title: Immune activation in α1-antitrypsin-deficiency emphysema. Beyond the protease-antiprotease paradigm.
abstract: BACKGROUND
  α1-Antitrypsin (AAT) is a potent protease inhibitor, deficiency of which is associated with the presence of emphysema. An imbalance of elastase and antielastase, along with innate inflammation in the lung, is believed to cause lung destruction in α1-antitrypsin deficiency (AATD). It is now apparent that AAT has important immune-regulatory roles that would be lost in AATD, yet adaptive immune responses in the lung have not been investigated in patients with AATD.
  
  
  OBJECTIVE
  To assess the adaptive immune response in severe AATD emphysema and compare it with that present in "usual" chronic obstructive pulmonary disease (COPD).
  
  
  METHODS
  The immune inflammatory response in explanted lungs from 10 subjects with AATD was characterized and quantified, and the results were compared with those of 26 subjects with usual COPD and those of 17 smoking and 11 nonsmoking control subjects with normal lung function.
  
  
  RESULTS
  Lymphoid follicles (LFs) in AATD and usual COPD were markedly increased when compared with control groups. Molecular analysis of B lymphocytes in LFs showed predominantly mono/oligoclonality. LF number correlated negatively with FEV1/FVC. B lymphocytes and CD4(+) and CD8(+) T lymphocytes were significantly increased in AATD and usual COPD when compared with control groups. IL-32, an important cytokine in induction of autoimmunity, was markedly up-regulated in AATD and usual COPD.
  
  
  CONCLUSIONS
  An important adaptive immune inflammation, comprising B, CD4(+), and CD8(+) lymphocytes, and LFs, is a prominent feature in AATD. These results change the paradigm of the mechanism of AATD-induced emphysema from a pure elastase-antielastase imbalance to a much more complex one involving the adaptive immune system, similarly to what occurs in usual COPD.
authors.affiliation: 1 Department of Cardiac, Thoracic, and Vascular Sciences, University of Padua and Padua City Hospital, Padua, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Baraldo
authors.forename: Graziella
authors.initials: G
authors.lastname: Turato
authors.forename: Francesca
authors.initials: F
authors.lastname: Lunardi
authors.forename: Erica
authors.initials: E
authors.lastname: Bazzan
authors.forename: Marco
authors.initials: M
authors.lastname: Schiavon
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ferrarotti
authors.forename: Beatrice
authors.initials: B
authors.lastname: Molena
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cazzuffi
authors.forename: Marco
authors.initials: M
authors.lastname: Damin
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Balestro
authors.forename: Maurizio
authors.initials: M
authors.lastname: Luisetti
authors.forename: Federico
authors.initials: F
authors.lastname: Rea
authors.forename: Fiorella
authors.initials: F
authors.lastname: Calabrese
authors.forename: Manuel G
authors.initials: MG
authors.lastname: Cosio
authors.forename: Marina
authors.initials: M
authors.lastname: Saetta
mesh_terms: D056704:Adaptive Immunity; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000276:immunology; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000276:immunology; D011656:Pulmonary Emphysema / Q000201:enzymology / Q000276:immunology*; D015842:Serine Proteinase Inhibitors / Q000276:immunology; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications* / Q000201:enzymology / Q000276:immunology
chemical_list: D015842:Serine Proteinase Inhibitors; D010196:Pancreatic Elastase
keywords: autoimmunity; chronic obstructive pulmonary disease; lymphocytes; lymphoid follicles; α1-antitrypsin