Immune Activation in α-1antitrypsin Deficiency Emphysema: Beyond the Protease/Antiprotease Paradigm.

Rationale: α1-antitrypsin (AAT) is a potent protease inhibitor which deficiency is associated with the presence of emphysema. An imbalance of elastase/antielastase, along with an 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. Objectives: To assess the adaptive immune response in severe AATD emphysema and compare it to that present in "usual" COPD . Methods: The immune inflammatory response in explanted lungs from 10 subjects with AATD was characterized and quantified and the results compared to 26 subjects with "usual" COPD, 17 smoking and 11 non-smoking controls with normal lung function. Results: Lymphoid follicles (LF) in AATD and "usual" COPD were markedly increased when compared to control groups. Molecular analysis of B-lymphocytes in LF showed predominantly mono/oligoclonality. LF number correlated with FEV1/FVC. B-lymphocytes, CD4+ and CD8+ T-lymphocytes were significantly increased in AATD and "usual" COPD when compared to control groups. IL-32, an important cytokine in induction of autoimmunity, was markedly upregulated in AATD and "usual" COPD. Conclusions: An important adaptive immune inflammation, comprising B, CD4+, CD8+ lymphocytes and mono/oligoclonal lymphoid follicles, 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.