Lung Defense Mechanisms and Lung Immunology Revisi

8/13/2019 Lung Defense Mechanisms and Lung Immunology Revisi

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IT 6 : LUNG DEFENSE MECHANISMS AND LUNG IMMUNOLOGY

I. INTRODUCTIONII. SPECIALIZEDREGIONAL DEFENSES

Nose and Oropharynx

Conduc!n" A!r#ays

The A$%eo$ar Spaces

Ly&phocyes !n he A$%eo$ar Space

III. DEFECTS IN 'OST DEFENSES T'AT CAN (E ASSOCIATED )IT'

RESPIRATOR* INFECTIONS

I+. 'OST DEFENSES IN T'E APPROAC' TO PATIENTS )IT' PUL,ONAR*

DISEASE

I. INTRODUCTION

The atmosphere that we breathe is more than just air. In reality, it isa complex mixture of ambient gases and environmental particulates to whichvirus- and bacteriacontaining droplets can be added when respiratorysecretions are coughed or sneeed out by others.!oreover, normal humansfre"uently aspirate secretions from the upper respiratory tract, particularlyduring sleep. The respiratory system must recognie and eliminate theseunwanted elements in inspired air to #eep pulmonary structures free ofinfection, yet not overreact inappropriately to every stimulus. This isaccomplished by local mechanisms and innate immune defenses spacedalong the entire respiratory tract to protect it. The fact that the normal lower

respiratory tract is infection free despite its constant exposure to foreignantigens and infectious agents is testimony to the efficiency of thesedefense mechanisms. The evolving appreciation of direct associationsbetween aging and brea#downs of these host defenses and resultantpulmonary diseases emphasies the need for all physicians to be familiar withthese critical protective processes.

$omponents of the defense system are spaced along the entirerespiratory tract, from the point of air inta#e at the nose and lips or mouth tothe level of oxygen upta#e at the alveolar surface. The conducting airwaysfunctionally extend from the nares down to the respiratory bronchioles andinclude the nasal turbinates, epiglottis, larynx, pharyngeal lymphoid tissue%&aldeyer's ring(, and other anatomic barriers. )ourteen generations ofdichotomous airway branching of the respiratory tree, as bronchi andbronchioles, in this segment cause the airstream flow to decelerate anddeflect the particles it contains onto themucosal surface, trapping them inairway mucus. In this location, inhaled particulates and infectious agents alsointeract with other locally produced proteins, such as secretoryimmunoglobulin * %Ig*(. +esulting ciliary clearance or coughing efficientlyremoves these particulates from the respiratory tree. eyond the respiratory

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bronchioles, other noncellular host defenses remain important in protectingthe alveolar units %)ig. (. These defenses are in the lining material fluid ofthe alveoli, which contains

Figure 1 *irway lumen mucosal components. * portion of the conducting airway surface isenlarged %*( and depicts the mucosa and its submucosal structures. The pseudostratifiedciliated epithelium has a covering layer of mucus %produced by goblet cells and bronchialglands( and fluid that contains various proteins, including immunoglobulins and secretorycomponent. * few surface cells may be present, such as lymphocytes %from bronchial-associated lymphoid aggregates( and macrophages. *mong the epithelial cells are absorptivemicrovillous brush cells and the dendritic cells, concentrated near lymphoid aggregates or in

the respiratory bronchiole area, whose cellular processes interdigitate with the mucosalsurface. In addition, the epithelial cells can produce proinflammatory cyto#ines that influencemucosal swelling and permeability. In the submucosa below the basement membrane, plasmacells and mast cells reside that secrete local immunoglobulins %such as Ig*( and mediators%such as histamine(. Interacting with all of these glandular and cellular networ#s are nerves,exerting their control through neuropeptides, and by adrenergic and cholinergic nerve fibers. *

rich bronchial arterial vascular supply also exists. (Modified from Reynolds HY: Pulmonary host

defenses-state of the art. Chest 95(Suppl):!"!#$ %9&9$ 'ith permission.)


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Inhaled air passes through the nose or mouth bac# to the glottis and into theextrathoracic portion of the trachea before it enters the thorax. &ith nasalbreathing, air is filtered and conditioned for humidity and body temperatureas it flows over the nasal turbinates and mucosa of the posterior pharynx.&ith nasal obstruction or ventilatory re"uirements for exertion that exceed

about 45 to 65 17min, mouth breathing occurs. Inhaled air then may pass intothe trachea without optimal filtering and climatic conditioning.

The nose provides formidable barriers to inhaled particulates. The nasal hairshelp to exclude large particles, and materials greater than 5 8m in diameterthat bypass the hairs impact upon the nasal mucosa. 2neeing %or blowing(then has the effect of coughing and provides high-velocity ejection fromthemucosal surface. )or substances that attach to the nasal mucosa,production of large "uantities of watery secretions helps to wash off thesurface %rhinorrhea(.!ucociliary clearance is also operant in the nasal cavity. 9ownspoutsleading from the ears, lacrimal glands, and sinus cavities provide numerouspoints for the addition of fluid to the nasal secretions.:owever, these

drainage systems also contain vulnerable points that are prone to bloc#age.The complex plumbing found in the nose wor#s well if there is goodgravitational flow and orifices stay open. If not, sinusitis, otitis media, parotidgland obstruction, and occluded tear ducts result. In some diseases, drynessof secretions %sicca syndrome( is problematic.

2everal substances in nasal secretions help control bacteria or viruses./rominent in this regard are lysoyme and immunoglobulins, especiallysecretory Ig* %2Ig*( which bathesmucosal surfaces. The nose and upperairways are contiguous immunologically with the lower airways and havebeen studied extensively. 0asal secretions, li#e those from other external ormucosal surfaces, are rich in Ig*, which is synthesied locally by submucosalplasma cells. )ree secretory component %2$( can also be detected in nasalwash fluid. ;f the nasal immunoglobulins, 2Ig* is the major source ofantibody, accounting for approximately 5 percent of the total proteincontent of nasal washings. Ig is present in smaller amounts. Ig< probably isnot secreted by normal, nonatopic people. ;nly in people with allergic rhinitiswill Ig< antibody be substantial. The usual specificity of Ig* antibody isantiviral. *fter nasalimmuniation of normal subjectswith various viral ormycoplasmal vaccines, many experimental studies have shown thatappropriate neutraliing Ig* antibody can be elicited. *lthough theseantibodies are protective against homologous and live microbial challenge,the duration of protection is often brief, and the antibody titers diminishrapidly unless repeated exposure occurs.

In the oral cavity, the tongue sweeps against many surfaces during chewingand swallowing. This should ma#e it difficult for bacteria to persist in theselocations. :owever, bacteria adhere to buccal s"uamous cells, and manyaccumulate in crevices around teeth and gums and colonie dentalpla"ue.!any #inds of bacteria arepresent= aerobes and anaerobes,spirochetes, gram-positive and gram-negative species, and some thatspecialie in ma#ing dental pla"ue and causing tooth decay. * common

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feature of host defense in the mouth and nose is the plentiful amount of 2Ig*in secretions that bathe each area. The parotid glands and probably thesubmandibular salivary glands secrete Ig* as their principal humoral immunesubstance> this immunoglobulin accounts for 4 to ? percent of the totalprotein in their secretions. In this fluid, albumin represents about 5 percentof the protein, but Ig is barely detectable %under percent(. In parotid fluid,

Ig* is found in monomeric and dimeric forms, and free secretory componentcan be detected as well. Thus, normal nasal and parotid %or salivary(secretions have about the same composition of immunoglobulins. *s with thenasal immune system, it has been possible to manipulate 2Ig* in the mouthto produce antibodies against certain cariogenic strains of streptococci thatwill subse"uently prevent bacterial adherence to teeth3the immuneexclusionfunction of 2Ig* antibody. The importance of a vaccine approach foraugmenting dental defenses has yet to be fully determined.

:ost defenses in the nose and mouth serve as a reminder that the upperportion of the respiratory tract has features in common with the lower part,

particularly at the mucosal surfaces. They also demonstrate that infections inthe nose, sinuses, ears, teeth, and gums may have ramifications for thediagnosis or successful treatment of illness in the lower respiratory tract. *sexamples, aspiration of anaerobic bacteria in oral secretions or dental pla"uecontributes to lung abscess formation> chronic sinusitis can be presentwithcystic fibrosis, dys#inetic ciliary syndromes, and dysgammaglobulinemia>atopic diseases can manifest with rhinitis, sinusitis, and asthma> and controlof asthma symptoms often re"uires vigorous treatment of concomitant sinusinfection.

Condu!ing Air"ays

ridging the upper airway %nose, oropharynx, and larynx( and the alveolarair-exchange area distal to the terminal bronchioles are the conductingairways %)ig.(.!ucociliary clearance and coughing are the principal means ofcleansing themucosal surfaces of these airways. 2Ig* antibodies also preventepithelial attachment of certain bacteria and viruses to the ciliated andnonciliated airway epithelial cells. The branching structureof the airways alsocauses airborne particulates to impact against themucosa, enhancing theefficiency of mucociliary clearance. ronchial-associated lymphoidaggregates are present, especially around branching points. This segment issusceptible to many diseases3e.g., epithelial cell infection with viruses or

bacteria such as ordetella pertussis Chlamydia pneumoniae$ orMyoplasma

pneumoniae* inflammation, edema, and bronchoconstriction in asthmaticsyndromes> chronic infection in bronchiectasis> irritation from noxious gases>and lung cancer. The conducting airways mucosa is coated to a depth of ? to55 8m with a mucous gel-a"ueous sol complex viscous fluid, which has alow p: %@.@ to @.A(. This is secreted by bronchial glands, goblet cells, and$lara cells %nonciliated bronchiolar secretory cells found in the terminalbronchioles(. *irway surface li"uid is also derived from transepithelial acid-

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base flux across the bronchial epithelium. 2pecial proteins, such as 2Ig* and2$, can be added locally along airways by immunoglobulin-secreting plasmacells and epithelial cells. *ntimicrobial factors such as lysoyme, lactoferrin,cathelicidin, and defensins are present.

*bout half of the mucosal epithelial cells have beating cilia that propel

secretions up the respiratory tree. /eriodic coughing can assist the process.*n intactmucosal lining and overlying mucous layer, containing mucinglycoproteins and proteoglycans, provide a protective barrier or blan#et thatprevents inhaled particulates from penetrating or stic#ing to the respiratorysurface. This seems to be an important component of host defense. acteriaand other infectious agents may transiently colonie the airways, butmucociliary clearance effectively removes them. Tight junctions betweenepithelial cells also limit the passage of macromolecules into the submucosa,and microvillous brush cells may help clear fluid. * number of circumstancescan alter these protective barriers, ma#ing this portion of the respiratory tractsusceptible to disease. They include %( malnutrition, which affects theintegrity of mucosal epithelial cells and enhances bacterial adherence> %4(

cigarette smo#e and noxious fumes, which disrupt the anatomy of epithelialjunctions and enhance the passage of airway substances into areas that areusually inaccessible> and %6( some bacteria, which elaborate proteolyticenymes that may brea# down Ig*, promoting selective coloniation andpersistence in matrix-enclosed biofilms that help avoid innate immunity andcreate chronic infections.

1ymphoid tissue is present along the entire respiratory tract, but the level oforganiation of the lymphoid tissue varies greatly. * ring of lymphoidstructures are situated in the naso-oropharynx. 1ymphoid nodules may occurin the mucosal surface of large and medium-sied bronchi and areparticularly numerous at points of airway branching. ;n the airway side,

these submucosal follicles are covered by a layer of flattened, nonciliatedsurface epithelium, which is often observed to be infiltratedwith lymphocytes.

These bronchialassociated lymphoid tissues %*1T( bear some resemblanceto gut-associated lymphoid tissues %/eyer's patches(, and are part of thebody's overall mucosal-associated lymphoid networ# %#nown as !*1T( that isimportant inmucosal immunity. &hereas *1T is easily demonstrated insome rodents and rabbits, subhuman primates and humans have decidedlyless obvious amounts of this lymphoid tissue, and it may not be as relevantto airway defenses as initially thought, especially in adults.

1oosely organied collections of lymphocytes %lymphoid aggregates( areconcentrated in the distal airways, especially at the bronchoalveolar junctionsat the interface between the ciliated epithelial cells of the terminalbronchioles and the alveolar lining cells. These aggregates provide anopportunity for close interaction between lymphoid cells and inhaled antigensthat have been deposited in the lower respiratory tract. *ntigens andmicrobes may adhere to surface macrophages or dendritic cells imbedded inthe mucosa where immune processing or elimination occurs. acteria such as

Pseudomonas aeru+inosa may become enmeshed in a biofilm containing theirexopolysaccharides, which can interfere with macrophage or dendritic cell

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elimination of them and contribute to airway coloniation and persistence.*lso, in the vicinity of the respiratory bronchioles, lymphatic channels beginthat might provide these lymphocytes with a route to draining lymph nodes%hilar nodes( where immunologic responses develop.

Respira!ory #ronhio$es

*natomically, lung structure changes at the level of the respiratorybronchioles, which are inserted between the distal conducting airways andthe acinar units %alveolar ducts and alveoli( of the air exchange surface. Theyfunctionally separate the upper and lower respiratory tracts. This segmentcan be a bottlenec# or cho#e point for airflow, but it is the last surface tocapture small airborne particulates and microbial or antigenic debris beforeentering the alveolar space> adaptive immune responses can begin here.2everal structural changes occur= the single-layer cuboidal epithelial surfaceflattens and differentiates into alveolar type I cells that primarily cover thealveolar lining surface> mucus-secreting cells disappear, although goblet cellscan be found in cigarette smo#ers> and another secretory cell type becomesprominent, the $lara cells. /ulmonary brush cells with a tuft of s"uatmicrovilli are found in this area, especially in rodent species, and may beinvolved with chemosensing or trapping inhaled particles and pollutants, orwith regulating fluid and solute absorption. 9endritic macrophage-li#e cells,which may constitute percent of the cells in the surface of this segment,are present to capture and process antigens. 1ymphatic channels form tocollect the lymphatic fluid emerging from the interalveolar interstitial spaces.

The changeover from the bronchial arterial blood supplying the conductingairways to the pulmonary artery-capillary blood flow structure that surroundsthe alveoli also occurs, which is necessary for aeration.

%he A$&eo$ar Spaes

9efenses in the airways %)ig.4( eliminate most particles and microbesinspired into the lungs. *s a result, the airways distal to the major bronchi areprobably sterile in normal subjects. :owever, some particles of small sie andspecial geometry can elude the airwaymucosal mechanisms and reach theair-exchange surface of the alveoli.&hen this occurs, another set of hostdefense mechanisms must ta#e over. !icrobial clearance and the removal ofother antigenic material from alveoli depend on cellular and humoral factorssuch as the lipoproteins, immunoglobulins, and complement factors in the

alveolar lining fluid and phagocytic cells such as alveolar macrophages and/!0s.

Inhaled microbes are an appropriate example. If a bacterium of critical sie%5.? to 6 8m in diameter( is deposited in an alveolus, it is li#ely to ma#econtact with the alveolar wall and roll along in about 5.4 8m of alveolar liningfluid, p: @.A, which is a ombination of a watery subphase with an overlyingfilm of surfactant secreted by type II pneumocytes. In the process, a microbeencounters several substances that can inactivate it and assist in its eventual

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phagocytosis. These substances include a variety of soluble lipoproteinsubstances, Ig, complement factor %$6b(, and nonimmune opsonins, such ashigh-molecular-weight fibronectin fragments. The lipoproteins in the form ofsurfactant are secreted by type II pneumocytes, and surfactant proteins *and 9 have opsonic effects through binding of surface carbohydrates, whichpromotes antibacterial activity against staphylococci and rough colony strains

of some gram-negative rod bacteria. The immunoglobulins are principally ofthe Ig class. They account for ? percent of the total protein in alveolar fluid,with subclasses Ig and Ig6 being the most important and lesserconcentrations of monomeric and secretory forms of Ig* being noted. Theseimmunoglobulins can develop specific opsonic antibody activity for thebacterium. The complement components, especially properdin factor ,interact with the bacterium and can trigger the alternative complementpathway, thereby lysing the microbe directly. ;ne or all of these interactionscan prepare the bacterium for ingestion by an alveolar macrophage. *lthoughalveolar macrophages avidly phagocytose some inert particles, they ingestviable bacteria with considerably less enthusiasm. $oating or opsoniing theorganisms will enhance phagocytosis appreciably as studied in an in vitro

culture system. The nonimmune opsonins nonspecifically enhance thisprocess. The immunoglobulins are capable of enhancing alveolarmacrophage phagocytosis in an antigen-specific fashion, and the $6bcomplement fragment can function in concert with Ig to enhance or amplifythis process.

/hagocytosis, the ingestion of particulate matter by cells, is divided into twophases= receptor attachment of the particle to the cell surface andinternaliation. *ttachment of the particle to the surface of the phagocyticcell is essential before ingestion occurs. *lthough binding occurs randomly, itis greatly enhanced by opsoniation of the particle by antibody %especiallyIg( or a component of the complement system, $6b. ;psonin-dependent

phagocytosis is mediated by receptors on the cell surface for the )ccomponent of the opsoniing immunoglobulin or complement. 2pecificreceptors for the )c portion of Ig%)cB( %Ig6 and Ig primarily( and for thethird component of complement %$6b( are present on human monocytes andalveolar macrophages. +eceptors for Ig*are also found on alveolarmacrophages.There is evidence that the number and function of thesereceptors can be modulated by lymphocyte-derived cyto#ines such asinterferon-B %I)0-B(. Ingestion of membrane-bound particles occurs via aprocess that is energy-dependent as the plasma membrane of the ingestingcell surrounds the bound particle, enclosing it in an endocytic vesicle. This isfollowed by the activation of a number of well-developed mechanisms thatoperate to #ill internalied pathogens.

)ollowing internaliation of bacteria, the fate of alveolar macrophages is notcertain. They are long-lived tissue cells that can survive at least for severalmonths and presumably are capable of handling repeated bacterial and othermicrobial challenges %reusable phagocytes(. ecause they are mobile cells,they can migrate "uic#ly to other alveoli through the pores of Cohn, or moveto more proximal areas of the respiratory tract %to the region of therespiratory bronchioles( for elimination from the lungs by the mucociliary

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escalator. In addition, macrophages may gain entry into lung lymphatics atthe same location and be carried to regional lymph nodes. This exit givesthem access to systemic lymphoid tissue and is important in initiating cellularimmune responses. Dndoubtedly, macrophages are also instrumental indegrading antigenic material and presenting it in an appropriate manner tolocal T lymphocytes as part of innate and adaptive immunity in the lung.

Increasingly, attention is being given to the immune effector role ofmacrophages. The alveolar macrophage has a dual role in the respiratorytract3one as a phagocyte to dispose of debris, process foreign antigens, and#ill ingested microorganisms and a second as an effector cell to initiateimmuneandinflammatory responses. *lveolarmacrophages are usuallysuccessful in inactivating inhaled microorganisms. *s a result, clinical diseaseand pneumonitis rarely develop after day-to-day exposures.:owever, if asufficiently large bacterial inoculum reaches the lower respiratory tract, or ifparticularly virulent microorganisms are inhaled, the macrophage system canbe overwhelmed. y the secretion of proinflammatory chemotactic factorssuch as the chemo#ine family cyto#ines, alveolar macrophages then recruit

/!0s and other cells to the lung, and pneumonitis develops. *lso, airwayepithelial cells can generate proinflammatory cyto#ines to assist with /!0attraction.

ram-negative rod bacteria provide an interesting example. 2omecomplement components, particularly factor , are present in small amountsin bronchoalveolar fluids. The bacterial endotoxin in the gram-negative rodbacteria can directly activate the alternative complement pathway3leadingto the formation of $?a, which is a potent stimulus for /!0 chemotaxis. *lso,the inflammatory responsemay activate the #inin system> this results ingeneration of #alli#rein, which has chemotactic activity, and brady#inin,which is capable of increasing vascular permeability. The latter allows for the

seepage of fluid and other humoral and bioactive substances from theintravascular compartment into the alveoli. *nother mechanism ofinflammation emanates from the alveolar macrophage itself. )ollowingphagocytosis of opsonied bacteria or other forms of activation,proinflammatory chemo#ines are synthesied and secretedbymacrophagesthat will attract /!0s and other cells. 2everal substances with chemotacticactivity have been found to be produced by human alveolar macrophages.

These include interleu#in-E %I1-E(, macrophage inflammatory protein-4 %!I/(,monocyte chemoattractant protein- %!$/-(, tumor necrosis factor %T0)(,and lipoxygenase pathway metabolites of arachidonic acid, namelyleu#otrienes. 1eu#otriene F %1TF( is one of the most important of these.

Inflammation is the ultimate host response to contain common bacteria thatreach the alveolar space. This response can be activated in several ways= %(directly by microbes or substances such as lipopolysaccharide %endotoxin(that can activate the complement cascade, probably via the alternatecomplement pathway> %4( through the generation of phlogistic factors fromthe #alli#rein and brady#inin pathways> and %6( from the effector cell functionof macrophages. It is also #nown that other airway cells, such as epithelial

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cells, elsewhere in the respiratory tract, can produce chemo#ines li#e I1-Eand that this can stimulate inflammation in other sites %bronchitis(.

2pecial interest has focused on the macrophagesecreted proinflammatorychemo#ines, a family of cyto#ines that can stimulate cellular motion%chemo#inesis( and promote directed migration of different populations of

responder cells %chemotaxis(. These populations are primarily /!0s in theacute inflammatory responses. 1ymphocytes, monocytes, and eosinophils arealso recruited in the chronic phase of pneumonia, chronic inflammatorydisorders such as hypersensitivity pneumonitis and sarcoidosis, and atopicand eosinophilic syndromes. Investigation has elucidated the cellularmechanisms whereby $G$ chemo#ines activate and initiate the migratoryprocess of /!0s. *n extensive review of the literature is summaried to saythat this process involves a number of cell surface adhesion molecules, foundon endothelial cells %adhesion molecule I$*!-, 1- and/-selectins andintegrins( and granulocytes, that bind to one another. *t sites ofinflammation mediators such as I1-, T0), and I)0-B induce or augment theexpression of these adhesion molecules. *s a result, intravascular /!0s slow

down, roll along, deform, and then anchor on the endothelium. They thenenter the interstitium via traversing capillary endothelial cells, which contractor pull apart to allow a gap through which /!0s pass, and plasma fluid canlea#, and the cells emerge through the alveolar type I pneumocyte liningbarrier into the alveoli.!icrovillous brush cells may also absorb fluid orregulate ion-solute flux.


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TheTandlymphocytes are indistinguishable by usual morphologic criteria butcan be differentiated by membrane surface mar#ers. They are alsofunctionally distinct, with T cells playing an important role in cell-mediatedimmunity and cell-mediated cytotoxicity while the cells serve as precursorsfor cells that synthesieimmunoglobulins and, hence, antibody molecules thatare the basis of the humoral immune response.

*s shown in Table A-, approximately 5 percent of the lymphocytes inlavage fluid are T cells and approximately ? percent are cells. The ratio of Tto cells in lavage fluid is roughly that of peripheral blood, although in bloodmore circulating cells are usually identified %approximately? percent(.*pproximately to ? percent of lung lymphocytes seem to be able to releaseor secrete class-specific immunoglobulin.


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These cell populations have different functions based on the different array ofcyto#ines that they produce. TheT:cells secrete I)0-Band I1-4, whichactivate macrophages and play a major role in cell-mediated immunity. The

T:4 cells produce I1-F, I1-?, and I1-@, which stimulatelymphocytes toproduce immunoglobulins and, by their production of I1-5 and I1-6,suppress monocyte7macrophage activity and cell-mediated immune

responses. Thus, T:4 cells play a particularly important role in generatingtissue eosinophilia and stimulating Ig< production, processes that areextremely important in atopy, allergic asthma, and other inflammatorypulmonary disorders. I1-4, formerly called T-cell growth factor %T$)(, isamong the most important T-cellJregulating cyto#ines. It is produced byactivated T cells and acts in an autocrine or paracrine fashion to stimulate

T: cells and T:4-cell precursors.

I1-4 can also activate #iller T cells. * few #iller lymphocytes can be identifiedamong alveolar T cells, but these cells seem to be dormant in normalsubjects until stimulated. 1astly, I1-4 can stimulate lymphocytes todifferentiate into plasma cells that synthesie various classes of

immunoglobulins. This is a mechanism by which local production ofimmunoglobulin in the lung can occur. In all cases, the effects of I1-4 aremediated by the multimeric I1-4 receptor, a component of which is the Tac-surface ligand. The expression of the I1-4 receptor is highly regulatable, andthe expression of the Tac antigen can be used as a mar#er of T-cellactivation.!ost T cells have T-cell receptors with alpha and beta subunits %K/H T-cellreceptors(. In the normal lung, a lesser number of T cells have gamma anddelta T-cell receptors.

The function of these cells is poorly understood. They may, however, play animportant role in mucosal immunity, since they are increased in atopic

allergic subsets. *lveolar macrophages and lymphocytes have the capacity toproduce many cellular mediators %cyto#ines( that in turn affect each other aswell as other inflammatory, structural, and immune effector cells. Thisdynamic and complex interaction is illustrated in )ig. A-4, which reviewsdendritic cell, alveolar macrophage, and lymphocyte interactions in theairways and alveolar milieu. !onocyte precursors from the blood differentiateinto mature macrophages under the influence of vitamin 9 metabolites andundoubtedly other stimuli and become long-lived, aerobically metaboliingalveolar phagocytes. Their principal activity is to cleanse the alveolar surfaceand ingest debris that accumulates or microbes aerosolied into the lungs. Inthe process, the macrophages may become activated and are then capableof secreting an enormousarrayof enymesandcyto#ines. These moieties canaffect the function of resident cells of the lung such as lymphocytes orepithelial cells. In addition, the release of proinflammatory chemo#inesattracts/!0s,lymphocytes,monocytes, and other cells into the alveoli. ;fparticular note are 1TF, I1-E, T0)-, !I/-, !$/-, and I1-. &hen secretedby activated macrophages %especially in active lung forms of sarcoidosis( I1-may attract T lymphocytes to the lungs. In the other direction, activated T:cells can produce several mono#ines that affect macrophage function. 2uch asubstance is migration inhibition factor, which immobilies macrophages

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engaged in phagocytosis. ;f special interest is I)0-B, which activatesmacrophages, increasing their expression of membrane receptors, which inturn enhances macrophage phagocytic upta#e. I)0-B also has other functionsthat promote cellular immunity.

Figure ( :ost defenses in the alveolar space. acteria %( that escape clearance mechanisms inthe upperrespiratory tract %D+T( can reach the alveolus %represented by an enlargement ofone(. !ost of the alveolar surface is lined by type I epithelial cells with pulmonary microvillousbrush cells interspersed, and type II cells positioned in the corners that secrete surfactant. *variable amount of interstitial space separates the epithelium from the capillary endotheliumwhere se"uestered /!0s and platelets reside. * bacterium deposited in an alveolus mayencounter at least three different but coordinated sets of innateimmunity immunologic materials and cells that can destroy it= opsonins, both Ig andsurfactant proteins * and 9, or complement factors that facilitate phagocytosis or create alysis of the microbe> activated macrophages stimulated by cyto#ines produced by nearbylymphocytes> and other inflammatory phagocytic cells, usually /!0s attracted into thealveolar space by proinflammatory chemo#ines produced locally by macrophages and

epithelial cells. (Modified from Reynolds HY: Respiratory infetions may reflet defiienies in

host defense mehanisms. ,is Mon !%:%"9&$ %9&5$ 'ith permission.)

*lmost mutually exclusive sets of chemo#ines can be induced by T:immune responses %I1-4 and I)0-B( and by T:4 cells %I1-F and I1-6( towardinfectious challenges. The scheme shown in )ig. 6 may help to explain certainderangements found in a number of lung diseases that have excessive ordeficient secretion of cyto#ines and feature changes in the relativeproportions of macrophages and lymphocytes.


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Figure ) !ajor immunity pathways. &ithin the body, mucosal surfaces are positioned at initialinta#e andcontact points to L Lmeet external substances that enter with inhaled air, ingested

food and li"uids, or reproductive secretions.!ucosae in the nose, airways, and gastrointestinaland genital tracts must discriminate between pathogens and harmless microbes or possibletoxins and essential nutrients, and then respond "uic#ly to exclude, tolerate, or initiateimmune responses.

+espiratory host defenses balance two important immune mechanismscreated for dealing with airway microbes or other entering antigens= %( aninnate or "uic# reaction response producing inflammation as an end point%bronchitis or pneumonitis(, and %4( a more deliberate approach throughstimulation of lymphocytic pathways that creates a versatile and adaptiveresponse involving specific T-cell activity and7or production of

immunoglobulins %antibodies(. )oreign substances or microbes or theirexoproducts %lipopolysaccharide from gram-negative rod bacteria( that enterthe airway lumen and adhere to the mucosa will be pic#ed up bymacrophages %!( or dendritic cells %9$s(. Toll receptor recognition andattachment are important, and dealt with in a variety of ways. /hagocyticupta#e and intracellular #illing of bacteria might suffice, or recruitment of/!0s may be needed through secretion of proinflammatory cyto#ines bymacrophages, creating pneumonitis for example. 1ater, active resolution ofinflammation re"uires inhibition of /!0 influx %suppress chemotaxis( and

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cellular cleanup %apoptosis(. *lternatively, 9$s %or macrophages( can processantigens, present these to major histocompatibility complex %!:$(compatible but naMNve $9F+ cells, facilitated with the stimulatory cyto#ine I1-4> I1-4 produced by $9F+T cells can direct T: lymphocytes to develop andproliferate. In turn, T: cells can produce I1- and I)0- B that can stimulatemacrophages for the inflammatory pathway, or induce clonal expansion of

$9F+lymphocytes that contribute to building granulomata for containment ofcertain microbes or particles. +eturning to the 9$-antigenJpresenting cellprocess involving the $9F cells, another subset of 9$s %or macrophages( canproduce I1-5, an inhibitory cyto#ine that promotes the T: responsepreferentially in normal subjects and suppresses the T:4 cellular pathway.:owever, pending the allergic status of the host %atopy( and7or the particularantigen present, T:4 lymphocytes can be stimulated and in turn produce I1-F, ?, @, and 6 cyto#ines that culminate in allergy %asthma and allergicrhinitis( with stimulation of mast cells and then eosinophils and production ofreaginic antibodies %Ig


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respiratory infections and bronchiectasis should raise the possibility of aciliary dys#inesis syndrome. Infertility, especially in males,may be associated,and the evaluation of this problem may bring the respiratory symptoms tothe physician's attention.&ith age, ciliary beat fre"uency decreases andmight be a factor in greater susceptibility to lung infections in the elderly.* variety of B-globulin abnormalities are associated with recurrent infection.

In patients with hypogammaglobulinemia, the lac# of opsonic antibody canpromote infections with encapsulated bacteria. 2everal common bacteria thatcolonie the airways of patients with chronic bronchitis and chronic

obstructive pulmonary disease %Streptoous pneumoniae$ Haemophilus

influen2ae$ and 3eisseria( can also produce a specific Ig* protease thatcleaves the Ig* heavy chain in its hinge region adjacent to the )c portion. ythis mechanism, these bacteria could inactivate a substantial portion

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of the secretory Ig* coating the conducting airways and gain better access tothe ciliated epithelial cells for attachment. &hile this mechanism is somewhattheoretical, associations between deficiencies in Ig and recurrent infectionare well documented. /articularly important are the associations between

deficiencies of Ig subclasses Ig4 and IgF, alone and in combination withIg* deficiencies and chronic inflammation and bronchiectasis. /resumably, anabsence of these subclasses denies phagocytic cells potential opsonicantibody, thereby diminishing membrane receptor attachment of opsoniedparticles or bacteria and subse"uent phagocyte ingestion. $linically,establishing the diagnosis of an Ig deficiency is "uite important because, incontrast to many other immunodeficiencies, replacement preparations ofIgare often available for these patients. $ytotoxic antineoplasticchemotherapy and other forms of immunosuppression also compromise host

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defenses in a major way. * major side effect of these therapies isgranulocytopenia, which prevents the mobiliation of /!0s and creates apoor inflammatory reaction.

I-. *OS% DEFENSES IN %*E APPROAC* %O PA%IEN%S +I%* PL/ONAR,DISEASE

*s noted above, normal hosts can develop respiratory infections orinflammation as a result of exposure to particularly virulent agents or a largeinoculum of aerosolied particulates. In others, respiratory infections areassociated with obvious clinical features that compromise pulmonarydefenses %Table A-4(. ;ccasionally, however, the physician is confrontedwith a relatively young person who has an unexpected number of respiratoryproblems that seem inappropriate. The illness can manifest as recurrentinfection or poorly controlled allergic rhinitis, asthma, fre"uent sinusitis,recurrent nasal polyps, and7or bouts of otitis media. ecause the severity ofthese respiratory problems may not seem great, the physician may notinitially suspect that something unusual is present. The propensity forinfection may not have been obvious in childhood but became apparent asthe patient reached adolescence or adulthood. *lthough genetic defectsusually are manifested in infancy, minor forms of host deficiency, creatingantibody deficiency diseases, may not be recognied until later in life. $ysticfibrosis %adult onset(, selective absence of Ig subclassimmunoglobulins,structural ciliary defects, and Ig*deficiency are the principal diseases thatshould be considered in this differential diagnosis. +ecurrent sinopulmonaryinfections are an important clue to all these syndromes.

The physician should be prepared to examine such a patient thoroughly. *detailed history will immediately provide important information aboutaffected siblings, infertility, or a stri#ing change in respiratory health thatma#es an ac"uired abnormality li#ely. /reliminary screening tests are acomplete blood count and "uantitative serum immunoglobulins, and perhapspulmonary function tests, even if the chest radiograph is normal inappearance> also indicated may be microbial cultures of respiratorysecretions and analysis of the electrolytes contained in a sample of sweat or

nasal potential difference measurements. !ucoid strains of Pseudomonas

aeru+inosa and elevated sweat chloride values can be noted in cystic fibrosis.;ther useful secondary-level screening tests are "uantitation of subclasses ofIg> secretory Ig* as sampled in parotid fluid or nasal wash samples>

subtyping of blood lymphocytes> measurement of antibody responses toprotein and7or polysaccharide antigens> search for genetic mutations of thecystic fibrosis transmembrane conductance regulator %$)T+(> assessment ofciliary clearance with an aerosolied, isotopic tracer> nasalmucosal biopsy forelectron-microscopic ultrastructural analysis of cilia> sperm motility in malesof appropriate age> and documentation of bronchiectasis by high-resolutioncomputed tomographic scans of the chest. * thorough evaluation by anotolaryngologist is also often helpful because of the recurrent sinusitis, otitismedia, and nasal polyps that might be present.

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*lternatively, certain forms of pneumonia point to possible deficiencies inlung cells such as alveolar macrophages, lymphocytes, or /!0s. *sopsoniation of certain encapsulated bacteria is necessary for optimalphagocytosis by macrophages and /!0s, the lac# of appropriate Ig

antibodies against pneumococci, Haemophilus species, 4lesiella pneumoniae$and staphylococci may contribute to infections with these commonbacteria.:owever, other causes of pneumonia may reflect abnormal

lymphocyte function and cellmediated immunity. Infection with e+ionella

bacteria is an example. *fter an infection with . pneumophila$ the hostdevelops specific Ig! and Ig serum antibodies. These antibodies, in thepresence of complement, do not create a lytic state that is sufficient to #illthe bacteria.:owever, they do behave as opsonins to ensure that the

e+ionella organisms can attach and be ingested by various phagocytic cells,including /!0s, blood monocytes, and alveolar macrophages. ;nce inside

the phagocytes, e+ionellamultiply and eventually can #ill and disrupt thehost cells.&hen alveolar macrophages are activated with I)0-B these

stimulated phagocytes will inhibit the growth of the bacteria. This may be theresult of the ability of I)0-B to down-regulate the transferrin receptors onthese cells, thereby limiting the accumulation of intracellular iron which is an

essential metabolite for e+ionella. 2upport for this concept comes from

experiments with an experimental e+ionella pulmonary infection rat model,in which administration of intratracheal I)0-B reduced intrapulmonaryreplication of the bacteria, improving host defenses.*nother example of defects at the level of the lymphocyte is *I92, in whichthe human host is infected with human immunodeficiency virus %:IO( thatdestroys $9F T: lymphocytes. These patients experience recurrentrespiratory infections with diverse organisms, including viruses

%cytomegalovirus or herpes simplex(, Pneumoystis arinii$ Myoateriumtuerulosis$ M. a6ium-intraellulare$ fungi such asCryptoous species,

and7o8oplasma +ondii ande+ionella.These infectious agents have a common feature of residing in macrophagesor similar cells as facultative intracellular organisms.

;ne reason why a patient with *I92 has trouble with this group of infectionsrelates to the relative imbalance of lymphocytes found in the alveoli, assampled by *1 of the lung.0ormal values for T lymphocytes have beengiven in Table A-. )rom subjects with *I92, the recoverable alveolarlymphocytes reflect a decrease in the $9F T: cells from :IO infection, offsetby an increase in the suppressor-cytotoxic species of T lymphocytes.

*lthough alveolar macrophages normally exist in an environment where theycan be activated sufficiently to #ill or control microbes of this sort, the $9Fdeficiency in lungs of patients with *I92 compromises this activation process.

This causes an impressive defect in cell-mediated immunity and the ability of

macrophages to contain or #ill organisms such as Pneumoystis ormycobacterial species.

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Lung Defense Mechanisms and Lung Immunology Revisi

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