from a single origin 66 generations or 2,000 years ago after the divergence of the races (6, 7). The high frequency in southern Scandinavia suggests that the mutation arose in the Viking population. The date of origin implies that the allele arose when the Vikings populated mid- or northern Europe and before their migration to Scandinavia. It is likely that the Z allele of {alpha}1-antitrypsin was then distributed across northern Europe by the Viking raiders between 800 and 1,100 A.D., and then to the United States and rest of the world during migration during the past 200 years. The S allele appears to have arisen in the north of the Iberian Peninsula, but the date of origin is uncertain (7). This mutation was similarly introduced into North America by mass migration.

Z {alpha}1-ANTITRYPSIN IS RETAINED AS POLYMERS WITHIN HEPATOCYTES TO CAUSE LIVER DISEASE

The Z allele causes the abnormal accumulation of mutant {alpha}1-antitrypsin as diastase-resistant, periodic acid-Schiff–positive inclusions of {alpha}1-antitrypsin within the periportal cells of the liver. This intrahepatic accumulation of Z {alpha}1-antitrypsin starts in utero and results in neonatal hepatitis with approximately 80% of homozygote children having abnormal liver function tests in the first year of life (8). Liver function tests return to normal in many cases, but 15% of homozygotes develop a cholestatic jaundice, with 10% of these progressing to established cirrhosis. Most children avoid significant liver damage in childhood, but are still at risk of disease in adult life (9). The factors that predict progressive disease are unclear, but males and the obese appear to be most at risk (10). The retention of Z {alpha}1-antitrypsin within hepatocytes results in a lack of circulating plasma {alpha}1-antitrypsin. This leaves the lungs exposed to enzymatic damage that is thought to underlie the early onset adult emphysema (see later).

The Z variant of {alpha}1-antitrypsin is retained within hepatocytes because it causes a unique conformational transition and protein–protein interaction (11). The Z mutation distorts the relationship between the reactive center loop and beta-sheet A within the {alpha}1-antitrypsin molecule (Figure 1). The consequent perturbation in structure shifts the equilibrium toward an unstable intermediate (M*) and the formation of polymers in which the reactive center loop of one {alpha}1-antitrypsin molecule sequentially inserts into beta-sheet A of another (11–17). Polymers form spontaneously under physiologic conditions with the resulting species being stable in high concentrations of denaturants, such as 8 M urea. It is these polymers that accumulate within the endoplasmic reticulum of hepatocytes to form the periodic acid-Schiff–positive inclusions that are the hallmark of Z {alpha}1-antitrypsin liver disease (11, 16, 18). The process of intrahepatic polymerization also underlies the severe plasma deficiency of the rare Siiyama and Mmalton deficiency alleles (19, 20) and the mild plasma deficiency of the S and I (Arg39Cys) variants (21, 22). There is a strong genotype–phenotype correlation that can be explained by the molecular instability caused by the mutation and, in particular, the rate at which the mutant forms polymers. Those mutants that cause the most rapid polymerization cause the most retention of {alpha}1-antitrypsin within the liver. This in turn correlates with the greatest risk of liver damage and cirrhosis and the most severe plasma deficiency.


Figure 1
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  		Figure 1. The protective effect of {alpha}1-antitrypsin polymers. The Z mutation (black arrow on M) or S, I, Siiyama, and Mmalton variants in the shutter domain (blue circle) open beta-sheet A (green) of the monomeric protein (M) to favor the formation of a dimer (D), which then extends into polymers (P) (11, 13, 60). The polymers are illustrated both as linked molecules and as an electron micrograph. In the molecular representation, the individual {alpha}1-antitrypsin molecules are in yellow, red, and blue for clarity. These polymers form spontaneously in the endoplasmic reticulum of hepatocytes to form the periodic acid-Schiff–positive inclusions that characterize Z {alpha}1-antitrypsin deficiency. The 10–15% of Z {alpha}1-antitrypsin that escapes into the circulation, and that produced by local tissues (such as bronchial and gastrointestinal epithelial cells and macrophages), has the propensity to form polymers. After an acute bacterial or viral infection, there is an increased release of Z {alpha}1-antitrypsin from the liver and a concentration of {alpha}1-antitrypsin at the site of infection. This, together with raised temperature and low pH, favors the formation of polymers that in turn cause an exaggerated inflammatory response and so clearance of the infective insult.

 
Z {alpha}1-ANTITRYPSIN FORMS INTRAPULMONARY POLYMERS THAT CAUSE INAPPROPRIATE INFLAMMATION

Individuals who are homozygous for the Z allele are at risk of early-onset emphysema, particularly if they smoke (23, 24). Emphysema associated with Z {alpha}1-antitrypsin deficiency differs from "usual chronic obstructive pulmonary disease," with normal levels of M {alpha}1-antitrypsin, in that it affects predominantly the bases rather than the apices of the lungs, it is associated with panlobular rather than centrilobular disease, and it results from the expression of different genes when assessed by microarray analysis (25). Emphysema associated with {alpha}1-antitrypsin deficiency is also characterized by excessive intrapulmonary inflammation. Examination of lung lavage from individuals with PI ZZ {alpha}1-antitrypsin deficiency reveals an excess of inflammatory cytokines or neutrophils at the early stages of disease in nonsmokers (26), at a time of established airflow obstruction (27) or transplantation (28), and during exacerbations (29). In all cases, the inflammation was more marked than in individuals with a comparable severity of airflow obstruction or emphysema and the normal PI MM {alpha}1-antitrypsin phenotype (26–29). The excessive inflammation has been attributed to raised levels of interleukin (IL)-8 or leukotriene B4 (LTB4) (30), but these are likely to be effector molecules rather than the underlying etiologic factor. An alternative suggestion is that the lack of intrapulmonary Z {alpha}1-antitrypsin, combined with the fivefold reduction in association rate kinetics with neutrophil elastase caused by the Z mutation (31, 32), result in an excess of free enzyme that in turn drives inflammation and tissue destruction. However, although this may be the case during exacerbations (29), there is little evidence of free enzyme in lung lavage from individuals with PI ZZ {alpha}1-antitrypsin deficiency who have stable disease (33). Nevertheless, because neutrophil elastase is the major target proteinase of {alpha}1-antitrypsin, it is likely that this enzyme plays a central role in tissue destruction in the lungs of patients with {alpha}1-antitrypsin deficiency.

The recognition that Z {alpha}1-antitrypsin formed polymers within hepatocytes provoked an examination of their role in the associated emphysema. {alpha}1-Antitrypsin is present within the lung by passive diffusion or local secretion by bronchial epithelial cells (34) and macrophages (35). In each case, the secreted protein contains the Z (or other) mutation and hence the propensity to spontaneously form polymers. Indeed, polymers have been identified within lung lavage (36, 37) and within the alveoli of explanted tissue from patients with emphysema associated with Z {alpha}1-antitrypsin deficiency (28), but not in samples from individuals with emphysema and normal {alpha}1-antitrypsin phenotypes. This conformational transition from monomer to polymer inactivates {alpha}1-antitrypsin as a proteinase inhibitor (32), thereby further reducing the already depleted levels of {alpha}1-antitrypsin that are available to protect the alveoli. Thus, the {alpha}1-antitrypsin that is present within the lung may be ineffective. Moreover, the conversion of {alpha}1-antitrypsin from a monomer to a polymer converts it from a proteinase inhibitor to a chemoattractant for human and mouse neutrophils (28, 37, 38). In one study, this was apparent after treating neutrophils with LPS (39). The magnitude of the effect is similar to that of the chemoattractants C5a or IL-8 and present over a range of physiologic concentrations (EC50, 4.5 ± 2 µg/ml) (37, 38). It is this observation that may explain the excessive inflammation within the lung of individuals with {alpha}1-antitrypsin deficiency. Despite this observation, much remains to be determined, inter alia, do polymers form in response to smoking, infective organisms, or the inhalation of environmental dusts? Are they cleared from the lung and, if so, over what period of time and by which pathway? Is there a gradient of polymers between the alveolar surface and the blood that drives chemotaxis? What is the mechanism or receptor by which polymers activate neutrophils and do they activate other inflammatory cells (especially T cells and macrophages)? Can polymers prime inflammatory cells such that they are sensitized to other chemoattractants? Is there interplay between polymers and bronchial epithelial cells and how do they interact with other inflammatory mediators or other genetic factors (40) to cause disease? Despite these and many other unresolved issues, a central role for polymers in the pathogenesis of emphysema is possible. It may explain the differences in pathology (there are no polymers in the lungs of individuals with emphysema as a result of "usual chronic obstructive pulmonary disease" [28]) as well as the basal distribution of disease. One can envisage a mechanism by which the additional blood flow to the bases of the lungs brings with it higher concentrations of Z {alpha}1-antitrypsin and so more polymers, more inflammation, and more disease. The only study in which this has been assessed reported no difference in the distribution of polymers between the bases and apices (28). However, the lungs were assessed at the time of transplantation and therefore had widespread emphysema with end-stage tissue destruction. The distribution of polymers still needs to be determined in individuals with early or moderate emphysema.

Z {alpha}1-ANTITRYPSIN POLYMERS AND SYSTEMIC INFLAMMATION

The observation that polymers are proinflammatory may also explain the association of Z {alpha}1-antitrypsin with other inflammatory conditions. Several anecdotal and epidemiologic studies have linked Z {alpha}1-antitrypsin deficiency (or the Z allele) to panniculitis (or Christian-Weber syndrome) (41), Wegener's granulomatosis (42), glomerulonephritis (43), asthma (44), bronchiectasis (45), and pancreatitis (46), although the association between {alpha}1-antitrypsin deficiency and bronchiectasis has been disputed in another study (47). One can consider the inflammatory response in individuals with {alpha}1-antitrypsin deficiency to be set at a higher level than in normal individuals. Thus they respond to inflammatory insults with more vigorous recruitment of neutrophils that not only clears the invading organism or insult but also causes collateral tissue damage. Given that polymers are proinflammatory for neutrophils (and possibly other cells of the inflammatory response), it is feasible that they underlie this exuberant inflammation in different organs. However, there have been no studies investigating the role of polymers in any of these conditions.

THE SURVIVAL ADVANTAGE OF Z AND S {alpha}1-ANTITRYPSIN

The heightened inflammatory response seen in Z homozygotes, and to a lesser extent in MZ heterozygotes (48), is central to the proposed hypothesis because it is also likely to be important in protecting against invading pathogens. This is particularly the case because {alpha}1-antitrypsin is an acute-phase protein. Invading organisms cause a systemic inflammatory response that results in an increase in secretion of Z {alpha}1-antitrypsin by hepatocytes (although not to the same extent as in M {alpha}1-antitrypsin homozygotes). They also cause a rise in body temperature and the concentration of mutant {alpha}1-antitrypsin at the site of the inflammatory insult (49). Moreover, {alpha}1-antitrypsin is produced locally by the lung (34) and the gut (50), the two organs that are the most common site of entry of pathogens. The acute inflammatory response lowers the pH at the site of bacterial invasion. The high concentration of Z {alpha}1-antitrypsin at the site of infection, the raised temperature, and the low pH combine together to favor the polymerization of mutant {alpha}1-antitrypsin (11, 12, 32). The chemotactic properties of polymers would in turn amplify the inflammatory response and enhance the recruitment of protective neutrophils (Figure 1).

Over the centuries of evolution and in the preantibiotic era, the largest threat to man has been infectious disease; pneumonia, tuberculosis, influenza, and gastroenteritis accounted for 40% of all deaths in the United States in 1900. Thus, more inflammation would lead to a more rapid clearance of infection and a higher chance of recovery. The risk of death from liver disease in childhood, even in a Z {alpha}1-antitrypsin homozygote, is relatively small (1–2%) and so would not itself cause a significant depletion in allele frequency given that infant mortality in the United States and Europe in 1900 was 100–140/1,000 live births. Moreover, the average life expectancy in the middle of the 19th century was 43 years (www.prb.org), and so the risk of emphysema at ages 50 to 60 years was not sufficient to negate the protective advantage against infectious disease. Finally, the most significant factor in driving lung inflammation, tobacco smoking, was not widely adopted until this century (51). Thus, the proinflammatory response of the Z {alpha}1-antitrypsin allele (most probably driven by polymers) was likely to be hugely advantageous to a population living with malnutrition, poor housing, overcrowding, poor sanitation, and the high risk of infectious disease that for many characterized the preantibiotic era. Only since the advent of improved living standards, antibiotics, increased longevity, and smoking has this previously protective allele become a disadvantage.

The high gene frequency of the S mutation in southern Europe implies that there must also be a selective pressure to retain this allele. Again, this can be explained by the protective effects of polymerization. The S allele also causes {alpha}1-antitrypsin to spontaneously form polymers, but at a rate that is less than that of the Z allele (12, 21, 22). The slower polymerization causes less S {alpha}1-antitrypsin to be retained in the liver when compared with Z {alpha}1-antitrypsin, and hence plasma levels are 60% of the normal M allele. However, the levels will rise in response to infection to a greater extent than for Z {alpha}1-antitrypsin, higher concentrations will be concentrated at sites of inflammation and this, along with the raised temperature and low pH, will result in polymerization. Although polymerization of S {alpha}1-antitrypsin is less marked than that of the Z allele (12), it is likely to be compensated in part by the higher concentration of protein that is available to form polymers. Furthermore, because the S variant has no effect on the ability of {alpha}1-antitrypsin to inhibit neutrophil elastase (21) and because it has a much smaller effect on the local concentration of {alpha}1-antitrypsin at sites of inflammation, S {alpha}1-antitrypsin is still effective at protecting tissues from any excessive release of proteolytic enzymes. Thus polymerization can also explain the selective advantage of S {alpha}1-antitrypsin. Indeed, the retained inhibitory function of {alpha}1-antitrypsin containing the S mutation may explain why there has been a higher selection pressure, and hence a higher gene frequency of this allele over that of the Z allele. The combination of polymerization and retained activity seen with S {alpha}1-antitrypsin may also explain the potential advantage of the MZ or MS {alpha}1-antitrypsin heterozygote. The Z and S allele allows the formation of polymers at sites of inflammation and a vigorous local inflammatory response, whereas the M allele allows a normal acute phase reaction that limits excessive tissue destruction.

It is important to consider the null alleles that make up the third most common cause of {alpha}1-antitrypsin deficiency (52). These are rare as presumably they offer no selective advantage for carriers. The point mutations often introduce a premature stop codon that results in a misfolded protein that is targeted for degradation (53, 54). The null mutations do not result in secreted protein or the formation of polymers and therefore would not stimulate the inflammatory response and thereby provide protection.

Alternative suggestions for the selective advantage of {alpha}1-antitrypsin deficiency have included protection against tuberculosis and increased fertility (55, 56). A protective effect against tuberculosis was suggested because this was a significant cause of death in Europe in the preantibiotic era. The hypothesis was based on the concept that deficiency of {alpha}1-antitrypsin would allow increased proteolytic activity at sites of inflammation that in turn might reduce the spread of infection (56). This may still be important in the mechanism that is proposed in this perspective, but it is likely that it is local polymerization that drives inflammation rather than a lack of {alpha}1-antitrypsin per se. Moreover, if the selective advantage of {alpha}1-antitrypsin deficiency were solely from a lack of {alpha}1-antitrypsin at sites of inflammation, then perhaps one would expect a greater frequency of null alleles within the European population. This argument would not explain the high gene frequency of the S allele that causes only mild plasma deficiency.

The concept of increased fertility in association with {alpha}1-antitrypsin deficiency was suggested because sperm require the enzyme acrosin to penetrate the zona pellucida of the ovum during fertilization. The deficiency of a proteinase inhibitor may favor migration/penetration of sperm and therefore increase fertility. However, the association rate constant of acrosin with {alpha}1-antitrypsin is so slow as to make it unlikely that this interaction is important in vivo (57). Twin studies have suggested that the S and Z alleles increase the chance of ovulation rate and so enhance the success of multiple pregnancies (58, 59). However, concurrent studies did not show any increase in family size and, again, if this were the explanation for the selective advantage, then one would expect a far greater frequency of null alleles underlying deficiency of {alpha}1-antitrypsin. Nevertheless, this mechanism may have also contributed to the survival advantage of {alpha}1-antitrypsin deficiency during the era of high infant mortality. It should be balanced, however, by the increased risk of maternal and perinatal mortality that accompanied twin pregnancies when there was poor or nonexistent obstetric and neonatal care. Therefore, although both existing hypotheses are attractive, the new understanding of the basic mechanisms of {alpha}1-antitrypsin deficiency allows the advancement of a more satisfying explanation for the selective advantage of the S- and Z-deficiency alleles.

THE BALANCE OF EVIDENCE AND FURTHER STUDIES

When proposing a new hypothesis, it is important to state what is known and which issues are speculation and require further study. The following are generally accepted: (1) {alpha}1-antitrypsin is an acute-phase protein and therefore likely to be important in the acute inflammatory response, (2) the lung disease associated with Z {alpha}1-antitrypsin deficiency is characterized by an excessive inflammatory response, (3) the systemic conditions that have been associated with Z {alpha}1-antitrypsin deficiency (panniculitis, vasculitis, pancreatitis, glomerulonephritis, bronchiectasis, and asthma) are all characterized by excessive inflammation, (4) Z {alpha}1-antitrypsin deficiency results from the formation of intracellular hepatic polymers and similar polymers can also be detected in extracellular bronchoalveolar lavage samples and in tissue sections from the lungs of individuals with emphysema secondary to Z {alpha}1-antitrypsin deficiency, (5) {alpha}1-antitrypsin polymers are inflammatory in vitro and when instilled into the lungs of mice, (6) polymerization also explains the plasma deficiency of the more frequent S allele, and (7) the gene frequencies of the Z and S alleles are far more common than would occur by chance. These observations provide support for the hypothesis that the Z (and to a lesser extent S) allele favors the formation of polymers at sites of inflammation and that these polymers focus and amplify the inflammatory response to aid the eradication of invasive organisms. This is likely to be the selective advantage for both S and Z {alpha}1-antitrypsin heterozygotes and homozygotes. Since mankind developed antibiotics, the risk of invasive disease causing death is much reduced. Moreover, the widespread adoption of smoking has heightened an already vigorous response to cause excessive tissue destruction and emphysema. Thus previously protective genes are now harmful to health.

What needs to be done to confirm or refute this hypothesis? Many questions remain. Some have been described within this review, but fundamentally very little is known about the generation of polymers of Z {alpha}1-antitrypsin at sites of inflammation, how they are handled by the lung, and how they interact with inflammatory cells. It is unknown whether inflammatory polymers can be beneficial to humans and nothing is known about the production of S {alpha}1-antitrypsin polymers within the lung. The hypothesis for S {alpha}1-antitrypsin is based on the very high frequency of the S allele, the demonstration that the protein can polymerize in vitro (12, 21, 22), and extrapolation from the work undertaken on the more severe Z-deficiency allele. These issues can be addressed in part by the analysis of sputum, lavage, and lung biopsies for polymers and inflammatory cells/mediators from individuals with normal pulmonary function and a range of severity of emphysema and different {alpha}1-antitrypsin deficiency alleles. In particular, it will be important to assess whether individuals with PI SS and PI MS {alpha}1-antitrypsin phenotypes, like those with the PI ZZ or PI MZ phenotype (26–28, 48), have more baseline pulmonary inflammation than controls and if they produce intrapulmonary polymers in response to infective insults. One relatively straightforward approach is to assess the generation of polymers, and the severity of inflammation, after exposure of transgenic mice that express S or Z {alpha}1-antitrypsin to inhaled toxins such as cigarette smoke, infective bacteria, and bacterial products. If the hypothesis is correct, then one would expect more exuberant inflammation in transgenic mice in association with the generation of intrapulmonary polymers. Clearly, much needs to be done to and, as with all hypotheses, it remains to be seen whether it will stand the test of time.

Acknowledgments

The author thanks Prof. Robin Carrell, Department of Medicine, University of Cambridge, United Kingdom, for his critical review of the manuscript and Dr. Diane Cox, University of Alberta, Canada, for her advice on the origin of the Z allele. The author also thanks all past and present members of the research team for their many years of hard work that have underpinned this hypothesis.

FOOTNOTES

Supported by the Medical Research Council (UK), the Wellcome Trust, Papworth NHS Trust, and the Alpha-1 Foundation.

Originally Published in Press as DOI: 10.1164/rccm.200511-1797PP on January 26, 2006

Conflict of Interest Statement: D.A.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form November 23, 2005; accepted in final form January 26, 2006

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