Molecular pathology of alpha 1-antitrypsin deficiency and its significance to clinical medicine.

alpha 1-Antitrypsin (AAT) deficiency is associated with predisposition to developing liver cirrhosis in early childhood, and chronic degenerative lung disease in early adult life. The probable molecular basis for the disease associations is known. One of the common variants, Z, has the propensity to form polymers, a phenomenon which is concentration- and temperature-dependent. This results in accumulation of the protein in hepatocytes, the predominant tissue source of AAT, and leads to cell damage. AAT deficiency results in loss of protection in the lung against neutrophil elastase (NE) the major target for AAT. NE is capable of destroying the architecture of the lung, leading to pulmonary emphysema. The disease process is exacerbated by cigarette smoke, which is capable of oxidizing a critical methionine residue at the active site, rendering AAT an inefficient inhibitor of NE. The combination of deficiency and cigarette smoking are critical to the development of pulmonary emphysema. We have identified a mutation in an enhancer sequence which, in all probability, predisposes to disease by a novel mechanism related to diminished expression of AAT during inflammation. Our understanding of the mechanisms of disease should lead to improved therapeutic interventions.