HPE Alpha 1 Antitrypsin Deficiency | Page 7

effect on TNF-a-driven inflammation. This effect is mediated by preventing TNF-a from interacting with its receptors on neutrophils and other cells. 18 In AATD, this results in increased degranulation of neutrophils 19 and production of autoantibodies, which can contribute significantly to the disease state. 18 AATD patients receiving AAT therapy with plasma-purified AAT show reduced TACE activity and TNF-α signalling and normalised neutrophil apoptosis. 20 In this regard, AAT also binds to and inhibits caspase-3, thereby preventing lung endothelial cell apoptosis. 21 AAT prolongs allograft survival and modulates cellular immunity in mice that have undergone pancreatic islet allograft. 22–25 The mechanism by which AAT protects islet cells is unclear but AAT likely potentiates insulin secretion and the effects of glucagon-like peptide-1 and forskolin. Furthermore, AAT has been shown to given that NE possesses the ability to damage every component of the extracellular matrix. 7 Unopposed NE also amplifies the inflammatory burden and increases mucin secretion. 8,9 NE impairs host defence further by cleaving complement receptors 10 and CXCR1 receptors 11 on neutrophils and cleaving complement 12 and immunoglobulins. 3 NE, when in excess, cleaves anti-proteases 14,15 including AAT, depriving the body not only of its anti-protease but also of its anti-inflammatory effects. In these disease states, the anti-NE effects of AAT are impeded either by not enough AAT, as is found in AATD, or inactivation of AAT at the site of inflammation. Anti-inflammatory effects of AAT In recent years, there has been increased awareness of the anti-inflammatory properties of AAT. This is of major interest in the study of lung disease as many of these conditions are characterised by neutrophil-dominated inflammation. AAT can modulate interleukin (IL)-8-induced neutrophil chemotaxis by binding IL-8 and preventing it from interacting with its receptor on neutrophils. 16 The glycosylation of AAT plays a pivotal role in this anti- inflammatory effect as non-glycosylated AAT fails to bind IL-8, and increased sialylation of AAT during inflammation leads to increased IL-8 binding. AAT also decreases neutrophil chemotaxis in response to soluble immune complexes (sICs) through a different mechanism. Neutrophil engagement of sICs leads to increased tumour necrosis factor-alpha (TNF-α)-converting enzyme (TACE) activity, with release of the glycosylphosphatidylinositol anchored Fc receptor (FcγRIIIB), necessary for chemotaxis. AAT inhibits TACE activity, preventing the release of membrane FcγRIIIB. 16 Another major contributor to neutrophil chemotaxis in the lung is leukotriene B4 (LTB4), which also increases neutrophil adhesion and degranulation. NE can signal back to the neutrophil causing increased production of LTB4 and upregulation of its receptor BLT1 on the neutrophil membrane. AAT can bind LTB4, thereby preventing neutrophil activation. 17 AAT also has an The classic cause of AATD is the autosomal, codominant, genetic disorder of that name, which is characterised by low circulating levels of AAT due to a mutation of the SERPINA1 gene protect a diabetic cell line against TNF-α-mediated apoptosis and to significantly reduce apoptosis caused by a combination of TNF-α, IL-1β and interferon (IFN)-γ. 26 FIGURE 1 AAT phenotype and risk of lung disease 2.5 2.0 1.5 1.0 0.5 0.0 MM MS AAT Phenotype MZ SS Background SZ ZZ High Risk of lung disease Deficiency of AAT: genetic and functional The classic cause of AATD is the autosomal, codominant, genetic disorder of that name, which is characterised by low circulating levels of AAT due to a mutation of the SERPINA1 gene. Healthy individuals usually carry two copies of the non- mutated M allele, which in homozygous individuals leads to AAT plasma levels >1.04g/l or 20μM (Figure 1) and lung levels of approximately 4μM. 27,28 There are at least 120 genetic deficiency variants of the SERPINA1 gene with the Z (Glu342Lys) and S (Glu264Val) mutations being the most common. The Z mutation gives rise to the most severe plasma deficiency and occurs in more than 95% of individuals with AATD. Z homozygous individuals have an AAT serum level of approximately 5μM and an epithelial lining fluid level of approximately 0.5μM. 28 They have an increased risk of emphysema due to low levels of AAT in the lung, leading to loss of anti-NE protection. This risk is significantly exacerbated by cigarette smoking. Loss of AAT function can occur in other lung conditions, even in the presence of normal AAT levels. In CF, there is usually normal production of M-AAT by the liver and indeed the serum and lung levels of AAT are increased in CF. 29 However, the AAT on the airway epithelial surface in CF is functionally inactive. 30 This is due mainly to cleavage by proteases such as NE. This NE-driven proteolytic inactivation also occurs in non-CF bronchiectasis 31 and pneumonia, 32 where this is an increased NE burden on the respiratory epithelial surface, a powerful illustration of disruption of the protease–anti-protease balance, in this case by excess proteases. Emphysema usually occurs in MM AAT individuals with normal serum and lung levels of AAT. Carp et al were the first to show evidence of oxidative inactivation of AAT in the lungs of smokers with concomitant decreased hospitalpharmacyeurope.com | 2019 | 7