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Alpha-1 Antitrypsin Deficiency
LETTER
Alpha-1 Antitrypsin Deficiency To the Editor: Although it is true that the protection of pulmonary tissue from aggressive proteolytic enzymes is an important physiological function of the alpha-1 antitrypsin (A1AT) molecule,1 the fact that one of the proteolytic enzymes inhibited by A1AT, namely proteinase-3 (PR3), also is a target for antineutrophil cytoplasmic antibody (ANCA)2 potentially generates an alternative role for A1AT. The alternative role comes into play as a result of the fact that a deficiency of A1AT deprives PR3 of its natural inhibitor, giving it free rein to express its proteolytic potential. In addition, A1AT deficiency gives the PR3 molecule serologic exposure, thereby allowing it to generate an antibody response in the form of PR3-ANCA. ANCA augments PR3-related vascular injury by triggering degranulation of tumor necrosis factor-primed neutrophils, with resulting release of proteolytic enzymes and oxygen radicals.3 This might be the sequence of events leading to vasculitis and glomerulonephritis in A1AT-deficient subjects with ANCA positivity.4 In ANCA-negative subjects with A1AT deficiency, the alternative mechanism for glomerulopathy might be glomerular deposition of polymers of the “Z” subtype of A1AT (ZA1AT).5,6 These polymers originate from the hepatocytes of patients with the “Z” type of A1AT deficiency and are released into the bloodstream, eventually being sequestrated in renal tissue of some of these patients.5,6 ZA1AT polymers have neutrophil chemoattractant properties and also are capable of triggering neutrophil degranulation,7 with the possible eventual consequence of release of aggressive proteolytic enzymes. The eventual outcome might be the glomerulopathy associated with ZA1AT deposition in severe A1AT deficiency,5,6 a glomerulopathy arguably distinct
0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved.
from the immune complex-mediated glomerulopathy typically associated with other forms of cirrhosis,8 in which no glomerular deposition of ZA1AT polymers has been identified. O. M. P. Jolobe, MRCP(UK) Medical Division Manchester Medical Society Manchester, Lancashire United Kingdom
doi:10.1016/j.amjmed.2008.02.027
References 1. Kohnlein T, Welte T. Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment. Am J Med. 2008;121: 3-9. 2. Savige JA, Chang L, Cook J, et al. Alpha-1 antitrypsin deficiency and anti-proteinase 3 antibodies in antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis. Clin Exp Immunol. 1995;100: 194-197. 3. Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A. 1990;87:4115-4119. 4. Esnault VLM, Testa A, Audrain M, et al. Alpha 1-antitrypsin genetic polymorphism in ANCA-positive systemic vasculitis. Kidney Int. 1993; 43:1329-1332. 5. Davis ID, Burke B, Freese D, et al. The pathologic spectrum of the nephropathy associated with alpha 1-antitrypsin deficiency. Hum Pathol. 1992;23:57-62. 6. Elzouki A-N, Lindgren S, Nilson S, et al. Severe alpha1-antitrypsin deficiency (PiZ homozygosity) with membranoproliferative glomerulonephritis and nephritic syndrome, reversible after orthotopic liver transplantation. J Hepatol. 1997;26:1403-1407. 7. Parmar JS, Mahadeva R, Reed BJ, et al. Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema. Am J Respir Cell Mol Biol. 2002;26:723-730. 8. Callard P, Feldman G, Prandi D, et al. Immune complex type glomerulonephritis in cirrhosis of the liver. Am J Pathol. 1975;80:329-338.
Alpha-1 Antitrypsin Deficiency To the Editor: Although it is true that the protection of pulmonary tissue from aggressive proteolytic enzymes is an important physiological function of the alpha-1 antitrypsin (A1AT) molecule,1 the fact that one of the proteolytic enzymes inhibited by A1AT, namely proteinase-3 (PR3), also is a target for antineutrophil cytoplasmic antibody (ANCA)2 potentially generates an alternative role for A1AT. The alternative role comes into play as a result of the fact that a deficiency of A1AT deprives PR3 of its natural inhibitor, giving it free rein to express its proteolytic potential. In addition, A1AT deficiency gives the PR3 molecule serologic exposure, thereby allowing it to generate an antibody response in the form of PR3-ANCA. ANCA augments PR3-related vascular injury by triggering degranulation of tumor necrosis factor-primed neutrophils, with resulting release of proteolytic enzymes and oxygen radicals.3 This might be the sequence of events leading to vasculitis and glomerulonephritis in A1AT-deficient subjects with ANCA positivity.4 In ANCA-negative subjects with A1AT deficiency, the alternative mechanism for glomerulopathy might be glomerular deposition of polymers of the “Z” subtype of A1AT (ZA1AT).5,6 These polymers originate from the hepatocytes of patients with the “Z” type of A1AT deficiency and are released into the bloodstream, eventually being sequestrated in renal tissue of some of these patients.5,6 ZA1AT polymers have neutrophil chemoattractant properties and also are capable of triggering neutrophil degranulation,7 with the possible eventual consequence of release of aggressive proteolytic enzymes. The eventual outcome might be the glomerulopathy associated with ZA1AT deposition in severe A1AT deficiency,5,6 a glomerulopathy arguably distinct
0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved.
from the immune complex-mediated glomerulopathy typically associated with other forms of cirrhosis,8 in which no glomerular deposition of ZA1AT polymers has been identified. O. M. P. Jolobe, MRCP(UK) Medical Division Manchester Medical Society Manchester, Lancashire United Kingdom
doi:10.1016/j.amjmed.2008.02.027
References 1. Kohnlein T, Welte T. Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment. Am J Med. 2008;121: 3-9. 2. Savige JA, Chang L, Cook J, et al. Alpha-1 antitrypsin deficiency and anti-proteinase 3 antibodies in antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis. Clin Exp Immunol. 1995;100: 194-197. 3. Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A. 1990;87:4115-4119. 4. Esnault VLM, Testa A, Audrain M, et al. Alpha 1-antitrypsin genetic polymorphism in ANCA-positive systemic vasculitis. Kidney Int. 1993; 43:1329-1332. 5. Davis ID, Burke B, Freese D, et al. The pathologic spectrum of the nephropathy associated with alpha 1-antitrypsin deficiency. Hum Pathol. 1992;23:57-62. 6. Elzouki A-N, Lindgren S, Nilson S, et al. Severe alpha1-antitrypsin deficiency (PiZ homozygosity) with membranoproliferative glomerulonephritis and nephritic syndrome, reversible after orthotopic liver transplantation. J Hepatol. 1997;26:1403-1407. 7. Parmar JS, Mahadeva R, Reed BJ, et al. Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema. Am J Respir Cell Mol Biol. 2002;26:723-730. 8. Callard P, Feldman G, Prandi D, et al. Immune complex type glomerulonephritis in cirrhosis of the liver. Am J Pathol. 1975;80:329-338.