1.BE Airway Defense

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  Airway Defense Mechanisms Grant W. Waterer,  MD, PhD a,b Human airwaysareregularly incontactwithawidevariety of potential pathogens. In response, wehave developed strategies to protect ourselves. As many of these organisms have developedmechanisms to help them bypass immune de-fenses, so has the human immune system devel-oped a complex array of overlapping strategies tocounter them.In bronchiectasis, the balance between hostand pathogen has been tipped in favor of theassailants. Not only are there often one or moredeficits in the immune response that has led tobronchiectasis, the destruction of normal bron-chial architecture leads to a variety of immunedeficits in the region of damaged airways. Although the immune response is critical toremoving pathogens, inflammation is likely tocontribute not only to further lung damage but,at least temporarily, impairs immune responsemaking the host more vulnerable to subsequentinfections; the so-called vicious cycle hypothesisin bronchiectasis. 1  A comprehensive summary of all airway de-fense mechanisms is a textbook in itself, and farbeyond the scope of this article. This article high-lights both the key airway defense mechanismstypically compromised in bronchiectasis, as wellas key insights into the response to pathogensthat have been discovered in the past decade. Itfocuses particularly on the innate immune systembecause this is where most of the developmentshave occurred that are particularly relevant tobronchiectasis. MECHANICAL DEFENSES Cilia Basic mechanical adaptations to protect airwaysare extremely important. The respiratory tract isfor the most part covered with ciliated epithelium.On top of the cilia is a thick mucus blanket rangingfrom 5 to 10  m m in depth where inhaled particlesare deposited. 2 Coordinated movements of thecilia propel microorganisms and other inhaledparticles trapped in the mucus blanket. In theupper airways, the cilia propel particles towardthe pharynx where they are swallowed; in thelowerairwaytheyarepropelledtowardthetracheawhere they can be coughed up. A wide variety of inherited and acquired disor-ders of cilia numbers and/or function have nowbeen described. 3 The correlation between thedegree of impairment of ciliary function and theextent and severity of lung and sinus disease is a University of Western Australia, Royal Perth Hospital, Level 4 MRF Building, GPO Box X2213, Perth 6847,Australia b Northwestern University, Chicago, IL, USA E-mail address: KEYWORDS   Immunity    Airways    Innate KEY POINTS   The immune system is complex, with multiple redundancies and overlapping mechanisms; evolu-tion of this complex system is probably a response to the ability of pathogens to develop ways toovercome the immune barriers of their hosts.   The key role that small proteins and peptides such as defensins, cathelicidins, and collectins playprovide major new insights into protection against pathogens.   These proteins and peptides are an area of new research, particularly intervention with inhaled ther-apies, including stem cell approaches. Clin Chest Med 33 (2012) 199–209doi:10.1016/j.ccm.2012.03.0030272-5231/12/$ – see front matter  2012 Elsevier Inc. All rights reserved.  c      h     e     s      t     m     e      d .      t      h     e     c      l      i     n      i     c     s .     c     o     m  evidence of how important this basic defensemechanism is in protecting airways. Mucus The mucus layer is composed of a variety of high-molecular-weight glycoproteins (2%–3%),salts (1%), and water (95%), and is produced bygoblet cells and by serous and mucus glandsin the submucosa. 4  Although the superficial partof the mucus layer is moved by the action of thecilia, the deeper layer of periciliary fluid is not. 2 The salt concentration of the mucus layer is tightlycontrolled and may be important in limiting bacte-rial growth. Failure to regulate the salt concentra-tion, as occurs, for example, with defects of the cystic fibrosis transmembrane conductanceregulator, 5 causes significant changes in theviscoelastic properties of the mucus, with thepotentially devastating effects on mucosal immu-nity seen in patients with cystic fibrosis. Apart from glycoproteins, the mucus layer alsocontainsavarietyofproteinsimportantintheinnateimmuneresponse.Althoughsomeoftheseproteinsarise by transudation from plasma, others, such asimmunoglobulin (Ig) A, lysozyme, and lactoferrin,are actively secreted into the mucus layer. 6 INNATE IMMUNITY Toll-like Receptors Recognition of the specific type of pathogenbegins with the toll-like receptors (TLRs), a familyofcellsurfaceproteinsthathelptriggerbothinnateand adaptive immune responses, although theyare not obligatory for the latter. Eleven TLRs withdiffering pathogen specificity are currently recog-nized (  Table 1  ), although the ligand, and thereforespecificity, for TLR-10 remains unknown. 7 TLRsare expressed on a variety of cells includingneutrophils, macrophages, dendritic cells, regula-tory T cells, B-cells, and epithelial cells. 7–9 The signaling pathways activated by binding of TLR to their ligands have been well characterized,as have disorders of signaling resulting in clinicaldisease. 7 In general, signaling from TLRs can bedivided into MyD88-dependent and MyD88-inde-pendent pathways, with the MyD88-dependentroute being the main pathway for most TLRs. 7 There is some evidence that TLR regulation maybe different in bronchiectasis, but whether thisprecedes or is induced by disease is unclear. 10 The primary result of TLR activation is the releaseof a variety of cytokines that have neutrophils andmacrophages as their primary targets. 7 Key cyto-kines include tumor necrosis factor  a , interleukin(IL)-1  b  and IL-6.In addition to initiating an inflammatory cascade,stimulation ofTLR2 11 and TLR3 12 inducemucin ex-pression and activate epidermal growth factors. 13  Although these effects should be protective, ex-cess mucus production may have adverse con-sequences, particularly by impairing neutrophilrecruitment. 14 Non-TLR Recognition of Pathogens and Inflammatory Signaling TLRs are not the only mechanism by which theimmune system recognizes the type of invadingpathogen and initiates the most appropriateinflammatory response. The nucleotide oligomeri-zation domain (NOD)–like receptors are a largefamily of intracellular receptors that sensemicrobial components in the cytosol. Of the 23 Table 1Toll-like receptors and their specificityToll-like Receptor(s) Ligand Pathogen 1, 2, and 6 Lipopeptides Gram-positive bacteria and fungi3 Poly I:C, dsDNA Viruses4 Lipopolysaccharide Gram-negative bacteria5 Flagellin Bacterial flagellum7 ssRNA, resiquimod, imiquimod, loxoribine Viruses8 ssRNA Viruses9 Unmethylated DNA, CPG-DNA Bacteria, DNA10 Unknown unknown11 Unknown component of uropathic Escherichia coli  , profilinlike moleculeUropathic  E coli  , 99 toxoplasma 100  Abbreviations:  CPG, cytosine-phosphate-guanine; dsDNA, double-strand DNA; ssRNA, single-strand RNA. Data from  Moresco EM, LaVine D, Beutler B. Toll-like receptors. Curr Biol 2011;21:R488–93. Waterer 200  NOD-like receptors so far reported, the best-described members of the family are NOD1 andNOD2, both of which recognize bacterialpeptidoglycan, although NOD1 is more specificto gram-negative peptidoglycan. 15–17 Stimulationof NOD-like receptors results in increased NF- k Bactivation via RIP2 kinase. 18 TNF receptor 1 (TNFR1) is abundant on thesurface of many inflammatory cells and the airwayepithelium. 19  As well as TNF, TNFR1 also recog-nizes staphylococcal protein A and seems to bethe primary sensing mechanism for  Staphylo-coccus aureus  in the airways because MyD88,and hence TLR signaling, is not important withthis pathogen. 20 C-type lectins are unusual in that they arefocused primarily in the detection of fungi, particu-larly through binding to carbohydrates such as b -glycans. 21 The C-lectin family, which includesdectin-1, dectin-2 and mincle, have been alsobeen shown to have an important role in detectingcarbohydrates from yeast and mycobacteria. 22  Although present in airway epithelial cells, 23 mostresearch has been done in myeloid cells, and theirrole in resisting airways pathogens is still poorlyunderstood. However, given that C-lectins are expressed on neutrophils 24 and macrophages, 25 it is reasonable to presume that they have animportant role in the airways’ response to invadingfungal and mycobacterial pathogens. Nonspecific Antimicrobial Agents  A variety of chemical defenses are embeddedwithinthemucuslayeroftherespiratoryepithelium.The first described chemical agent was lysozyme,which has nonspecific antibacterial activity bylysing the cell wall of bacteria and various fungi. 2 Other important molecules include lactoferrin, uricacid, leukoprotease inhibitor, peroxidase, amino-peptidase,secretoryphospholipaseA2,anddefen-sins.Nitricoxideisalsofoundinboththeupperandlower respiratory tract and may have antibacterialactivity. Defensins and Cathelicidins In the past decade, there has been a significantincrease in knowledge of the role of defensinsand cathelicidins against a broad range of micro-bial threats including bacteria, viruses and fungi.Both defensins and cathelicidins are amphipathicpeptides, having both hydrophobic and hydro-philic properties that enable them to disruptmicrobial membranes. Although many cells seemto have the capacity to produce antimicrobialpeptides, themain sourceseemsto beneutrophilsand epithelial cells. Although generally thought tobe protective, there is increasing evidence that,in some circumstances, antimicrobial peptides,like many inflammatory molecules, may haveadverse effects including impairing neutrophilphagocytosis in patients with bronchiectasis. 26 Defensins are divided into 2 families:  a -defen-sins and  b -defensins. As well as some differencesin the pairing of cysteine residues,  a -defensins aremainly produced by neutrophils, 27 whereas  b -de-fensins come mainly from epithelial cells. 28 Inaddition, defensins seem to have a key role inimmunity in both the gut 29 and the reproductivetract. 30  Although at least 4  b -defensins have been wellcharacterized based on their disulfide connectivity(eg, Cys1-Cys5, Cys2-Cys4), many others havebeen identified by whole-genome screening. 31 The type of   b -defensin produced depends on theinflammatory cell of srcin. 32 Cathelicidins are  a -helical cationic peptides thatareproducedasprecursorsconsistingofacathelin-like domain and the active peptide and hencerequire proteolytic conversion to the active form. 33  As with defensins, cathelicidins seem to play anti-microbial roles in the respiratory, digestive, andreproductive tracts. The main cathelicidin releasedby neutrophils, LL-37, displays a wide range of effects beyond antimicrobial activity, includingneutralizingmicrobialproductslikelipopolysaccha-ride (LPS), chemoattraction of inflammatory cells,and upregulation of epithelial proliferation andrepair activity. 34 Of particular note in the setting of bronchiectasis is that cathelicidins including LL-37have antibiofilm activity against  Pseudomonas . 35 Collectins: Surfactant Protein A and D  Another family of proteins important for opsoniz-ing bacterial pathogens are collectins. Amongthe collectins are mannose-binding lectin (dis-cussed later) and surfactant A (SP-A) and surfac-tant D (SP-D), which are lipoproteins synthesizedby type II pneumocytes and Clara cells. Althoughknown for a long time to modulate surfacetension, more recently the role of surfactant inhost defense against infection and inflammationhas been discovered. All collectins share a collagenlike domain that iscapable of binding oligosaccharides found onbacterial, nonencapsulated fungal, and some viralenvelope surfaces. 36 Both SP-A and SP-D bind toa wide range of pathogens, suppress microbialgrowth, damage bacterial membranes,and modu-late macrophage phagocytosis. 37 Removal anddetoxification of LPS by alveolar macrophages isalso facilitated by SP-A and SP-D. 38 Airway Defense Mechanisms  201   Although able to activate several signalingcascades, including TLR2 and TLR4, 37 SP-A and SP-D tend to suppress the production of proinflammatory cytokines by macrophages. 39,40 Consistent with an antiinflammatory regulatoryrole for SP-A and SP-D, they have also beenshown to increase alveolar macrophage produc-tion of IL-10 and TGF- b . 41 Bactericidal/Permeability-Increasing Protein The role of bactericidal/permeability-increasingprotein (BPI), although first described in the1970s, 42 has been better delineated in the pastdecade, particularly with respect to its key role indefense against gram-negative bacteria. As wellas being found in neutrophil azurophilic granules(discussed later), BPI is also found in eosinophils 43 and epithelial cells, 44 and has emerged as anotherof the key antimicrobial peptides.BPI seems to have 2 main functions. First, itbinds to and neutralizes LPS with high efficacy,significantly reducing the inflammatory res-ponse. 45 This anti-LPS activity makes BPI particu-larly important against gram-negative pathogens.Second, BPI has innate bactericidal activity,particularly against gram-negative bacteria like Pseudomonas . 46,47 Complement  The complement system is an important compo-nent of both the adaptive an innate immunesystems. The complement system consists of more than 25 plasma and cell surf ace proteinswith 3 different activation pathways. 48 The mainfunction of the cascade of activity that occursthrough activation of one of the pathways is tomark pathogens for destruction by phagocytes.The classic pathway is activated by antigen-antibody complexes. The alternative pathway isactivatedwithoutantibodybymicrobialstructures. A third pathway is triggered by microbial cell wallcomponents containing mannans and is calledthe lectin pathway (discussed further later). 49 Interferons Interferons (IFN) are an important part of the innatehost defense against viruses. Virally infectedepithelial cells secrete 2 classes of IFNs. Type IIFNsincludeIFN- a ,IFN- b ,INF- k ,IFN- ε ,andlimitin.TheclassIIFNssignalviatheIFN- a  /  b receptorandproduce their effects via the Janus kinase/signaltransducers and activators of transcription (JAK-STAT) pathways. 50 Type III IFNs IFN- l 1 (alsoknown as IL29), IFN- l 2 (also known as IL28A)and IFN- l 3 (also known as IL28B) signal via IL-28R, which is expressed in epithelial cells anda limited number of other cell types. 51 The prod-ucts of IFN-induced genes act to limit viral replica-tion and spread by degrading viral RNA, inhibitingcellular translation machinery used for viral repli-cation, and limiting interaction with viral poly-merase complexes. 50 Cytokines Cytokines are a diverse group of proteins andpeptides that can have autocrine, paracrine, and/ or endocrine activities that modulate immunefunction. Although there is an extensive list, themajor proinflammatory cytokines that have beenextensively studied in humans are TNF a , IL-1 b ,IL-6, IL-8, IL-12, and IFN- g . Although some of the functions of these cytokines are addressedelsewhere, TNF a , IL b , and IL-6 all play an impor-tant role in vasodilatation, increasing vascularpermeability, and upregulating cellular adhesionmolecules. Key antiinflammatory cytokines in-clude IL-10, TGF- b , and IL1-Ra.Recently, IL-23 has emerged as another keycytokine in innate host defense against bacterialpathogens. IL-23 shares a common p40 subunitwith IL-12 but has a unique p19 subunit. 52 IL-23seems to be predominantly produced by antigen-presenting cells and stimulates the production of IL-17 by TH17 and  gd  T cells in a TLR-dependentmanner. 53 Several studies have shown that theIL-23/IL-17 response is critical for clearing gram-negative infections such as  Klebsiella pneumo- niae 54 and  Pseudomonas aeruginosa . 55 IL-17 isa family of 6 related proteins, IL-17 A to F, with IL-17A usually termed IL-17 and IL-17E also knownas IL-25. 56  Although most of the IL-17 family haveproinflammatory effects, the source and site of action differ. 56 IL-25 is unusual in the IL-17 familyin that it inhibits some proinflammatory responsesin addition to promoting a Th2-type response. 56 Chemokines Chemokines are cytokines that induce leukocyteinfiltration into the site of infection. Chemokinesare grouped into 4 main types based on the pres-ence of a cysteine toward the N-terminus: C, CC,CXC, and CX3C. 57  A large number of human che-mokines have been reported; however, the mostimportant in humans seems to be IL-8. 58 Neutrophils Neutrophils are a predominant feature in theairways of patients with bronchiectasis. If contain-ment of pathogens fails by all the mechanismalready discussed and the airways’ bacterial loadis less than 10 6 colony-forming units/mL thena neutrophil inflammatory response is initiated. 59 Waterer 202


Apr 16, 2018

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Apr 16, 2018
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