News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2020)

The gene encoding alpha-1 antitrypsin (SERPINA1) is the strongest genetic risk locus for Chronic obstructive pulmonary disease (COPD) susceptibility. While the deficiency alleles PI types S and Z increase the risk for COPD in ZZ homozygotes and ZS compound heterozygotes as compared with wild-type allele homozygotes (MM), contradictory data exists regarding MZ heterozygotes. Ortega et al (Am J Respir Crit Care Med. 2019 Oct 29. https://doi.org/10.1164/rccm.201904-0769OC) performed deep next-generation sequencing and a comprehensive genetic study of this locus in a large cohort of current and former heavy smokers complemented by alpha-1 antitrypsin measurements. MZ heterozygotes as confirmed by sequencing had lower lung function and increased CT-based emphysema compared with MM subjects. Additional rare SERPINA1 variants associated with lower lung function in Z-containing compound heterozygotes and with emphysema in heterozygotes of 5 non-S/Z variants also associated with lower alpha-1 antitrypsin concentrations. These findings may ultimately help lead to the development of more individualized diagnostic and preventative strategies for respiratory disease related to alpha-1 antitrypsin deficiency. Figure attribution: Public Domain at Wikimedia Commons by users Laura Fregonese and Jan Stolk [CC BY (https://creativecommons.org/licenses/by/2.0)].Rare SERPINA1 variants associated with lower lung functionVictor E. OrtegaView Large Image Figure ViewerDownload Hi-res image Download (PPT) Rare SERPINA1 variants associated with lower lung function We asked first author Victor E. Ortega, MD, PhD, ATSF, from Wake Forest School of Medicine, Winston-Salem, North Carolina, to comment on the article. He writes, “This deep sequencing study of the gene encoding alpha1-antitrypsin is the most comprehensive genetic study of this locus in a multi-ethnic cohort with a history of heavy smoking with varying severities of COPD not recruited for a history of alpha1-antitrypsin deficiency. This study confirms the effects of MZ heterozygosity on COPD risk while demonstrating effects across several novel, ethnic-specific rare variants in at-risk smokers.” Children have a higher likelihood of developing allergic asthma than adults, although the underlying reasons are incompletely understood. Wang et al ( Immunity 2019;51:1102-18.e7. https://doi.org/10.1016/j.immuni.2019.10.002) have identified a developmental transition of sympathetic nerves from dopaminergic to adrenergic states from postnatal to adult lungs. Dopamine signaling induced a TH2 phenotype in CD4+ T cells and allergic airway inflammation in vivo to a greater degree in younger mice than adult mice. Collectively, the results implicate production of dopamine from pulmonary sympathetic nerves in the enhanced susceptibility of pediatric patients to the development of allergic asthma. Figure attribution: The original uploader was Kelson at French Wikipedia. [CC BY-SA (http://creativecommons.org/licenses/by-sa/3.0/)].Dopamine signaling induced a TH2 phenotypeXingbin AiView Large Image Figure ViewerDownload Hi-res image Download (PPT) Dopamine signaling induced a TH2 phenotype We asked senior author Xingbin Ai, PhD, from Massachusetts General Hospital in Boston, Massachusetts, to comment on the article. She writes, “We are very excited to identify a potentially targetable pathway in CD4+ T cells for the treatment of allergic asthma in childhood.” Guvenel et al (J Clin Invest 2019Dec 9. https://doi.org/10.1172/JCI131696) examined the dynamics of airway CD4+ T-cell activity after infection with respiratory syncytial virus (RSV) in healthy adult human volunteers and identified novel RSV epitopes. Using MHC II tetramers specific to an immunodominant RSV epitope, the authors identified an RSV-specific resident memory CD4+ T-cell population in the lower airway with altered differentiation and expression of costimulatory molecules and CXCR3 over the course of infection. The authors have identified immunogenic RSV epitopes and generated tools to precisely track RSV-specific CD4+ T cells, which will aid vaccine development.Tools to precisely track RSV-specific CD4+ T cellsPeter J. Openshaw and Christopher Chiu.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Tools to precisely track RSV-specific CD4+ T cells We asked senior authors Peter J. Openshaw, MD, PhD, FMedSci, from the National Heart and Lung Institute in London, United Kingdom, and Christopher Chiu, MD, PhD, from Imperial College London in London, United Kingdom, to comment on the article. They write, “CD4+ (helper) T cells are critical for the generation and maintenance of long-term immunity but relatively under-investigated in humans due to their low frequency, lack of specific reagents, and heterogeneity. By identifying immunodominant antigenic targets in RSV and developing novel tools to track virus-specific T cells, we can now study the quantity and quality of CD4+ T-cell responses in both blood and lung. This will assist the development and selection of RSV vaccines and enable improved understanding of human T helper cells against acute viral infections.” Because previous observational studies had suggested that the use of beta-blockers may be of benefit in patients with COPD, Dransfield et al (N Engl J Med 2019;381:2304-14. https://doi.org/10.1056/NEJMoa1908142) performed a randomized trial to assess the efficacy of metoprolol in decreasing the risk of exacerbations in patients with moderate or severe COPD without absolute indications for beta-blocker use. The use of metoprolol did not affect the time until the first exacerbation or the overall frequency of exacerbations as compared with placebo. However, the study was stopped early because of safety concerns as the use of metoprolol increased the risk for severe exacerbations requiring hospitalization and mechanical ventilation. In total, this trial presents strong evidence that beta-blockers should not be used in COPD patients without other indications for their use, although further investigation is required in patients with significant cardiovascular disease. Figure attribution: Public Domain at Wikimedia Commons by user Mark Oniffrey [CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0)].Metoprolol increased the risk for severe exacerbations requiring hospitalizationMark T. DransfieldView Large Image Figure ViewerDownload Hi-res image Download (PPT) Metoprolol increased the risk for severe exacerbations requiring hospitalization We asked first author Mark T. Dransfield, MD, from the University of Alabama – Birmingham, Birmingham, Alabama, to comment on the article. He writes, “Numerous observational studies suggested that beta-blockers may reduce the risk of exacerbations and mortality in patients with COPD, but all were subject to bias inherent to their design. We found no evidence of a beneficial effect in COPD patients without strong indications for their use.”News items were written by medical writer Jared Travers, MD, PhD. News items were written by medical writer Jared Travers, MD, PhD.