Medical Research Section 2
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Why do some adults with PiMZ Alpha 1 antitrypsin develop bronchiectasis
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Immune-modulating effects of Alpha 1 antitrypsin
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The Role of Neutrophils in Alpha-1 Antitrypsin Deficiency
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Alpha-1 Antitrypsin Therapy for Autoimmune Disorders
Why do some adults with PiMZ Alpha 1-antitrypsin
develop bronchiectasis
Bronchiectasis is an aetiologically heterogeneous, chronic and often progressive disease resulting in the permanent dilatation of one or more bronchi or bronchioli. Several reports indicated an association among inherited α1-antitrypsin deficiency (α1-ATD), pulmonary infections and bronchiectasis.
Our findings in a young 18 yr patient highlight the quantitative and qualitative deficiency of MZ α1-AT and increased neutrophil expression of elastase mRNA, which offers an explanation for the early-age onset of bronchiectasis. Recently, MILGER et al. also reported a case of α1-ATD presenting with severe cystic
bronchiectasis and the absence of classical emphysema. Interestingly, this case had a novel mutation leading to a dysfunctional truncated α1-AT protein. These atypical cases with bronchiectasis highlight α1-AT as a differential diagnosis in bronchiectasis
Immune-modulating effects of Alpha 1 antitrypsin
Mario R. Ehlers
Alpha-1 antitrypsin (AAT) is a circulating serine protease inhibitor (serpin) that inhibits neutrophil elastase in the lung, and AAT deficiency is associated with early-onset emphysema. AAT is also a liver-derived acute phase protein that, in vitro and in vivo, reduces production of proinflammatory cytokines, inhibits apoptosis, blocks leukocyte degranulation and migration, and modulates local and systemic inflammatory responses. In monocytes, AAT has been shown to increase intracellular cAMP, regulate expression of CD14, and suppress NFκB nuclear translocation. These effects may be mediated by AAT's serpin activity or by other protein-binding activities. In preclinical models of autoimmunity and transplantation, AAT therapy prevents or reverses autoimmune disease and graft loss, and these effects are accompanied by tolerogenic changes in cytokine and transcriptional profiles and T cell subsets. This review highlights advances in our understanding of the immune-modulating effects of AAT and their potential therapeutic utility.
The Role of Neutrophils in Alpha-1 Antitrypsin Deficiency
Noel G. McElvaney
(Conclusion)
The lung disease in AATD is characterized by neutrophillic inflammation and increased proteolytic activity, predominantly through the unopposed activity of serine proteases released from neutrophil granules, specifically NE, but also including Cath G and PR3 (73) and other non neutrophil derived proteases. AAT is an effective antiprotease, but also possesses a number of important anti-inflammatory and immune-modulating properties, which are of pivotal importance in understanding the pathogenesis of the inflammatory lung disease in AATD and further systemic manifestations. The role of AAT in modulating neutrophil chemotaxis and degranulation points to a systemic effect, as does its ability to decrease autoantibody production. This has significant implications for our understanding of AATD moving us away from a compartmentalized version of the protease–antiprotease imbalance to a broader understanding of an ongoing interaction between loss of function and gain of function. This concept perhaps is best exemplified by the AATD neutrophil
with excess Z-AAT in its ER, exhibiting ER stress while, at the same time, being exposed to an unopposed TNF-a–mediated inflammation, ultimately leading to premature apoptosis. Finally, it should be noted that many of these anti-inflammatory effects of AAT operate through different pathways, some through hydrophobic interactions between AAT and the signaling molecule, and others through electrostatic bonds, through direct AAT binding, and also through binding of AAT to related receptors. This exciting anti-inflammatory repertoire lends itself to pharmacological manipulation, which should result in more specific anti-inflammatory therapeutic options in the future.
Alpha-1 Antitrypsin Therapy for Autoimmune Disorders
Sihong Song
Autoimmune diseases are conditions caused by an over reactive immune system that attacks self-tissues and organs. Although the pathogenesis of autoimmune disease is complex and multi-factorial, inflammation is commonly involved. Therefore, anti-inflammatory therapies hold potential for the treatment of autoimmune diseases. However, long-term control of inflammation is challenging and most of the currently used drugs have side effects. Alpha-1 antitrypsin (AAT) is an anti-inflammatory protein with a well-known safety profile. The therapeutic potential of AAT has been tested in several autoimmune disease models. The first study using a recombinant adeno-associated viral (rAAV) vector showed that AAT gene transfer prevented the development of type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model. Subsequent studies showed that treatment with AAT protein prevented and reversed type 1 diabetes. The beneficial effects of AAT treatment have also been observed in other autoimmune disease models such as rheumatoid arthritis and systemic lupus erythematosus. This paper reviews the therapeutic application of AAT and discusses possible mechanisms of
action in various autoimmune diseases.