Besides limiting elastase activity to limit tissue degradation, A1PI also acts to induce locomotion of lymphocytes through tissue including immature T cells through the thymus where immature T cells mature to become immunocompetent T cells that are released into tissue to elevate immune responsiveness.Like all serine protease inhibitors, A1AT has a characteristic secondary structure of beta sheets and alpha helices. Mutations in these areas can lead to non-functional proteins that can polymerise and accumulate in the liver (infantile hepatic cirrhosis). Role in disease
Disorders of this protein include alpha-1 antitrypsin deficiency, an autosomal co-dominant hereditary disorder in which a deficiency of alpha-1 antitrypsin leads to a chronic uninhibited tissue breakdown. This causes the degradation especially of lung tissue and eventually leads to characteristic manifestations of pulmonary emphysema. Evidence has shown that cigarette smoke can result in oxidation of methionine 358 of α1-antitrypsin (382 in the pre-processed form containing the 24 amino acid signal peptide), a residue essential for binding elastase; this is thought to be one of the primary mechanisms by which cigarette smoking (or second-hand smoke) can lead to emphysema. Because A1AT is expressed in the liver, certain mutations in the gene encoding the protein can cause misfolding and impaired secretion, which can lead to liver cirrhosis. An extremely rare form of Pi, termed PiPittsburgh, functions as an antithrombin (a related serpin), due to a mutation (Met358Arg). One person with this mutation has been reported to have died of a bleeding diathesis.A liver biopsy will show abundant PAS-positive globules within periportal hepatocytes.
The serum levels of some of the common genotypes are:

PiMM: 100% (normal)
PiMS: 80% of normal serum level of A1AT
PiSS: 60% of normal serum level of A1AT
PiMZ: 60% of normal serum level of A1AT
PiSZ: 40% of normal serum level of A1AT
PiZZ: 10-15% (severe alpha-1 antitrypsin deficiency)
PiZ is caused by a glutamate to lysine mutation at position 342 (366 in pre-processed form)
PiS is caused by a glutamate to valine mutation at position 264 (288 in pre-processed form)Other rarer forms have been described; in all, there are over 80 variants. Medical uses
Alpha-1 antitrypsin concentrates are prepared from the blood plasma of blood donors. The US Food and Drug Administration (FDA) has approved the use of four alpha-1 antitrypsin products derived from a human plasma: Prolastin, Zemaira, Glassia, and Aralast. These products for intravenous augmentation A1AT therapy can cost up to $100,000 per year per patient. They are administered intravenously at a dose of 60 mg/kg once a week; higher doses do not provided additional benefit although they can be used in anticipation of an interruption of weekly administration, such as for a vacation.Alpha1-proteinase inhibitor (Respreeza) was approved for medical use in the European Union in August 2015. It is indicated for maintenance treatment, to slow the progression of emphysema in adults with documented severe alpha1-proteinase inhibitor deficiency (e.g., genotypes PiZZ, PiZ (null), Pi (null, null), PiSZ). People are to be under optimal pharmacologic and non-pharmacologic treatment and show evidence of progressive lung disease (e.g.