Alpha-1 antitrypsin deficiency today: New insights in the immunological pathways

More than fifty years ago the observation that absence of the α1 band from protein electrophoresis was associated with severe emphysema established the link between α-1 antitrypsin deficiency (AATD) and lung damage. From this discovery derived the classic paradigm of protease/antiprotease imbalance, linking lung destruction in patients with AATD to the unopposed effect of proteases. By extension this paradigm was also applied to patients with “usual” COPD, in whom large increases in smoke-induced proteases could overwhelm the anti-protease capability of α-1 antitrypsin. However, it has become increasingly evident that α-1 antitrypsin has important anti-inflammatory and immune-regulatory activities which, beside its antiprotease function, may be critically involved in lung destruction. In this perspective we will consider recent evidence, based on epidemiological, clinical and immune-pathological studies, suggesting that it s time to move on from the original protease/antiprotease paradigm toward a more complex view of the condition which embrace its immune-modulating functions. Of importance, the potent immune-regulatory, tolerogenic role of α-1 antitrypsin may support its therapeutic use in a number of diseases other than AATD, particularly in immune-related disorders.