title: Cigarette smoke exposure exacerbates lung inflammation and compromises immunity to bacterial infection.
abstract: 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-γ 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-exposed 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.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Amit A
authors.initials: AA
authors.lastname: Lugade
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Paul N
authors.initials: PN
authors.lastname: Bogner
authors.affiliation: Department of Medicine, University of Rochester, Rochester, NY 14620; and.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Thatcher
authors.affiliation: Department of Medicine, University of Rochester, Rochester, NY 14620; and Department of Environmental Medicine, University of Rochester, Rochester, NY 14620.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
authors.affiliation: Department of Medicine, University of Rochester, Rochester, NY 14620; and Department of Environmental Medicine, University of Rochester, Rochester, NY 14620.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; yasmin.thanavala@roswellpark.org.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Thanavala
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000276:immunology; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001425:Bacterial Outer Membrane Proteins / Q000494:pharmacology; D002908:Chronic Disease; D005260:Female; D006192:Haemophilus Infections / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006193:Haemophilus influenzae / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D051379:Mice; D018410:Pneumonia, Bacterial / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D012907:Smoking / Q000009:adverse effects* / Q000276:immunology / Q000473:pathology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D014028:Tobacco Smoke Pollution; D015847:Interleukin-4; D007371:Interferon-gamma
references.citation: J Infect Dis. 2006 Nov 15;194(10):1375-84
references.pmid: 17054066
references.citation: Infect Immun. 2006 Sep;74(9):5169-76
references.pmid: 16926409
references.citation: Clin Immunol. 2006 Oct;121(1):90-9
references.pmid: 16901757
references.citation: PLoS One. 2012;7(10):e46989
references.pmid: 23071691
references.citation: Vaccine. 2013 Jul 25;31(34):3417-26
references.pmid: 23092856
references.citation: Am J Physiol Lung Cell Mol Physiol. 2011 Jun;300(6):L821-30
references.pmid: 21335520
references.citation: Vaccine. 2005 May 20;23(27):3590-6
references.pmid: 15855018
references.citation: Am J Respir Crit Care Med. 1998 May;157(5 Pt 1):1498-505
references.pmid: 9603129
references.citation: Am J Respir Crit Care Med. 2009 Apr 15;179(8):666-75
references.pmid: 19179487
references.citation: Respir Res. 2005 Jul 08;6:68
references.pmid: 16004610
references.citation: Int Immunopharmacol. 2013 Jan;15(1):58-66
references.pmid: 23127823
references.citation: Environ Health. 2005 May 12;4(1):7
references.pmid: 15890079
references.citation: Thorax. 2009 Feb;64(2):144-9
references.pmid: 18852155
references.citation: Open Nurs J. 2013 Mar 22;7:29-34
references.pmid: 23802028
references.citation: Eur Respir Rev. 2011 Sep 1;20(121):175-82
references.pmid: 21881145
references.citation: J Clin Immunol. 2008 Jul;28(4):361-9
references.pmid: 18379862
references.citation: Am J Physiol Lung Cell Mol Physiol. 2013 Jul 15;305(2):L165-74
references.pmid: 23686858
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Sep;295(3):L412-21
references.pmid: 18567739
references.citation: Adv Exp Med Biol. 2011;780:125-41
references.pmid: 21842370
references.citation: Clin Microbiol Rev. 2001 Apr;14(2):336-63
references.pmid: 11292642
references.citation: Eur Respir J. 2011 Sep;38(3):500-1
references.pmid: 21885411
references.citation: PLoS One. 2011;6(5):e19781
references.pmid: 21611194
references.citation: Allergy Asthma Clin Immunol. 2013 Jul 03;9(1):23
references.pmid: 23822853
references.citation: Am J Respir Crit Care Med. 2007 Jul 15;176(2):162-6
references.pmid: 17400730
references.citation: Mucosal Immunol. 2009 Jan;2(1):63-73
references.pmid: 19079335
references.citation: Am J Respir Crit Care Med. 2002 Apr 1;165(7):967-71
references.pmid: 11934723
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Sep;289(3):L391-9
references.pmid: 15863442
references.citation: Clin Sci (Lond). 2014 Feb;126(3):207-21
references.pmid: 23875733
references.citation: Proc Natl Acad Sci U S A. 2013 May 7;110(19):7726-31
references.pmid: 23610437
references.citation: Front Immunol. 2011 Apr 27;2:10
references.pmid: 22566801
references.citation: Nat Rev Drug Discov. 2012 Oct;11(10):763-76
references.pmid: 23023676
references.citation: Thorax. 2012 Nov;67(11):957-63
references.pmid: 22684094
references.citation: Vaccine. 1999 Aug 20;18(1-2):29-37
references.pmid: 10501232
references.citation: J Allergy Clin Immunol. 2013 Mar;131(3):627-34; quiz 635
references.pmid: 23360757
references.citation: N Engl J Med. 2004 Jun 24;350(26):2645-53
references.pmid: 15215480
references.citation: Int Immunopharmacol. 2012 Dec;14(4):504-12
references.pmid: 23044435
references.citation: Chest. 2000 Feb;117(2 Suppl):5S-9S
references.pmid: 10673466
references.citation: N Engl J Med. 2002 Aug 15;347(7):465-71
references.pmid: 12181400
references.citation: Curr Opin Infect Dis. 2006 Jun;19(3):225-30
references.pmid: 16645482
references.citation: Am J Pathol. 2007 Mar;170(3):855-64
references.pmid: 17322371
references.citation: PLoS One. 2011;6(5):e20333
references.pmid: 21647421
references.citation: Nature. 2007 Feb 8;445(7128):648-51
references.pmid: 17187052
references.citation: Thorax. 2013 Aug;68(8):709-16
references.pmid: 23370438
references.citation: Lancet. 2004 Aug 21-27;364(9435):709-21
references.pmid: 15325838
references.citation: Curr Opin Infect Dis. 2003 Apr;16(2):129-34
references.pmid: 12734445
references.citation: Nat Rev Immunol. 2009 May;9(5):377-84
references.pmid: 19330016
references.citation: Microbes Infect. 2010 Jan;12(1):11-8
references.pmid: 19782149
references.citation: Am J Physiol Lung Cell Mol Physiol. 2012 Nov 1;303(9):L814-23
references.pmid: 22962013
references.citation: N Engl J Med. 2008 Nov 27;359(22):2355-65
references.pmid: 19038881