Editing Alpha-1 antitrypsin (section)

== Clinical significance ==
[[File:Alpha 1-antitrypsin (labelled).png|thumb|Alpha-1 antitrypsin (white) with highlighted 'reactive centre loop' (blue) and A-sheet (light blue). (PDB: 1QLP)]]
{{main|Alpha-1 antitrypsin deficiency}}
Disorders of this protein include [[alpha 1-antitrypsin deficiency|alpha-1 antitrypsin deficiency]], an [[Dominance (genetics)#Co-dominance|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 [[emphysema|pulmonary emphysema]].<ref name=DeMeo_2004>{{cite journal | vauthors = DeMeo DL, Silverman EK | title = Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk | journal = Thorax | volume = 59 | issue = 3 | pages = 259–64 | date = March 2004 | pmid = 14985567 | pmc = 1746953 | doi = 10.1136/thx.2003.006502 }}
</ref> Evidence has shown<ref>{{cite journal | vauthors = Taggart C, Cervantes-Laurean D, Kim G, McElvaney NG, Wehr N, Moss J, Levine RL | title = Oxidation of either methionine 351 or methionine 358 in alpha 1-antitrypsin causes loss of anti-neutrophil elastase activity | journal = The Journal of Biological Chemistry | volume = 275 | issue = 35 | pages = 27258–65 | date = September 2000 | pmid = 10867014 | doi = 10.1074/jbc.M004850200 | doi-access = free }}</ref> that cigarette smoke can result in oxidation of [[methionine]] 358 of α<sub>1</sub>-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 ''P<sub>i</sub>'', termed ''P<sub>i</sub>''<sub>Pittsburgh</sub>, functions as an [[antithrombin]] (a related [[serine protease inhibitor|serpin]]), due to a mutation ([[Methionine|Met]]358[[Arginine|Arg]]). One person with this mutation has been reported to have died of a [[bleeding diathesis]].<ref>{{cite journal | vauthors = Owen MC, Brennan SO, Lewis JH, Carrell RW | title = Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder | journal = The New England Journal of Medicine | volume = 309 | issue = 12 | pages = 694–8 | date = September 1983 | pmid = 6604220 | doi = 10.1056/NEJM198309223091203 }}</ref>

A liver biopsy will show abundant [[Periodic acid–Schiff stain|PAS]]-positive globules within periportal hepatocytes.

Patients with [[rheumatoid arthritis]] (RA) have been found to make [[Autoantibody|autoantibodies]] toward the [[Carbamylation|carbamylated]] form of A1AT in the [[synovial fluid]]. This suggests that A1AT may play an anti-inflammatory or tissue-protecting role outside the lungs. These antibodies are associated with a more severe disease course, can be observed years before disease onset, and may predict the development of RA in [[arthralgia]] patients. Consequently, carbamylated A1AT is currently being developed as an [[antigen]]ic [[biomarker]] for RA.<ref name=Verheul_2017>{{cite journal | vauthors = Verheul MK, Yee A, Seaman A, Janssen GM, van Veelen PA, Drijfhout JW, Toes RE, Mahler M, Trouw LA | title = Identification of carbamylated alpha 1 anti-trypsin (A1AT) as an antigenic target of anti-CarP antibodies in patients with rheumatoid arthritis | journal = Journal of Autoimmunity | volume = 80 | pages = 77–84 | date = June 2017 | pmid = 28291659 | doi = 10.1016/j.jaut.2017.02.008 }}</ref>