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Alpha-1 antitrypsin or α1-antitrypsin ( A1AT, α1AT, A1A, or AAT) is a protein belonging to the serpin superfamily. It is encoded in humans by the SERPINA1 gene. A protease inhibitor, it is also known as alpha1–proteinase inhibitor ( A1PI) or alpha1-antiproteinase ( A1AP) because it inhibits various (not just trypsin). As a type of enzyme inhibitor, it protects tissues from of inflammation cells, especially neutrophil elastase.
When the blood contains inadequate or defective A1AT (as in alpha-1 antitrypsin deficiency), neutrophil elastase can excessively break down elastin, leading to the loss of elasticity in the . This results in pulmonology, such as chronic obstructive pulmonary disease, in adults. Normally, A1AT is produced in the liver and enters the systemic circulation. However, defective A1AT may accumulate in the liver, potentially causing cirrhosis in both adults and pediatrics.
A1AT not only binds to neutrophil elastase from inflammatory cells but also to elastase on the cell surface. In this latter role, elastase acts as a signaling molecule for cell movement, rather than as an enzyme. Besides liver cells, A1PI is also produced in bone marrow, lymphoid tissue, and the Paneth cells of the gut.
Inactivation of A1AT by other enzymes during inflammation or infection can halt T cell migration precisely at the site of the pathological insult. This suggests that α1PI plays a key role in lymphocyte movement and immune surveillance, particularly in response to infection. A1AT is both an endogenous protease inhibitor and an exogenous one used as medication. The pharmaceutical form is purified from blood donation and is sold under the nonproprietary name alpha1–proteinase inhibitor (human) and under various trade names (including Aralast NP, Glassia, Prolastin, Prolastin-C, and Zemaira). Recombinant DNA versions are also available but are currently used in medical research more than as medication.
The term alpha-1 refers to the protein's behavior on protein electrophoresis. On electrophoresis, the protein component of the blood is separated by electric current. There are several clusters, the first being serum albumin, the second being the alpha, the third beta and the fourth gamma (). The non-albumin proteins are referred to as .
The alpha region can be further divided into two sub-regions, termed "1" and "2". Alpha-1 antitrypsin is the main protein of the alpha-globulin 1 region.
Another name used is alpha-1 proteinase inhibitor (α1-PI).
Over 100 different variants of α1-antitrypsin have been described in various populations. North-Western are most at risk for carrying one of the most common mutant forms of A1AT, the Z mutation (Glu342Lys on M1A, rs28929474).
Most serpins inactivate by binding to them . These enzymes are released locally in relatively low concentrations where they are immediately cleared by proteins such as A1AT. In the acute phase reaction, a further elevation is required to "limit" the damage caused by activated neutrophil granulocytes and their enzyme elastase, which breaks down the connective tissue fiber elastin.
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 and alpha helix. in these areas can lead to non-functional proteins that can and accumulate in the liver (infantile hepatic cirrhosis).
An extremely rare form of Pi, termed PiPittsburgh, functions as an antithrombin (a related serpin), due to a mutation (Methionine358Arginine). 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.
Patients with rheumatoid arthritis (RA) have been found to make Autoantibody toward the Carbamylation 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 biomarker for RA.
The level of A1AT in serum is most often determined by adding an antibody that binds to A1AT, then using turbidimetry to measure how much A1AT is present. Other detection methods include the use of enzyme-linked-immuno-sorbent-assays and radial immunodiffusion.
Different analytical methods are used to determine A1AT phenotype. As protein electrophoresis is imprecise, the A1AT phenotype is analysed by isoelectric focusing (IEF) in the pH range 4.5-5.5, where the protein migrates in a gel according to its isoelectric point or charge in a pH gradient.
Normal A1AT is termed M, as it migrates toward the center of such an IEF gel. Other variants are less functional and are termed A-L and N-Z, dependent on whether they run proximal or distal to the M band. The presence of deviant bands on IEF can signify the presence of alpha-1 antitrypsin deficiency. Since the number of identified mutations has exceeded the number of letters in the alphabet, subscripts have been added to most recent discoveries in this area, as in the Pittsburgh mutation described above.
As every person has two allele of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing, although heterozygote with one null mutant that abolishes expression of the gene will only show one band.
In blood test results, the IEF results are notated as in PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that patient.
Alpha-1 antitrypsin levels in the blood depend on the genotype. Some mutant forms fail to fold properly and are, thus, targeted for destruction in the proteasome, whereas others have a tendency to , being retained in the endoplasmic reticulum. The serum levels of some of the common genotypes are:
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. lower forced expiratory volume per second (FEV1) predicted, impaired walking capacity or increased number of exacerbations) as evaluated by a healthcare professional experienced in the treatment of alpha1-proteinase inhibitor deficiency.
The most common side effects include dizziness, headache, dyspnoea (shortness of breath) and nausea. Allergic reactions have been observed during treatment, some of which were severe.
Aerosolized-augmented A1AT therapy is under study. This involves inhaling purified human A1AT into the lungs and trapping the A1AT into the lower respiratory tract. However, inhaled A1AT may not reach the elastin fibers in the lung where elastase injury occurs. Further study is currently underway. Recombinant DNA alpha-1 antitrypsin is not yet available for use as a medication but is under development.
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