Editorial Material
Respiratory System
Alessandro N. Franciosi, Tomas P. Carroll, Noel G. McElvaney
Summary: The study showed that individuals with SZ-AATD have a risk of lung disease comparable to MZ-AATD, not ZZ-AATD.
Article
Medicine, Research & Experimental
Maximilian Ebert, Uwe Jerke, Claudia Eulenberg-Gustavus, Lovis Kling, Dieter Jenne, Marieluise Kirchner, Philipp Mertins, Markus Bieringer, Saban Elitok, Kai-Uwe Eckardt, Adrian Schreiber, Alan D. Salama, Ralph Kettritz
Summary: The levels of PR3 and AAT were significantly increased in patients with both PR3-AAV and MPO-AAV, but only in PR3-AAV did the level of PR3 correlate with the ANCA titer, inflammatory response, and disease severity. Mechanistically, AAT prevented PR3 from binding to CD177, reducing the binding of PR3-ANCA to neutrophil surface antigens. Active patients with PR3-AAV showed methionine oxidation in plasma AAT, which was replicated by ANCA-activated neutrophils. The protective effects of PR3-related AAT were compromised by oxidation in the AAT reactive center loop, but preserved with valine and leucine substitution for critical methionines.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Hematology
Robert A. Campbell, Heather D. Campbell, J. Samuel Bircher, Claudia Valeria de Araujo, Frederik Denorme, Jacob L. Crandell, John L. Rustad, Josh Monts, Mark J. Cody, Yasuhiro Kosaka, Christian C. Yost
Summary: Placentally expressed HTRA1 cleaves A1AT to generate NIPs that regulate NET formation. Neonatal mice lacking HTRA1 had no detectable NIPs and exhibited earlier NET competence after birth. A1ATM(383)S-CF improved survival in neonatal sepsis, indicating its potential therapeutic use in inhibiting pathogenic NET formation.
Article
Immunology
Xiyuan Bai, An Bai, Michele Tomasicchio, James R. Hagman, Ashley M. Buckle, Arnav Gupta, Vineela Kadiyala, Shaun Bevers, Karina A. Serban, Kevin Kim, Zhihong Feng, Kathrin Spendier, Guy Hagen, Lorelenn Fornis, David E. Griffith, Monika Dzieciatkowska, Robert A. Sandhaus, Anthony N. Gerber, Edward D. Chan
Summary: This study identifies a new mechanism for the gene regulation, anti-inflammatory, and host-defense properties of AAT. AAT binds to the cytoplasmic glucocorticoid receptor (GR) in human macrophages, leading to inhibition of NF-kB activation and IL-8 production, as well as induction of angiopoietin-like 4 protein. This AAT-GR interaction contributes to a host-protective role against mycobacteria in macrophages.
JOURNAL OF IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Juan Luis Rodriguez Hermosa, Gianna Vargas Centanaro, Maria Estela Gonzalez Castro, Marc Miravitlles, Lourdes Lazaro-Asegurado, Beatriz Maria Jimenez-Rodriguez, Rosanel Amaro Rodriguez, Rosaly Moreno Mendez, Maria Torres-Duran, Jose Maria Hernandez-Perez, Ana Maria Humanes-Navarro, Myriam Calle Rubio
Summary: This study found that patients with allelic variants of SERPINA1 gene, which is associated with severe cases of COVID-19, were more likely to have alpha-1 antitrypsin deficiency (AATD), making them more susceptible to severe COVID-19. Therefore, increased precautionary measures are recommended for AATD patients.
Article
Cell Biology
Adriana Ordonez, Heather P. Harding, Stefan J. Marciniak, David Ron
Summary: The study explored the cellular factors affecting the secretion of circulating polymers of alpha 1-antitrypsin, finding that cargo receptors LMAN1 and SURF4 are crucial for polymer secretion. Disruption of these receptors leads to a defect in alpha 1-antitrypsin secretion, particularly polymers, indicating their important role in regulating the process.
Article
Respiratory System
Maria Torres-Duran, Jose Luis Lopez-Campos, Juan Luis Rodriguez-Hermosa, Cristina Esquinas, Cristina Martinez-Gonzalez, Jose Maria Hernandez-Perez, Carlota Rodriguez, Ana Bustamante, Francisco Casas-Maldonado, Miriam Barrecheguren, Cruz Gonzalez, Marc Miravitlles
Summary: There is a high prevalence of PI*SZ in Spain, and patients with this genotype tend to have less severe lung disease but a higher prevalence of asthma.
Article
Respiratory System
Charlie Strange, N. Gerard McElvaney, Claus F. Vogelmeier, Marcos Marin-Galiano, Michaela Buch-Haensel, Xiang Zhang, Younan Chen, Oliver Vit, Marion Wencker, Kenneth R. Chapman
Summary: Acute exacerbations of COPD have an effect on PD15 lung density in alpha(1)-antitrypsin deficiency. AECOPD within 2 weeks has a significant impact on PD15, lasting less than 6 weeks. Patient characteristics have minimal correlation with PD15, and an exacerbation-free period before CT scan is recommended to reduce noise.
Article
Genetics & Heredity
Lela Lackey, Aaztli Coria, Auyon J. Ghosh, Phil Grayeski, Luke Hatfield, Vijay Shankar, John Platig, Zhonghui Xu, Silvia B. Ramos, Edwin K. Silverman, Victor E. Ortega, Michael H. Cho, Craig P. Hersh, Brian D. Hobbs, Peter Castaldi, Alain Laederach
Summary: The study identifies a novel alternative polyadenylation event that regulates A1AT protein expression in COPD, involving two polyadenylation sites in the SERPINA1 mRNA. Additionally, differences in SERPINA1 distal ratio distribution among cell types in the liver and lung were observed in single-cell RNA-seq analysis.
Review
Medicine, General & Internal
Andrea Vianello, Gabriella Guarnieri, Fausto Braccioni, Beatrice Molena, Sara Lococo, Alessia Achille, Federico Lionello, Leonardo Salviati, Marco Caminati, Gianenrico Senna
Summary: This review examines the correlation between alpha 1-antitrypsin deficiency, SARS-CoV-2 infection, and COVID-19 mortality rates, suggesting that ethnic differences in SERPINA1 allele frequencies may partially explain the geographic disparities. Shared pathogenetic pathways are also discussed as theoretical basis for the epidemiological findings, along with the potential use of AAT augmentation therapy in patients with COVID-19.
JOURNAL OF CLINICAL MEDICINE
(2021)
Article
Biotechnology & Applied Microbiology
Jonathan B. Rosenberg, P. De Bishnu, Alessandria Greco, Nicholas Gorman, Vikrum Kooner, Alvin Chen, Melissa Yost-Bido, Carlos Munoz-Zuluaga, Stephen M. Kaminsky, Mahboubeh Rostami, Sebastien Monette, Ronald G. Crystal, Dolan Sondhi
Summary: Alpha 1-antitrypsin (AAT) deficiency is a common hereditary disorder with a risk of early-onset emphysema. AAT, produced in the liver, protects the lungs from protease damage, but deficiency leads to lung tissue destruction. Oxidative damage to AAT prevents it from inhibiting target proteases. In this study, the safety of intravenous administration of an engineered AAT variant, AAV8hAAT(AVL), was evaluated in mice. The study showed that AAV8hAAT(AVL) is safe with no significant adverse effects, demonstrating its potential for further clinical studies.
HUMAN GENE THERAPY
(2023)
Article
Hematology
Julie Riis, Borge G. Nordestgaard, Shoaib Afzal
Summary: The study revealed an association between the alpha(1)-antitrypsin Z genetic variant and an increased risk of venous thromboembolism, with hazard ratios of 2.2 for homozygotes and 1.1 for heterozygotes. The absolute risk of venous thromboembolism associated with alpha(1)-antitrypsin ZZ homozygosity was 7.8%.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Nanoscience & Nanotechnology
Michelle A. Cruz, Dillon Bohinc, Elizabeth A. Andraska, Jurgis Alvikas, Shruti Raghunathan, Nicole A. Masters, Nadine D. van Kleef, Kara L. Bane, Kathryn Hart, Kathryn Medrow, Michael Sun, Haitao Liu, Shannon Haldeman, Ankush Banerjee, Emma M. Lessieur, Kara Hageman, Agharnan Gandhi, Maria de la Fuente, Marvin T. Nieman, Timothy S. Kern, Coen Maas, Steven de Maat, Keith B. Neeves, Matthew D. Neal, Anirban Sen Gupta, Evi X. Stavrou
Summary: "Neutrophils play a crucial role in defense against infections and inflammation, but their uncontrolled recruitment and activation can lead to prolonged inflammation and worsen specific pathological conditions. This study presents a targeted drug delivery strategy to specifically target activated, pro-inflammatory neutrophils and neutrophil-platelet complexes, offering a novel therapeutic approach for neutrophil-driven pathologies."
NATURE NANOTECHNOLOGY
(2022)
Article
Pathology
Josiah D. Murray, Maria A. Willrich, Michael J. Krowka, Aleh Bobr, David L. Murray, Kevin C. Halling, Rondell P. Graham, Melissa R. Snyder
Summary: The study evaluated the effectiveness of a LC-MSIMS-based algorithm in detecting AAT deficiency, showing high sensitivity and cost-effectiveness with a significant reduction in IEF testing. The algorithm demonstrated a 99.9% sensitivity for detecting deficiency-associated phenotypes and was particularly successful in identifying heterozygous patients with specific allele pairings.
AMERICAN JOURNAL OF CLINICAL PATHOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Riccardo Ronzoni, Nina Heyer-Chauhan, Annamaria Fra, Andrew C. Pearce, Martin Rudiger, Elena Miranda, James A. Irving, David A. Lomas
Summary: The formation of ordered Z (Glu342Lys) alpha(1)-antitrypsin polymers in hepatocytes plays a central role in the development of liver disease in alpha(1)-antitrypsin deficiency. Studies have identified an intermediate conformational state (M*) that precedes polymer formation and in vivo experiments are ongoing to confirm this finding. Polymers of Z alpha(1)-antitrypsin exist in two distinct populations in cells, with different dynamics, and preventing the accumulation of the M* conformation may be a viable approach for pharmacological treatment of this condition.