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.
α1-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 α1-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 α1-antitrypsin deficiency now allow us to address this question. This perspective will review our understanding of α1-antitrypsin deficiency and then address the issue of the selective advantage provided by the S and Z mutations.
α1-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 α1-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. α1-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 α1-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 α1-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.
The Z allele causes the abnormal accumulation of mutant α1-antitrypsin as diastase-resistant, periodic acid-Schiff–positive inclusions of α1-antitrypsin within the periportal cells of the liver. This intrahepatic accumulation of Z α1-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 α1-antitrypsin within hepatocytes results in a lack of circulating plasma α1-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 α1-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 β-sheet A within the α1-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 α1-antitrypsin molecule sequentially inserts into β-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 α1-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 α1-antitrypsin within the liver. This in turn correlates with the greatest risk of liver damage and cirrhosis and the most severe plasma deficiency.
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 α1-antitrypsin deficiency differs from “usual chronic obstructive pulmonary disease,” with normal levels of M α1-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 α1-antitrypsin deficiency is also characterized by excessive intrapulmonary inflammation. Examination of lung lavage from individuals with PI ZZ α1-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 α1-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 α1-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 α1-antitrypsin deficiency who have stable disease (33). Nevertheless, because neutrophil elastase is the major target proteinase of α1-antitrypsin, it is likely that this enzyme plays a central role in tissue destruction in the lungs of patients with α1-antitrypsin deficiency.
The recognition that Z α1-antitrypsin formed polymers within hepatocytes provoked an examination of their role in the associated emphysema. α1-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 α1-antitrypsin deficiency (28), but not in samples from individuals with emphysema and normal α1-antitrypsin phenotypes. This conformational transition from monomer to polymer inactivates α1-antitrypsin as a proteinase inhibitor (32), thereby further reducing the already depleted levels of α1-antitrypsin that are available to protect the alveoli. Thus, the α1-antitrypsin that is present within the lung may be ineffective. Moreover, the conversion of α1-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 α1-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 α1-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.
The observation that polymers are proinflammatory may also explain the association of Z α1-antitrypsin with other inflammatory conditions. Several anecdotal and epidemiologic studies have linked Z α1-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 α1-antitrypsin deficiency and bronchiectasis has been disputed in another study (47). One can consider the inflammatory response in individuals with α1-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 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 α1-antitrypsin is an acute-phase protein. Invading organisms cause a systemic inflammatory response that results in an increase in secretion of Z α1-antitrypsin by hepatocytes (although not to the same extent as in M α1-antitrypsin homozygotes). They also cause a rise in body temperature and the concentration of mutant α1-antitrypsin at the site of the inflammatory insult (49). Moreover, α1-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 α1-antitrypsin at the site of infection, the raised temperature, and the low pH combine together to favor the polymerization of mutant α1-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 α1-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 α1-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 α1-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 α1-antitrypsin to be retained in the liver when compared with Z α1-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 α1-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 α1-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 α1-antitrypsin to inhibit neutrophil elastase (21) and because it has a much smaller effect on the local concentration of α1-antitrypsin at sites of inflammation, S α1-antitrypsin is still effective at protecting tissues from any excessive release of proteolytic enzymes. Thus polymerization can also explain the selective advantage of S α1-antitrypsin. Indeed, the retained inhibitory function of α1-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 α1-antitrypsin may also explain the potential advantage of the MZ or MS α1-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 α1-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 α1-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 α1-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 α1-antitrypsin per se. Moreover, if the selective advantage of α1-antitrypsin deficiency were solely from a lack of α1-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 α1-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 α1-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 α1-antitrypsin. Nevertheless, this mechanism may have also contributed to the survival advantage of α1-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 α1-antitrypsin deficiency allows the advancement of a more satisfying explanation for the selective advantage of the S- and Z-deficiency alleles.
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) α1-antitrypsin is an acute-phase protein and therefore likely to be important in the acute inflammatory response, (2) the lung disease associated with Z α1-antitrypsin deficiency is characterized by an excessive inflammatory response, (3) the systemic conditions that have been associated with Z α1-antitrypsin deficiency (panniculitis, vasculitis, pancreatitis, glomerulonephritis, bronchiectasis, and asthma) are all characterized by excessive inflammation, (4) Z α1-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 α1-antitrypsin deficiency, (5) α1-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 α1-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 α1-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 α1-antitrypsin polymers within the lung. The hypothesis for S α1-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 α1-antitrypsin deficiency alleles. In particular, it will be important to assess whether individuals with PI SS and PI MS α1-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 α1-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.
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.
1. | Blanco I, de Serres FJ, Fernández-Bustillo E, Lara B, Miravitlles M. Estimated numbers and prevalence of PI*S and PI*Z alleles of α1-antitrypsin deficiency in European countries. Eur Respir J 2006;27:77–84. |
2. | Laurell C-B, Eriksson S. The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. Scand J Clin Lab Invest 1963;15:132–140. |
3. | de Serres F. Worldwide racial and ethnic distribution of α1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest 2002;122:1818–1829. |
4. | Seyama K, Nukiwa T, Souma S, Shimizu K, Kira S. α1-Antitrypsin-deficient variant Siiyama (Ser53[TCC] to Phe53[TTC]) is prevalent in Japan: status of α1-antitrysin deficiency in Japan. Am J Respir Crit Care Med 1995;152:2119–2126. |
5. | Ferrarotti I, Baccheschi J, Zorzetto M, Tinelli C, Corda L, Balbi B, Campo I, Pozzi E, Faa G, Coni P, et al. Prevalence and phenotype of subjects carrying rare variants in the Italian registry for alpha1-antitrypsin deficiency. J Med Genet 2005;42:282–287. |
6. | Cox DW, Woo SL, Mansfield T. DNA restriction fragments associated with alpha 1-antitrypsin indicate a single origin for deficiency allele PI Z. Nature 1985;316:79–81. |
7. | Blanco I, Fernández E, Bustillo EF. Alpha-1-antitrypsin PI phenotypes S and Z in Europe: an analysis of the published surveys. Clin Genet 2001;60:31–41. |
8. | Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976;294:1316–1321. |
9. | Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in alpha1-antitrypsin deficiency. N Engl J Med 1986;314:736–739. |
10. | Bowlus CL, Willner I, Zern MA, Reuben A, Chen P, Holladay B, Xie L, Woolson RF, Strange C. Factors associated with advanced liver disease in adults with alpha1-antitrypsin deficiency. Clin Gastroenterol Hepatol 2005;3:390–396. |
11. | Lomas DA, Evans DL, Finch JT, Carrell RW. The mechanism of Z α1-antitrypsin accumulation in the liver. Nature 1992;357:605–607. |
12. | Dafforn TR, Mahadeva R, Elliott PR, Sivasothy P, Lomas DA. A kinetic mechanism for the polymerisation of α1-antitrypsin. J Biol Chem 1999;274:9548–9555. |
13. | Sivasothy P, Dafforn TR, Gettins PGW, Lomas DA. Pathogenic α1-antitrypsin polymers are formed by reactive loop-β-sheet A linkage. J Biol Chem 2000;275:33663–33668. |
14. | Mahadeva R, Dafforn TR, Carrell RW, Lomas DA. Six-mer peptide selectively anneals to a pathogenic serpin conformation and blocks polymerisation: implications for the prevention of Z α1-antitrypsin-related cirrhosis. J Biol Chem 2002;277:6771–6774. |
15. | Gooptu B, Hazes B, Chang W-SW, Dafforn TR, Carrell RW, Read RJ, Lomas DA. Inactive conformation of the serpin α1-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease. Proc Natl Acad Sci USA 2000;97:67–72. |
16. | Janciauskiene S, Eriksson S, Callea F, Mallya M, Zhou A, Seyama K, Hata S, Lomas DA. Differential detection of PAS-positive inclusions formed by the Z, Siiyama and Mmalton variants of α1-antitrypsin. Hepatology 2004;40:1203–1210. |
17. | Purkayastha P, Klemke JW, Lavender S, Oyola R, Cooperman BS, Gai F. α1-antitrypsin polymerisation: a fluorescence correlation spectroscopic study. Biochemistry 2005;44:2642–2649. |
18. | An JK, Blomenkamp K, Lindblad D, Teckman JH. Quantitative isolation of alpha-l-antitrypsin mutant Z protein polymers from human and mouse livers and the effect of heat. Hepatology 2005;41:160–167. |
19. | Lomas DA, Elliott PR, Sidhar SK, Foreman RC, Finch JT, Cox DW, Whisstock JC, Carrell RW. Alpha1-antitrypsin Mmalton (52Phe deleted) forms loop-sheet polymers in vivo: evidence for the C sheet mechanism of polymerisation. J Biol Chem 1995;270:16864–16870. |
20. | Lomas DA, Finch JT, Seyama K, Nukiwa T, Carrell RW. α1-antitrypsin Siiyama (Ser53ØPhe): further evidence for intracellular loop-sheet polymerisation. J Biol Chem 1993;268:15333–15335. |
21. | Elliott PR, Stein PE, Bilton D, Carrell RW, Lomas DA. Structural explanation for the deficiency of S α1-antitrypsin. Nat Struct Biol 1996;3:910–911. |
22. | Mahadeva R, Chang W-SW, Dafforn TR, Oakley DJ, Foreman RC, Calvin J, Wight DG, Lomas DA. Heteropolymerisation of S, I and Z α1-antitrypsin and liver cirrhosis. J Clin Invest 1999;103:999–1006. |
23. | Larsson C. Natural history and life expectancy in severe alpha1-antitrypsin deficiency, PiZ. Acta Med Scand 1978;204:345–351. |
24. | Seersholm N, Dirksen A, Kok-Jensen A. Airways obstruction and two year survival in patients with severe alpha1-antitrypsin deficiency. Eur Respir J 1994;7:1985–1987. |
25. | Golpon HA, Coldren CD, Zamora MR, Cosgrove GP, Moore MD, Tuder RM, Geraci MW, Voelkel NF. Emphysema lung tissue gene expression profiling. Am J Respir Cell Mol Biol 2004;31:595–600. |
26. | Rouhani F, Paone G, Smith NK, Krein P, Barnes P, Brantly ML. Lung neutrophil burden correlates with increased pro-inflammatory cytokines and decreased lung function in individuals with α1-antitrypsin deficiency. Chest 2000;117:250S–251S. |
27. | Morrison HM, Kramps JA, Burnett D, Stockley RA. Lung lavage fluid from patients with α1-proteinase inhibitor deficiency or chronic obstructive bronchitis: anti-elastase function and cell profile. Clin Sci (Lond) 1987;72:373–381. |
28. | Mahadeva R, Atkinson C, Li Z, Stewart S, Janciauskiene S, Kelley DG, Parmar J, Pitman R, Shapiro SD, Lomas DA. Polymers of Z α1-antitrypsin co-localise with neutrophils in emphysematous alveoli and are chemotactic in vivo. Am J Pathol 2005;166:377–386. |
29. | Hill AT, Campbell EJ, Bayley DL, Hill SL, Stockley RA. Evidence for excessive bronchial inflammation during an acute exacerbation of chronic obstructive pulmonary disease in patients with α1-antitrypsin deficiency (PiZ). Am J Respir Crit Care Med 1999;160:1968–1975. |
30. | Woolhouse IS, Bayley DL, Stockley RA. Sputum chemotactic activity in chronic obstructive pulmonary disease: effect of α1-antitrypsin deficiency and the role of leukotriene B4 and interleukin 8. Thorax 2002;57:709–714. |
31. | Ogushi F, Fells GA, Hubbard RC, Straus SD, Crystal RG. Z-type α1-antitrypsin is less competent than M1-type α1-antitrypsin as an inhibitor of neutrophil elastase. J Clin Invest 1987;80:1366–1374. |
32. | Lomas DA, Evans DL, Stone SR, Chang W-SW, Carrell RW. Effect of the Z mutation on the physical and inhibitory properties of α1-antitrypsin. Biochemistry 1993;32:500–508. |
33. | King MB, Campbell EJ, Gray BH, Hertz MI. The proteinase-antiproteinase balance in α-1-proteinase inhibitor-deficient lung transplant recipients. Am J Respir Crit Care Med 1994;149:966–971. |
34. | Cichy J, Potempa J, Travis J. Biosynthesis of α1-proteinase inhibitor by human lung-derived epithelial cells. J Biol Chem 1997;272:8250–8255. |
35. | Mornex JF, Chytil-Weir A, Martinet Y, Courtney M, LeCocq J, Crystal RG. Expression of the alpha-1-antitrypsin gene in mononuclear phagocytes of normal and alpha-1-antitrypsin-deficient individuals. J Clin Invest 1986;77:1952–1961. |
36. | Elliott PR, Bilton D, Lomas DA. Lung polymers in Z α1-antitrypsin deficiency-related emphysema. Am J Respir Cell Mol Biol 1998;18:670–674. |
37. | Mulgrew AT, Taggart CC, Lawless MW, Greene CM, Brantly ML, O'Neill SJ, McElvaney NG. Z α1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant. Chest 2004;125:1952–1957. |
38. | Parmar JS, Mahadeva R, Reed BJ, Farahi N, Cadwallader KA, Keogan MT, Bilton D, Chilvers ER, Lomas DA. Polymers of α1-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema. Am J Respir Cell Mol Biol 2002;26:723–730. |
39. | Janciauskiene S, Zelvyte I, Jansson L, Stevens T. Divergent effects of α1-antitrypsin on neutrophil activation, in vitro. Biochem Biophys Res Commun 2004;315:288–296. |
40. | Silverman EK, Province MA, Rao DC, Pierce JA, Campbell EJ. A family study of the variability of pulmonary function in α1-antitrypsin deficiency: quantitative phenotypes. Am Rev Respir Dis 1990;142:1015–1021. |
41. | O'Riordan K, Blei A, Rao MS, Abecassis M. α1-Antitrypsin deficiency-associated panniculitis: resolution with intravenous α1-antitrypsin administration and liver transplantation. Transplantation 1997;63:480–482. |
42. | Elzouki A-NY, Segelmark M, Wieslander J, Eriksson S. Strong link between the alpha1-antitrypsin PiZ allele and Wegener's granulomatosis. J Intern Med 1994;236:543–548. |
43. | Davis ID, Burke B, Freese D, Sharp HL, Kim Y. The pathologic spectrum of the nephropathy associated with α1-antitrypsin deficiency. Hum Pathol 1992;23:57–62. |
44. | Eden E, Mitchell D, Mehlman B, Khouli H, Nejat M, Grieco MH, Turino GM. Atopy, asthma, and emphysema in patients with severe alpha-1-antitrypsin deficiency. Am J Respir Crit Care Med 1997;156:68–74. |
45. | King MA, Stone JA, Diaz PT, Mueller CF, Becker WJ, Gadek JE. α1-Antitrypsin deficiency: evaluation of bronchiectasis with CT. Radiology 1996;199:137–141. |
46. | Seersholm N, Kok-Jensen A. Extrapulmonary manifestations of alpha-1-antitrypsin deficiency. Am J Respir Crit Care Med 2001;163:A343. |
47. | Cuvelier A, Muir J-F, Hellot M-F, Benhamou D, Martin J-P, Bénichou J, Sesboüé R. Distribution of α1-antitrypsin alleles in patients with bronchiectasis. Chest 2000;117:415–419. |
48. | Malerba M, Ricciardolo F, Torregiani C, Radaeli A, Ceriani L, Mori E, Bontempelli M, Grassi V, Tantucci C. Neutrophilic inflammation and IL-8 levels in induced sputum of alpha-1-antitrypsin PiMZ subjects. Thorax 2006;61:129–133. |
49. | Stockley RA, Burnett D. Alpha-1-antitrypsin and leucocyte elastase in infected and noninfected sputum. Am Rev Respir Dis 1979;120:1081–1086. |
50. | Perlmutter DH, Daniels JD, Auerbach HS, De Schryver-Kecskemeti K, Winter HS, Alpers DH. The α1-antitrypsin gene is expressed in a human intestinal epithelial cell line. J Biol Chem 1989;264:9485–9490. |
51. | Proctor RN. The global smoking epidemic: a history and status report. Clin Lung Cancer 2004;5:371–376. |
52. | Brantly M, Nukiwa T, Crystal RG. Molecular basis of alpha-1-antitrypsin deficiency. Am J Med 1988;84:13–31. |
53. | Lin L, Schmidt B, Teckman J, Perlmutter DH. A naturally occurring nonpolymerogenic mutant of α1-antitypsin charcaterized by prolonged retention in the endoplasmic reticulum. J Biol Chem 2001;276:33893–33898. |
54. | Cabral CM, Liu Y, Sifers RN. Dissecting the glycoprotein quality control in the secretory pathway. Trends Biochem Sci 2001;26:619–624. |
55. | Fagerhol MK, Gedde-Dahl T Jr. Genetics of the Pi serum types: family studies of the inherited variants of serum alpha-1-antitrypsin. Hum Hered 1969;19:354–359. |
56. | Fagerhol MK, Cox DW. The Pi polymorphism: genetic, biochemical, and clinical aspects of human α1-antitrypsin. Adv Hum Genet 1981;11:1–62. |
57. | Hermans JM, Monard D, Jones R, Stone SR. Inhibition of acrosin by serpins: a suicide substrate mechanism. Biochemistry 1995;34:3678–3685. |
58. | Lieberman J, Borhani NO, Feinleib M. α1-Antitrypsin deficiency in twins and parents-of-twins. Clin Genet 1979;15:29–36. |
59. | Boomsma DI, Frants RR, Bank RA, Martin NG. Protease inhibitor (Pi) locus, fertility and twinning. Hum Genet 1992;89:329–332. |
60. | Elliott PR, Lomas DA, Carrell RW, Abrahams J-P. Inhibitory conformation of the reactive loop of α1-antitrypsin. Nat Struct Biol 1996;3:676–681. |