{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:23:00Z","timestamp":1790648580578,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2014,6,1]],"date-time":"2014-06-01T00:00:00Z","timestamp":1401580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The detrimental impact of tobacco on human health is clearly recognized, and despite aggressive efforts to prevent smoking, close to one billion individuals worldwide continue to smoke. People with chronic obstructive pulmonary disease are susceptible to recurrent respiratory infections with pathogens, including nontypeable Haemophilus influenzae (NTHI), yet the reasons for this increased susceptibility are poorly understood. Because mortality rapidly increases with multiple exacerbations, development of protective immunity is critical to improving patient survival. Acute NTHI infection has been studied in the context of cigarette smoke exposure, but this is the first study, to our knowledge, to investigate chronic infection and the generation of adaptive immune responses to NTHI after chronic smoke exposure. After chronic NTHI infection, mice that had previously been exposed to cigarette smoke developed increased lung inflammation and compromised adaptive immunity relative to air-exposed controls. Importantly, NTHI-specific T cells from mice exposed to cigarette smoke produced lower levels of IFN-\u03b3 and IL-4, and B cells produced reduced levels of Abs against outer-membrane lipoprotein P6, with impaired IgG1, IgG2a, and IgA class switching. However, production of IL-17, which is associated with neutrophilic inflammation, was enhanced. Interestingly, cigarette smoke\u2013exposed mice exhibited a similar defect in the generation of adaptive immunity after immunization with P6. Our study has conclusively demonstrated that cigarette smoke exposure has a profound suppressive effect on the generation of adaptive immune responses to NTHI and suggests the mechanism by which prior cigarette smoke exposure predisposes chronic obstructive pulmonary disease patients to recurrent infections, leading to exacerbations and contributing to mortality.<\/jats:p>","DOI":"10.4049\/jimmunol.1302584","type":"journal-article","created":{"date-parts":[[2014,4,22]],"date-time":"2014-04-22T03:46:49Z","timestamp":1398138409000},"page":"5226-5235","source":"Crossref","is-referenced-by-count":134,"title":["Cigarette Smoke Exposure Exacerbates Lung Inflammation and Compromises Immunity to Bacterial Infection"],"prefix":"10.1093","volume":"192","author":[{"given":"Amit A","family":"Lugade","sequence":"first","affiliation":[{"name":"Department of Immunology, Roswell Park Cancer Institute , Buffalo, NY 14263"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul N","family":"Bogner","sequence":"additional","affiliation":[{"name":"Department of Pathology, Roswell Park Cancer Institute , Buffalo, NY 14263"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H","family":"Thatcher","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Rochester , Rochester, NY 14620"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia J","family":"Sime","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Rochester , Rochester, NY 14620"},{"name":"Department of Environmental Medicine, University of Rochester , Rochester, NY 14620"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard P","family":"Phipps","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Rochester , Rochester, NY 14620"},{"name":"Department of Environmental Medicine, University of Rochester , Rochester, NY 14620"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin","family":"Thanavala","sequence":"additional","affiliation":[{"name":"Department of Immunology, Roswell Park Cancer Institute , Buffalo, NY 14263"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,6,1]]},"reference":[{"key":"2025032404314332300_r1","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S0140-6736(04)16900-6","article-title":"Pathophysiology of airflow limitation in chronic obstructive pulmonary disease","volume":"364","author":"Hogg","year":"2004","journal-title":"Lancet"},{"key":"2025032404314332300_r2","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1056\/NEJMoa032158","article-title":"The nature of small-airway obstruction in chronic obstructive pulmonary disease","volume":"350","author":"Hogg","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"2025032404314332300_r3","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.jaci.2013.01.010","article-title":"Clinical phenotypes of chronic obstructive pulmonary disease and asthma: recent advances","volume":"131","author":"Carolan","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025032404314332300_r4","doi-asserted-by":"crossref","first-page":"29","DOI":"10.2174\/1874434601307010029","article-title":"The differentiation of chronic obstructive pulmonary disease from asthma: a review of current diagnostic and treatment recommendations","volume":"7","author":"Spencer","year":"2013","journal-title":"Open. Nurs. J."},{"key":"2025032404314332300_r5","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1476-069X-4-7","article-title":"Lifetime environmental tobacco smoke exposure and the risk of chronic obstructive pulmonary disease","volume":"4","author":"Eisner","year":"2005","journal-title":"Environ. Health"},{"key":"2025032404314332300_r6","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/nri2530","article-title":"How cigarette smoke skews immune responses to promote infection, lung disease and cancer","volume":"9","author":"St\u00e4mpfli","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2025032404314332300_r7","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1042\/CS20130117","article-title":"The composition of cigarette smoke determines inflammatory cell recruitment to the lung in COPD mouse models","volume":"126","author":"John","year":"2014","journal-title":"Clin. Sci. (Lond)."},{"key":"2025032404314332300_r8","volume-title":"World Health Statistics 2012.","author":"World Health Organization","year":"2013"},{"issue":"2","key":"2025032404314332300_r9","doi-asserted-by":"crossref","first-page":"5S","DOI":"10.1378\/chest.117.2_suppl.5S","article-title":"The economic burden of COPD","volume":"117","author":"Sullivan","year":"2000","journal-title":"Chest"},{"key":"2025032404314332300_r10","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1097\/00001432-200304000-00009","article-title":"Respiratory infections caused by non-typeable Haemophilus influenzae","volume":"16","author":"Murphy","year":"2003","journal-title":"Curr. Opin. Infect. Dis."},{"key":"2025032404314332300_r11","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1097\/01.qco.0000224815.89363.15","article-title":"The role of bacteria in airway inflammation in exacerbations of chronic obstructive pulmonary disease","volume":"19","author":"Murphy","year":"2006","journal-title":"Curr. Opin. Infect. Dis."},{"key":"2025032404314332300_r12","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1164\/ajrccm.157.5.9711044","article-title":"Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation","volume":"157","author":"Soler","year":"1998","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025032404314332300_r13","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1128\/CMR.14.2.336-363.2001","article-title":"Bacterial infection in chronic obstructive pulmonary disease in 2000: a state-of-the-art review","volume":"14","author":"Sethi","year":"2001","journal-title":"Clin. Microbiol. Rev."},{"key":"2025032404314332300_r14","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1056\/NEJMoa012561","article-title":"New strains of bacteria and exacerbations of chronic obstructive pulmonary disease","volume":"347","author":"Sethi","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"2025032404314332300_r15","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1056\/NEJMra0800353","article-title":"Infection in the pathogenesis and course of chronic obstructive pulmonary disease","volume":"359","author":"Sethi","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"2025032404314332300_r16","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1136\/thoraxjnl-2011-201518","article-title":"Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality","volume":"67","author":"Suissa","year":"2012","journal-title":"Thorax"},{"key":"2025032404314332300_r17","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/mi.2008.70","article-title":"Mucosal immunization of mice with recombinant OMP P2 induces antibodies that bind to surface epitopes of multiple strains of nontypeable Haemophilus influenzae","volume":"2","author":"Ostberg","year":"2009","journal-title":"Mucosal Immunol."},{"key":"2025032404314332300_r18","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.1016\/j.vaccine.2012.10.033","article-title":"Kinetic analysis and evaluation of the mechanisms involved in the resolution of experimental nontypeable Haemophilus influenzae-induced otitis media after transcutaneous immunization","volume":"31","author":"Novotny","year":"2013","journal-title":"Vaccine"},{"key":"2025032404314332300_r19","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.micinf.2009.09.006","article-title":"Protection against nontypeable Haemophilus influenzae challenges by mucosal vaccination with a detoxified lipooligosaccharide conjugate in two chinchilla models","volume":"12","author":"Hong","year":"2010","journal-title":"Microbes Infect."},{"key":"2025032404314332300_r20","doi-asserted-by":"crossref","first-page":"5169","DOI":"10.1128\/IAI.00692-06","article-title":"Construction of a mutant and characterization of the role of the vaccine antigen P6 in outer membrane integrity of nontypeable Haemophilus influenzae","volume":"74","author":"Murphy","year":"2006","journal-title":"Infect. Immun."},{"key":"2025032404314332300_r21","doi-asserted-by":"crossref","first-page":"3590","DOI":"10.1016\/j.vaccine.2005.01.151","article-title":"Role of an immunodominant T cell epitope of the P6 protein of nontypeable Haemophilus influenzae in murine protective immunity","volume":"23","author":"McMahon","year":"2005","journal-title":"Vaccine"},{"key":"2025032404314332300_r22","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.clim.2006.06.005","article-title":"Identification of human T-cell epitopes and highly immunogenic analog peptides on the non-typeable Haemophilus influenzae P6 outer membrane protein","volume":"121","author":"Ishida","year":"2006","journal-title":"Clin. Immunol."},{"key":"2025032404314332300_r23","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s10875-008-9189-0","article-title":"Promiscuous peptides on the nontypeable Haemophilus influenzae P6 outer membrane protein","volume":"28","author":"Nomura","year":"2008","journal-title":"J. Clin. Immunol."},{"key":"2025032404314332300_r24","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1164\/ajrccm.165.7.2109009","article-title":"Lymphocyte proliferative response to P6 of Haemophilus influenzae is associated with relative protection from exacerbations of chronic obstructive pulmonary disease","volume":"165","author":"Abe","year":"2002","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025032404314332300_r25","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0264-410X(99)00166-8","article-title":"Immunization of mice with P6 of nontypeable Haemophilus influenzae: kinetics of the antibody response and IgG subclasses","volume":"18","author":"Badr","year":"1999","journal-title":"Vaccine"},{"key":"2025032404314332300_r26","doi-asserted-by":"crossref","first-page":"e19781","DOI":"10.1371\/journal.pone.0019781","article-title":"Lipid motif of a bacterial antigen mediates immune responses via TLR2 signaling","volume":"6","author":"Lugade","year":"2011","journal-title":"PLoS ONE"},{"key":"2025032404314332300_r27","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1136\/thx.2008.102681","article-title":"Suppression of pulmonary innate host defence in smokers","volume":"64","author":"Herr","year":"2009","journal-title":"Thorax"},{"key":"2025032404314332300_r28","doi-asserted-by":"crossref","first-page":"L412","DOI":"10.1152\/ajplung.00392.2007","article-title":"High-dose but not low-dose mainstream cigarette smoke suppresses allergic airway inflammation by inhibiting T cell function","volume":"295","author":"Thatcher","year":"2008","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025032404314332300_r29","doi-asserted-by":"crossref","first-page":"L821","DOI":"10.1152\/ajplung.00267.2010","article-title":"Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung","volume":"300","author":"Wu","year":"2011","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025032404314332300_r30","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1183\/09031936.00103211","article-title":"Immune system dysregulation in chronic lung disease","volume":"38","author":"Marsland","year":"2011","journal-title":"Eur. Respir. J."},{"key":"2025032404314332300_r31","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1136\/thoraxjnl-2012-201667","article-title":"Role of aberrant WNT signalling in the airway epithelial response to cigarette smoke in chronic obstructive pulmonary disease","volume":"68","author":"Heijink","year":"2013","journal-title":"Thorax"},{"key":"2025032404314332300_r32","doi-asserted-by":"crossref","first-page":"855","DOI":"10.2353\/ajpath.2007.060391","article-title":"Aryl hydrocarbon receptor-deficient mice develop heightened inflammatory responses to cigarette smoke and endotoxin associated with rapid loss of the nuclear factor-kappaB component RelB","volume":"170","author":"Thatcher","year":"2007","journal-title":"Am. J. Pathol."},{"key":"2025032404314332300_r33","doi-asserted-by":"crossref","first-page":"L165","DOI":"10.1152\/ajplung.00036.2013","article-title":"Neu-164 and Neu-107, two novel antioxidant and anti-myeloperoxidase compounds, inhibit acute cigarette smoke-induced lung inflammation","volume":"305","author":"Thatcher","year":"2013","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025032404314332300_r34","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/978-1-4419-5632-3_11","article-title":"Murine model of chronic respiratory inflammation","volume":"780","author":"Lugade","year":"2011","journal-title":"Adv. Exp. Med. Biol."},{"key":"2025032404314332300_r35","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1164\/rccm.200808-1306OC","article-title":"Bacteria challenge in smoke-exposed mice exacerbates inflammation and skews the inflammatory profile","volume":"179","author":"Gaschler","year":"2009","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025032404314332300_r36","doi-asserted-by":"crossref","first-page":"L814","DOI":"10.1152\/ajplung.00128.2012","article-title":"Acute cigarette smoke exposure impairs proteasome function in the lung","volume":"303","author":"van Rijt","year":"2012","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025032404314332300_r37","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/nrd3794","article-title":"Targeting IL-17 and TH17 cells in chronic inflammation","volume":"11","author":"Miossec","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"2025032404314332300_r38","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/nature05505","article-title":"Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis","volume":"445","author":"Zheng","year":"2007","journal-title":"Nature"},{"key":"2025032404314332300_r39","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1710-1492-9-23","article-title":"IL-17-producing peripheral blood CD177+ neutrophils increase in allergic asthmatic subjects","volume":"9","author":"Ramirez-Velazquez","year":"2013","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"2025032404314332300_r40","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.intimp.2012.10.018","article-title":"Increased expression of CD4+IL-17+ cells in the lung tissue of patients with stable chronic obstructive pulmonary disease (COPD) and smokers","volume":"15","author":"Zhang","year":"2013","journal-title":"Int. Immunopharmacol."},{"key":"2025032404314332300_r41","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.intimp.2012.09.011","article-title":"Imbalance of Th17\/Treg cells in mice with chronic cigarette smoke exposure","volume":"14","author":"Wang","year":"2012","journal-title":"Int. Immunopharmacol."},{"key":"2025032404314332300_r42","doi-asserted-by":"crossref","first-page":"L391","DOI":"10.1152\/ajplung.00062.2005","article-title":"The aryl hydrocarbon receptor is a regulator of cigarette smoke induction of the cyclooxygenase and prostaglandin pathways in human lung fibroblasts","volume":"289","author":"Martey","year":"2005","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025032404314332300_r43","doi-asserted-by":"crossref","first-page":"e20333","DOI":"10.1371\/journal.pone.0020333","article-title":"IL-17RA is required for CCL2 expression, macrophage recruitment, and emphysema in response to cigarette smoke","volume":"6","author":"Chen","year":"2011","journal-title":"PLoS ONE"},{"key":"2025032404314332300_r44","doi-asserted-by":"crossref","first-page":"e46989","DOI":"10.1371\/journal.pone.0046989","article-title":"Type II-activated murine macrophages produce IL-4","volume":"7","author":"La Flamme","year":"2012","journal-title":"PLoS ONE"},{"key":"2025032404314332300_r45","doi-asserted-by":"crossref","first-page":"7726","DOI":"10.1073\/pnas.1302906110","article-title":"Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate","volume":"110","author":"Xu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032404314332300_r46","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1086\/508428","article-title":"Impaired phagocytosis of nontypeable Haemophilus influenzae by human alveolar macrophages in chronic obstructive pulmonary disease","volume":"194","author":"Berenson","year":"2006","journal-title":"J. Infect. Dis."},{"key":"2025032404314332300_r47","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/1465-9921-6-68","article-title":"Toll-like receptor 2 expression is decreased on alveolar macrophages in cigarette smokers and COPD patients","volume":"6","author":"Droemann","year":"2005","journal-title":"Respir. Res."},{"key":"2025032404314332300_r48","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3389\/fimmu.2011.00010","article-title":"The role of TLR2 and bacterial lipoprotein in enhancing airway inflammation and immunity","volume":"2","author":"Lugade","year":"2011","journal-title":"Front. Immunol."},{"key":"2025032404314332300_r49","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1183\/09059180.00004211","article-title":"Beyond corticosteroids: future prospects in the management of inflammation in COPD","volume":"20","author":"Roche","year":"2011","journal-title":"Eur. Respir. Rev."},{"key":"2025032404314332300_r50","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1164\/rccm.200611-1630OC","article-title":"Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia","volume":"176","author":"Ernst","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/192\/11\/5226\/62515366\/1302584.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/192\/11\/5226\/62515366\/1302584.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T12:43:45Z","timestamp":1742820225000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/192\/11\/5226\/8001643"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,1]]},"references-count":50,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2014,6,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1302584","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,6]]},"published":{"date-parts":[[2014,6,1]]}}}