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BLOK 12 : RESPIRATORY SYSTEM IT 6 : LUNG DEFENSE MECHANISMS AND LUNG IMMUNOLOGY

I. II. INTRODUCTION SPECIALIZEDREGIONAL DEFENSES Nose and Oropharynx Conduc !n" A!r#ays The A$%eo$ar Spaces Ly&phocy es !n he A$%eo$ar Space DEFECTS IN 'OST DEFENSES T'AT CAN (E ASSOCIATED )IT' RESPIRATOR* INFECTIONS 'OST DEFENSES IN T'E APPROAC' TO PATIENTS )IT' PUL,ONAR* DISEASE

III. I+.

I. INTRODUCTION The atmosphere that we breathe is more than just air. In reality, it is a complex mixture of ambient gases and environmental particulates to which virus- and bacteriacontaining droplets can be added when respiratory secretions are coughed or snee ed out by others.!oreover, normal humans fre"uently aspirate secretions from the upper respiratory tract, particularly during sleep. The respiratory system must recogni e and eliminate these unwanted elements in inspired air to #eep pulmonary structures free of infection, yet not overreact inappropriately to every stimulus. This is accomplished by local mechanisms and innate immune defenses spaced along the entire respiratory tract to protect it. The fact that the normal lower respiratory tract is infection free despite its constant exposure to foreign antigens and infectious agents is testimony to the efficiency of these defense mechanisms. The evolving appreciation of direct associations between aging and brea#downs of these host defenses and resultant pulmonary diseases emphasi es the need for all physicians to be familiar with these critical protective processes. $omponents of the defense system are spaced along the entire respiratory tract, from the point of air inta#e at the nose and lips or mouth to the level of oxygen upta#e at the alveolar surface. The conducting airways functionally extend from the nares down to the respiratory bronchioles and include the nasal turbinates, epiglottis, larynx, pharyngeal lymphoid tissue %&aldeyer's ring(, and other anatomic barriers. )ourteen generations of dichotomous airway branching of the respiratory tree, as bronchi and bronchioles, in this segment cause the airstream flow to decelerate and deflect the particles it contains onto themucosal surface, trapping them in airway mucus. In this location, inhaled particulates and infectious agents also interact with other locally produced proteins, such as secretory immunoglobulin * %Ig*(. +esulting ciliary clearance or coughing efficiently removes these particulates from the respiratory tree. ,eyond the respiratory

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

Figure 1 *irway lumen mucosal components. * portion of the conducting airway surface is enlarged %*( and depicts the mucosa and its submucosal structures. The pseudostratified ciliated epithelium has a covering layer of mucus %produced by goblet cells and bronchial glands( and fluid that contains various proteins, including immunoglobulins and secretory component. * few surface cells may be present, such as lymphocytes %from bronchialassociated lymphoid aggregates( and macrophages. *mong the epithelial cells are absorptive microvillous brush cells and the dendritic cells, concentrated near lymphoid aggregates or in the respiratory bronchiole area, whose cellular processes interdigitate with the mucosal surface. In addition, the epithelial cells can produce proinflammatory cyto#ines that influence mucosal swelling and permeability. In the submucosa below the basement membrane, plasma cells 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.)

surfactant apoproteins and glycoproteins such as fibronectin, immunoglobulins such as Ig. opsonins, and complement %properdin factor ,(, which are active against aerosoli ed, inhaled particles or microorganisms. *lveolar macrophages are the principal phagocytic and scavenger cells on alveolar surfaces. /articulates and microbes that evade other host defense mechanisms and arrive on the alveolar surface are efficiently removed by these roaming cells. &hen further assistance is re"uired, an inflammatory reaction can be initiated,which attracts olymorphonuclear neutrophils %/!0s( and other vasomediators and humoral immune elements from systemic sources. *t all levels of the respiratory tract, specific and nonspecific defense mechanisms exist to protect respiratory structures. The nonspecific mechanisms, as noted above, include the mechanical barriers, cough, mucociliary elevator, and macrophage phagocytosis, which behave similarly regardless of the inhaled particulate. They also include aspects of the innate immune response, such as the inflammation triggered by Toll-li#e receptors %T1+(. In contrast, prior contact with a microbial agent or a sensiti ing substance can induce antigen-specific cellular or humoral immune responses, activating adaptive or ac"uired immunity. The latter includes the production of secretory Ig* antibody in the airway, which preventsmucosal adherence, and Ig. opsonins that facilitate phagocytosis. 2uch responses help the lung deal more efficiently with these agents and substances on rechallenge in the future. Insummary, the integratedaction of diversepulmonary defensemechanisms along the respiratory tract acts to remove or neutrali e microorganisms, particulates, and noxious gases that are inhaled or aspirated into respiratory structures.!any are mechanical barriers and reflex actions that are concentrated in the naso-oropharynx and along the conducting airways. There is also phagocytosis, which occurs in the alveoli and airways. These are surveillance mechanisms that function mechanically and can be activated by nonspecific %nonimmunologic( or immunogenic stimuli. In addition, several augmenting mechanisms exist that enhance the responsiveness of this defense system and ma#e it flexible and adaptable. $rucial in this regard are the pathways of innate immunity and the ability of dendritic-type macrophages in the lung to mount antigen-specific immune responses %humoral and cellular(3adaptive immunity3and a local inflammatory reaction. This allows components in plasma and blood cells to bolster local defenses in the airways and alveoli. * more indepth review of these innate defense mechanisms follows. *lso in the 2uggested +eading section, several reviews by the authors and others providemore details about this actively expanding topic.

II. SPECIALIZED REGIONAL DEFENSES Nose and Oropharynx

Inhaled air passes through the nose or mouth bac# to the glottis and into the extrathoracic portion of the trachea before it enters the thorax. &ith nasal breathing, air is filtered and conditioned for humidity and body temperature as 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 into the trachea without optimal filtering and climatic conditioning. The nose provides formidable barriers to inhaled particulates. The nasal hairs help to exclude large particles, and materials greater than -5 8m in diameter that bypass the hairs impact upon the nasal mucosa. 2nee ing %or blowing( then has the effect of coughing and provides high-velocity ejection from themucosal surface. )or substances that attach to the nasal mucosa, production of large "uantities of watery secretions helps to wash off the surface %rhinorrhea(. !ucociliary clearance is also operant in the nasal cavity. 9ownspouts leading from the ears, lacrimal glands, and sinus cavities provide numerous points 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 good gravitational flow and orifices stay open. If not, sinusitis, otitis media, parotid gland obstruction, and occluded tear ducts result. In some diseases, dryness of secretions %sicca syndrome( is problematic. 2everal substances in nasal secretions help control bacteria or viruses. /rominent in this regard are lyso yme and immunoglobulins, especially secretory Ig* %2Ig*( which bathesmucosal surfaces. The nose and upper airways are contiguous immunologically with the lower airways and have been studied extensively. 0asal secretions, li#e those from other external or mucosal surfaces, are rich in Ig*, which is synthesi ed locally by submucosal plasma cells. )ree secretory component %2$( can also be detected in nasal wash fluid. ;f the nasal immunoglobulins, 2Ig* is the major source of antibody, accounting for approximately -5 percent of the total protein content of nasal washings. Ig. is present in smaller amounts. Ig< probably is not secreted by normal, nonatopic people. ;nly in people with allergic rhinitis will Ig< antibody be substantial. The usual specificity of Ig* antibody is antiviral. *fter nasalimmuni ation of normal subjectswith various viral or mycoplasmal vaccines, many experimental studies have shown that appropriate neutrali ing Ig* antibody can be elicited. *lthough these antibodies are protective against homologous and live microbial challenge, the duration of protection is often brief, and the antibody titers diminish rapidly unless repeated exposure occurs. In the oral cavity, the tongue sweeps against many surfaces during chewing and swallowing. This should ma#e it difficult for bacteria to persist in these locations. :owever, bacteria adhere to buccal s"uamous cells, and many accumulate in crevices around teeth and gums and coloni e dental pla"ue.!any #inds of bacteria arepresent= aerobes and anaerobes, spirochetes, gram-positive and gram-negative species, and some that speciali e in ma#ing dental pla"ue and causing tooth decay. * common

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 the submandibular salivary glands secrete Ig* as their principal humoral immune substance> this immunoglobulin accounts for -4 to -? percent of the total protein in their secretions. In this fluid, albumin represents about -5 percent of the protein, but Ig. is barely detectable %under - percent(. In parotid fluid, Ig* is found in monomeric and dimeric forms, and free secretory component can be detected as well. Thus, normal nasal and parotid %or salivary( secretions have about the same composition of immunoglobulins. *s with the nasal immune system, it has been possible to manipulate 2Ig* in the mouth to produce antibodies against certain cariogenic strains of streptococci that will subse"uently prevent bacterial adherence to teeth3the immune exclusion function of 2Ig* antibody. The importance of a vaccine approach for augmenting dental defenses has yet to be fully determined. :ost defenses in the nose and mouth serve as a reminder that the upper portion of the respiratory tract has features in common with the lower part, particularly at the mucosal surfaces. They also demonstrate that infections in the nose, sinuses, ears, teeth, and gums may have ramifications for the diagnosis or successful treatment of illness in the lower respiratory tract. *s examples, aspiration of anaerobic bacteria in oral secretions or dental pla"ue contributes to lung abscess formation> chronic sinusitis can be presentwith cystic fibrosis, dys#inetic ciliary syndromes, and dysgammaglobulinemia> atopic diseases can manifest with rhinitis, sinusitis, and asthma> and control of asthma symptoms often re"uires vigorous treatment of concomitant sinus infection.

Condu !ing Air"ays ,ridging the upper airway %nose, oropharynx, and larynx( and the alveolar air-exchange area distal to the terminal bronchioles are the conducting airways %)ig.-(.!ucociliary clearance and coughing are the principal means of cleansing themucosal surfaces of these airways. 2Ig* antibodies also prevent epithelial attachment of certain bacteria and viruses to the ciliated and nonciliated airway epithelial cells. The branching structureof the airways also causes airborne particulates to impact against themucosa, enhancing the efficiency of mucociliary clearance. ,ronchial-associated lymphoid aggregates are present, especially around branching points. This segment is susceptible to many diseases3e.g., epithelial cell infection with viruses or bacteria such as (ordetella pertussis Chlamydia pneumoniae$ orMy)oplasma pneumoniae* inflammation, edema, and bronchoconstriction in asthmatic syndromes> chronic infection in bronchiectasis> irritation from noxious gases> and lung cancer. The conducting airways mucosa is coated to a depth of ? to -55 8m with a mucous gel-a"ueous sol complex viscous fluid, which has a low p: %@.@ to @.A(. This is secreted by bronchial glands, goblet cells, and $lara cells %nonciliated bronchiolar secretory cells found in the terminal bronchioles(. *irway surface li"uid is also derived from transepithelial acid-

base flux across the bronchial epithelium. 2pecial proteins, such as 2Ig* and 2$, can be added locally along airways by immunoglobulin-secreting plasma cells and epithelial cells. *ntimicrobial factors such as lyso yme, 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 mucin glycoproteins and proteoglycans, provide a protective barrier or blan#et that prevents inhaled particulates from penetrating or stic#ing to the respiratory surface. This seems to be an important component of host defense. ,acteria and other infectious agents may transiently coloni e the airways, but mucociliary clearance effectively removes them. Tight junctions between epithelial cells also limit the passage of macromolecules into the submucosa, and microvillous brush cells may help clear fluid. * number of circumstances can alter these protective barriers, ma#ing this portion of the respiratory tract susceptible to disease. They include %-( malnutrition, which affects the integrity of mucosal epithelial cells and enhances bacterial adherence> %4( cigarette smo#e and noxious fumes, which disrupt the anatomy of epithelial junctions and enhance the passage of airway substances into areas that are usually inaccessible> and %6( some bacteria, which elaborate proteolytic en ymes that may brea# down Ig*, promoting selective coloni ation and persistence in matrix-enclosed biofilms that help avoid innate immunity and create chronic infections. 1ymphoid tissue is present along the entire respiratory tract, but the level of organi ation of the lymphoid tissue varies greatly. * ring of lymphoid structures are situated in the naso-oropharynx. 1ymphoid nodules may occur in the mucosal surface of large and medium-si ed bronchi and are particularly numerous at points of airway branching. ;n the airway side, these submucosal follicles are covered by a layer of flattened, nonciliated surface epithelium, which is often observed to be infiltratedwith lymphocytes. These bronchialassociated lymphoid tissues %,*1T( bear some resemblance to gut-associated lymphoid tissues %/eyer's patches(, and are part of the body's overall mucosal-associated lymphoid networ# %#nown as !*1T( that is important inmucosal immunity. &hereas ,*1T is easily demonstrated in some rodents and rabbits, subhuman primates and humans have decidedly less obvious amounts of this lymphoid tissue, and it may not be as relevant to airway defenses as initially thought, especially in adults. 1oosely organi ed collections of lymphocytes %lymphoid aggregates( are concentrated in the distal airways, especially at the bronchoalveolar junctions at the interface between the ciliated epithelial cells of the terminal bronchioles and the alveolar lining cells. These aggregates provide an opportunity for close interaction between lymphoid cells and inhaled antigens that have been deposited in the lower respiratory tract. *ntigens and microbes may adhere to surface macrophages or dendritic cells imbedded in the mucosa where immune processing or elimination occurs. ,acteria such as Pseudomonas aeru+inosa may become enmeshed in a biofilm containing their exopolysaccharides, which can interfere with macrophage or dendritic cell

elimination of them and contribute to airway coloni ation and persistence. *lso, in the vicinity of the respiratory bronchioles, lymphatic channels begin that might provide these lymphocytes with a route to draining lymph nodes %hilar nodes( where immunologic responses develop. Respira!ory #ron hio$es *natomically, lung structure changes at the level of the respiratory bronchioles, which are inserted between the distal conducting airways and the acinar units %alveolar ducts and alveoli( of the air exchange surface. They functionally separate the upper and lower respiratory tracts. This segment can be a bottlenec# or cho#e point for airflow, but it is the last surface to capture small airborne particulates and microbial or antigenic debris before entering the alveolar space> adaptive immune responses can begin here. 2everal structural changes occur= the single-layer cuboidal epithelial surface flattens and differentiates into alveolar type I cells that primarily cover the alveolar lining surface> mucus-secreting cells disappear, although goblet cells can be found in cigarette smo#ers> and another secretory cell type becomes prominent, the $lara cells. /ulmonary brush cells with a tuft of s"uat microvilli are found in this area, especially in rodent species, and may be involved with chemosensing or trapping inhaled particles and pollutants, or with regulating fluid and solute absorption. 9endritic macrophage-li#e cells, which may constitute - percent of the cells in the surface of this segment, are present to capture and process antigens. 1ymphatic channels form to collect the lymphatic fluid emerging from the interalveolar interstitial spaces. The changeover from the bronchial arterial blood supplying the conducting airways to the pulmonary artery-capillary blood flow structure that surrounds the alveoli also occurs, which is necessary for aeration. %he A$&eo$ar Spa es 9efenses in the airways %)ig.4( eliminate most particles and microbes inspired into the lungs. *s a result, the airways distal to the major bronchi are probably sterile in normal subjects. :owever, some particles of small si e and special geometry can elude the airwaymucosal mechanisms and reach the air-exchange surface of the alveoli.&hen this occurs, another set of host defense mechanisms must ta#e over. !icrobial clearance and the removal of other antigenic material from alveoli depend on cellular and humoral factors such 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 si e %5.? to 6 8m in diameter( is deposited in an alveolus, it is li#ely to ma#e contact with the alveolar wall and roll along in about 5.4 8m of alveolar lining fluid, p: @.A, which is a ombination of a watery subphase with an overlying film of surfactant secreted by type II pneumocytes. In the process, a microbe encounters several substances that can inactivate it and assist in its eventual

phagocytosis. These substances include a variety of soluble lipoprotein substances, Ig., complement factor %$6b(, and nonimmune opsonins, such as high-molecular-weight fibronectin fragments. The lipoproteins in the form of surfactant are secreted by type II pneumocytes, and surfactant proteins * and 9 have opsonic effects through binding of surface carbohydrates, which promotes antibacterial activity against staphylococci and rough colony strains of some gram-negative rod bacteria. The immunoglobulins are principally of the Ig. class. They account for ? percent of the total protein in alveolar fluid, with subclasses Ig.- and Ig.6 being the most important and lesser concentrations of monomeric and secretory forms of Ig* being noted. These immunoglobulins can develop specific opsonic antibody activity for the bacterium. The complement components, especially properdin factor ,, interact with the bacterium and can trigger the alternative complement pathway, thereby lysing the microbe directly. ;ne or all of these interactions can prepare the bacterium for ingestion by an alveolar macrophage. *lthough alveolar macrophages avidly phagocytose some inert particles, they ingest viable bacteria with considerably less enthusiasm. $oating or opsoni ing the organisms will enhance phagocytosis appreciably as studied in an in vitro culture system. The nonimmune opsonins nonspecifically enhance this process. The immunoglobulins are capable of enhancing alveolar macrophage phagocytosis in an antigen-specific fashion, and the $6b complement fragment can function in concert with Ig. to enhance or amplify this process. /hagocytosis, the ingestion of particulate matter by cells, is divided into two phases= receptor attachment of the particle to the cell surface and internali ation. *ttachment of the particle to the surface of the phagocytic cell is essential before ingestion occurs. *lthough binding occurs randomly, it is greatly enhanced by opsoni ation of the particle by antibody %especially Ig.( or a component of the complement system, $6b. ;psonin-dependent phagocytosis is mediated by receptors on the cell surface for the )c component of the opsoni ing immunoglobulin or complement. 2pecific receptors for the )c portion of Ig.%)cB( %Ig.6 and Ig.- primarily( and for the third component of complement %$6b( are present on human monocytes and alveolar macrophages. +eceptors for Ig*are also found on alveolar macrophages.There is evidence that the number and function of these receptors can be modulated by lymphocyte-derived cyto#ines such as interferon-B %I)0-B(. Ingestion of membrane-bound particles occurs via a process that is energy-dependent as the plasma membrane of the ingesting cell surrounds the bound particle, enclosing it in an endocytic vesicle. This is followed by the activation of a number of well-developed mechanisms that operate to #ill internali ed pathogens. )ollowing internali ation of bacteria, the fate of alveolar macrophages is not certain. They are long-lived tissue cells that can survive at least for several months and presumably are capable of handling repeated bacterial and other microbial challenges %reusable phagocytes(. ,ecause they are mobile cells, they can migrate "uic#ly to other alveoli through the pores of Cohn, or move to more proximal areas of the respiratory tract %to the region of the respiratory bronchioles( for elimination from the lungs by the mucociliary

escalator. In addition, macrophages may gain entry into lung lymphatics at the same location and be carried to regional lymph nodes. This exit gives them access to systemic lymphoid tissue and is important in initiating cellular immune responses. Dndoubtedly, macrophages are also instrumental in degrading antigenic material and presenting it in an appropriate manner to local T lymphocytes as part of innate and adaptive immunity in the lung. Increasingly, attention is being given to the immune effector role of macrophages. The alveolar macrophage has a dual role in the respiratory tract3one as a phagocyte to dispose of debris, process foreign antigens, and #ill ingested microorganisms and a second as an effector cell to initiate immuneandinflammatory responses. *lveolarmacrophages are usually successful in inactivating inhaled microorganisms. *s a result, clinical disease and pneumonitis rarely develop after day-to-day exposures.:owever, if a sufficiently large bacterial inoculum reaches the lower respiratory tract, or if particularly virulent microorganisms are inhaled, the macrophage system can be overwhelmed. ,y the secretion of proinflammatory chemotactic factors such as the chemo#ine family cyto#ines, alveolar macrophages then recruit /!0s and other cells to the lung, and pneumonitis develops. *lso, airway epithelial cells can generate proinflammatory cyto#ines to assist with /!0 attraction. .ram-negative rod bacteria provide an interesting example. 2ome complement components, particularly factor ,, are present in small amounts in bronchoalveolar fluids. The bacterial endotoxin in the gram-negative rod bacteria can directly activate the alternative complement pathway3leading to the formation of $?a, which is a potent stimulus for /!0 chemotaxis. *lso, the inflammatory responsemay activate the #inin system> this results in generation of #alli#rein, which has chemotactic activity, and brady#inin, which is capable of increasing vascular permeability. The latter allows for the seepage of fluid and other humoral and bioactive substances from the intravascular compartment into the alveoli. *nother mechanism of inflammation emanates from the alveolar macrophage itself. )ollowing phagocytosis of opsoni ed bacteria or other forms of activation, proinflammatory chemo#ines are synthesi ed and secretedbymacrophages that will attract /!0s and other cells. 2everal substances with chemotactic activity have been found to be produced by human alveolar macrophages. These include interleu#in-E %I1-E(, macrophage inflammatory protein-4 %!I/(, monocyte chemoattractant protein-- %!$/--(, tumor necrosis factor %T0)(, and lipoxygenase pathway metabolites of arachidonic acid, namely leu#otrienes. 1eu#otriene ,F %1T,F( is one of the most important of these. Inflammation is the ultimate host response to contain common bacteria that reach 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 alternate complement pathway> %4( through the generation of phlogistic factors from the #alli#rein and brady#inin pathways> and %6( from the effector cell function of macrophages. It is also #nown that other airway cells, such as epithelial

cells, elsewhere in the respiratory tract, can produce chemo#ines li#e I1-E and that this can stimulate inflammation in other sites %bronchitis(. 2pecial interest has focused on the macrophagesecreted proinflammatory chemo#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 the acute inflammatory responses. 1ymphocytes, monocytes, and eosinophils are also recruited in the chronic phase of pneumonia, chronic inflammatory disorders such as hypersensitivity pneumonitis and sarcoidosis, and atopic and eosinophilic syndromes. Investigation has elucidated the cellular mechanisms whereby $G$ chemo#ines activate and initiate the migratory process of /!0s. *n extensive review of the literature is summari ed to say that this process involves a number of cell surface adhesion molecules, found on endothelial cells %adhesion molecule I$*!--, 1- and/-selectins and integrins( and granulocytes, that bind to one another. *t sites of inflammation mediators such as I1--, T0), and I)0-B induce or augment the expression of these adhesion molecules. *s a result, intravascular /!0s slow down, roll along, deform, and then anchor on the endothelium. They then enter the interstitium via traversing capillary endothelial cells, which contract or pull apart to allow a gap through which /!0s pass, and plasma fluid can lea#, and the cells emerge through the alveolar type I pneumocyte lining barrier into the alveoli.!icrovillous brush cells may also absorb fluid or regulate ion-solute flux. <ventually, all pneumonic responses run their course. If the host is successful in containing the infective microbes or particles that initially incited the host response, resolution usually occurs. +esolution can be passive, resulting from the removal of the initiating agent. +esolution can have an active phase as well. In the active phase, signals must go out to begin the healing and resorption phases that will restore the lung to normal respiratory function and architecture. 1ess is #nown about active resolution of inflame mation. * plateletderivedsubstance, sphingosine --phosphate %2 --p( may help restore the endothelial barrier by reducing /!0 infiltration and vascular lea#, as found with endotoxin injury.!oreover, cyto#ines such as transforming growth factor-H, I1-@, I1--5, and the I1-- receptor antagonist released by macrophages and possibly other cells are believed to be important mediators of this process. *s such, they provide a view of potential anti-inflammatory therapies of the future.

Ly'pho y!es in !he A$&eo$ar Spa e &hen cells are retrieved from the alveolar surface by bronchoalveolar lavage %,*1(, approximately I to -5 percent of the respiratory cells are lymphocytes. 2ome characteristics of these cells are given in Table -A--. Two major populations of lymphoid cells are recogni ed, those that depend on the thymus gland for differentiation %T cells( and those that differentiate independently of the thymus in the bone marrow %, cells(.

-6

TheTand,lymphocytes are indistinguishable by usual morphologic criteria but can be differentiated by membrane surface mar#ers. They are also functionally distinct, with T cells playing an important role in cell-mediated immunity and cell-mediated cytotoxicity while the , cells serve as precursors for cells that synthesi eimmunoglobulins and, hence, antibody molecules that are the basis of the humoral immune response. *s shown in Table -A--, approximately I5 percent of the lymphocytes in lavage fluid are T cells and approximately ? percent are , cells. The ratio of T to , cells in lavage fluid is roughly that of peripheral blood, although in blood more circulating , cells are usually identified %approximately-? percent(. *pproximately - to ? percent of lung lymphocytes seem to be able to release or secrete class-specific immunoglobulin. <numeration of these cells has found that Ig.- and Ig*-secreting cells are much more numerous than Ig!producing cells. 0atural #iller lymphocytes ma#e up about ? to E percent of lung lymphocytes. *s they do not express T-cell receptors or surface immunoglobulins for specific antigens, they can respond in an antigenindependent way to help contain viral infections and are thus important in innate immunity.&ith phenotypic mar#ers, T cells can be divided into two principal groups. The $9E cells usually have a suppressor-cytotoxic phenotype. The$9Fcells usually have a helper-inducer phenotype and thus are also called T-helper %T:( cells. In the ,*1 fluid from normal subjects there is a greater percentage of $9F cells, with approximately F? percent of the total T cells expressing this surface mar#er. In contrast, approximately 4? percent of lungTcells express the $9E phenotype. In lung lavage fluid, the ratio of these subtypes of T cells is approximately -.? to 4=-, which is approximately the same ratio found among peripheral blood lymphocytes. *s noted, most of the T lymphocytes in the alveoli are $9F-positive. &hen activated, these T: cells are capable of producing regulatory cyto#ines that in turn modulate the function of other immune and structural cells. +ecent studies suggest that there are at least two subsets of $9F T: cells, T-helperJ - %T:-( and T-helperJ4 %T:4( cells.

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These cell populations have different functions based on the different array of cyto#ines that they produce. TheT:-cells secrete I)0-Band I1-4, which activate macrophages and play a major role in cell-mediated immunity. The T:4 cells produce I1-F, I1-?, and I1-@, which stimulate,lymphocytes to produce 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 generating tissue eosinophilia and stimulating Ig< production, processes that are extremely important in atopy, allergic asthma, and other inflammatory pulmonary disorders. I1-4, formerly called T-cell growth factor %T$.)(, is among the most important T-cellJregulating cyto#ines. It is produced by activated 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 identified among alveolar T cells, but these cells seem to be dormant in normal subjects until stimulated. 1astly, I1-4 can stimulate , lymphocytes to differentiate into plasma cells that synthesi e various classes of immunoglobulins. This is a mechanism by which local production of immunoglobulin in the lung can occur. In all cases, the effects of I1-4 are mediated by the multimeric I1-4 receptor, a component of which is the Tacsurface ligand. The expression of the I1-4 receptor is highly regulatable, and the expression of the Tac antigen can be used as a mar#er of T-cell activation. !ost T cells have T-cell receptors with alpha and beta subunits %K/H T-cell receptors(. In the normal lung, a lesser number of T cells have gamma and delta T-cell receptors. The function of these cells is poorly understood. They may, however, play an important role in mucosal immunity, since they are increased in atopic allergic subsets. *lveolar macrophages and lymphocytes have the capacity to produce many cellular mediators %cyto#ines( that in turn affect each other as well as other inflammatory, structural, and immune effector cells. This dynamic and complex interaction is illustrated in )ig. -A-4, which reviews dendritic cell, alveolar macrophage, and lymphocyte interactions in the airways and alveolar milieu. !onocyte precursors from the blood differentiate into mature macrophages under the influence of vitamin 9 metabolites and undoubtedly other stimuli and become long-lived, aerobically metaboli ing alveolar phagocytes. Their principal activity is to cleanse the alveolar surface and ingest debris that accumulates or microbes aerosoli ed into the lungs. In the process, the macrophages may become activated and are then capable of secreting an enormousarrayof en ymesandcyto#ines. These moieties can affect the function of resident cells of the lung such as lymphocytes or epithelial cells. In addition, the release of proinflammatory chemo#ines attracts/!0s,lymphocytes,monocytes, and other cells into the alveoli. ;f particular note are 1T,F, I1-E, T0)- , !I/--, !$/--, and I1--. &hen secreted by 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 a substance is migration inhibition factor, which immobili es macrophages

-.

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

Figure ( :ost defenses in the alveolar space. ,acteria %,( that escape clearance mechanisms in the upper respiratory tract %D+T( can reach the alveolus %represented by an enlargement of one(. !ost of the alveolar surface is lined by type I epithelial cells with pulmonary microvillous brush cells interspersed, and type II cells positioned in the corners that secrete surfactant. * variable amount of interstitial space separates the epithelium from the capillary endothelium where se"uestered /!0s and platelets reside. * bacterium deposited in an alveolus may encounter at least three different but coordinated sets of innate immunity immunologic materials and cells that can destroy it= opsonins, both Ig. and surfactant proteins * and 9, or complement factors that facilitate phagocytosis or create a lysis of the microbe> activated macrophages stimulated by cyto#ines produced by nearby lymphocytes> and other inflammatory phagocytic cells, usually /!0s attracted into the alveolar space by proinflammatory chemo#ines produced locally by macrophages and epithelial cells. (Modified from Reynolds HY: Respiratory infe)tions may refle)t defi)ien)ies in host defense me)hanisms. ,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( toward infectious challenges. The scheme shown in )ig. 6 may help to explain certain derangements found in a number of lung diseases that have excessive or deficient secretion of cyto#ines and feature changes in the relative proportions of macrophages and lymphocytes. <xamples of

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Figure ) !ajor immunity pathways. &ithin the body, mucosal surfaces are positioned at initial inta#e and contact 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 gastrointestinal and genital tracts must discriminate between pathogens and harmless microbes or possible toxins and essential nutrients, and then respond "uic#ly to exclude, tolerate, or initiate immune responses.

+espiratory host defenses balance two important immune mechanisms created for dealing with airway microbes or other entering antigens= %-( an innate or "uic# reaction response producing inflammation as an end point %bronchitis or pneumonitis(, and %4( a more deliberate approach through stimulation of lymphocytic pathways that creates a versatile and adaptive response involving specific T-cell activity and7or production of immunoglobulins %antibodies(. )oreign substances or microbes or their exoproducts %lipopolysaccharide from gram-negative rod bacteria( that enter the airway lumen and adhere to the mucosa will be pic#ed up by macrophages %!( or dendritic cells %9$s(. Toll receptor recognition and attachment are important, and dealt with in a variety of ways. /hagocytic upta#e and intracellular #illing of bacteria might suffice, or recruitment of /!0s may be needed through secretion of proinflammatory cyto#ines by macrophages, creating pneumonitis for example. 1ater, active resolution of inflammation re"uires inhibition of /!0 influx %suppress chemotaxis( and

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cellular cleanup %apoptosis(. *lternatively, 9$s %or macrophages( can process antigens, present these to major histocompatibility complex %!:$( 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 and proliferate. In turn, T:- cells can produce I1-- and I)0- B that can stimulate macrophages for the inflammatory pathway, or induce clonal expansion of $9F+lymphocytes that contribute to building granulomata for containment of certain microbes or particles. +eturning to the 9$-antigenJpresenting cell process involving the $9F cells, another subset of 9$s %or macrophages( can produce I1--5, an inhibitory cyto#ine that promotes the T:- response preferentially in normal subjects and suppresses the T:4 cellular pathway. :owever, pending the allergic status of the host %atopy( and7or the particular antigen present, T:4 lymphocytes can be stimulated and in turn produce I1F, ?, @, and -6 cyto#ines that culminate in allergy %asthma and allergic rhinitis( with stimulation of mast cells and then eosinophils and production of reaginic antibodies %Ig<, Ig. F(. The T:4 immune response is also effective against certain parasites. (-rom Reynolds HY: Modulatin+ air'ay defenses a+ainst mi)ro.es. Curr /pin Pulm Med &:%50"%15$ ## .) such cellular imbalances include sarcoidosis, hypersensitivity pneumonitis, and ac"uired immunodeficiency syndrome %*I92(.

III. DEFEC%S IN *OS% DEFENSES %*A% CAN #E ASSOCIA%ED +I%* RESPIRA%OR, INFEC%IONS Infection can occur everywhere along the respiratory tract-upper airways %nose, sinuses, ears, and oropharynx(, conducting airways %trachea and bronchi down to the respiratory bronchioles(, or the alveolar area. *lthough exposure to a virulent microorganism or to a large inoculum, if inhaled or aspirated into the lungs, may cause illness in a normal person, recurrent or chronic infections may point to deficiency or malfunction of a particular component of the host defense system %Table -A-4(. * number of situations associated with fre"uent respiratory infections serve as examples. <ndotracheal tubes give direct access to the lung but, in so doing, bypass the larynx and the other upper-airway protective structures. /atients with depressed consciousness or with postoperative chest or abdominal pain become infected because of their inability to cough and clear airway secretions. In addition, patients with viral infections have an increased incidence of bacterial superinfection. The cause of this association appears to be multifactorial, including the ability of these infectious agents to damage ciliated epithelial cells and diminish the clearance of airway secretions> also viruses and other microbes can infect alveolar macrophages, diminishing their bactericidal activity. In combination, these host defense defects are believed to contribute to the fre"uent association of influen a infection and staphylococcal superinfection. Dltrastructural defects in the cilia located on the apical edge of the airway epithelial lining cells cause mucociliary dysfunction. *s a result, the removal of mucus and respiratory secretions is depressed, and recurrent infections and bronchiectasis occur. The constellation ofmultiple upper and lower

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respiratory infections and bronchiectasis should raise the possibility of a ciliary dys#inesis syndrome. Infertility, especially in males,may be associated, and the evaluation of this problem may bring the respiratory symptoms to the physician's attention.&ith age, ciliary beat fre"uency decreases and might 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 can promote infections with encapsulated bacteria. 2everal common bacteria that coloni e the airways of patients with chronic bronchitis and chronic obstructive pulmonary disease %Strepto)o))us pneumoniae$ Haemophilus influen2ae$ and 3eisseria( can also produce a specific Ig* protease that cleaves the Ig* heavy chain in its hinge region adjacent to the )c portion. ,y this mechanism, these bacteria could inactivate a substantial portion

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of the secretory Ig* coating the conducting airways and gain better access to the ciliated epithelial cells for attachment. &hile this mechanism is somewhat theoretical, associations between deficiencies in Ig. and recurrent infection are well documented. /articularly important are the associations between deficiencies of Ig. subclasses Ig.4 and Ig.F, alone and in combination with Ig* deficiencies and chronic inflammation and bronchiectasis. /resumably, an absence of these subclasses denies phagocytic cells potential opsonic antibody, thereby diminishing membrane receptor attachment of opsoni ed particles or bacteria and subse"uent phagocyte ingestion. $linically, establishing the diagnosis of an Ig. deficiency is "uite important because, in contrast to many other immunodeficiencies, replacement preparations of Ig.are often available for these patients. $ytotoxic antineoplastic chemotherapy and other forms of immunosuppression also compromise host

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defenses in a major way. * major side effect of these therapies is granulocytopenia, which prevents the mobili ation of /!0s and creates a poor inflammatory reaction.

I-. *OS% DEFENSES IN %*E APPROAC* %O PA%IEN%S +I%* P.L/ONAR, DISEASE *s noted above, normal hosts can develop respiratory infections or inflammation as a result of exposure to particularly virulent agents or a large inoculum of aerosoli ed particulates. In others, respiratory infections are associated with obvious clinical features that compromise pulmonary defenses %Table -A-4(. ;ccasionally, however, the physician is confronted with a relatively young person who has an unexpected number of respiratory problems that seem inappropriate. The illness can manifest as recurrent infection or poorly controlled allergic rhinitis, asthma, fre"uent sinusitis, recurrent nasal polyps, and7or bouts of otitis media. ,ecause the severity of these respiratory problems may not seem great, the physician may not initially suspect that something unusual is present. The propensity for infection may not have been obvious in childhood but became apparent as the patient reached adolescence or adulthood. *lthough genetic defects usually are manifested in infancy, minor forms of host deficiency, creating antibody deficiency diseases, may not be recogni ed until later in life. $ystic fibrosis %adult onset(, selective absence of Ig. subclassimmunoglobulins, structural ciliary defects, and Ig*deficiency are the principal diseases that should be considered in this differential diagnosis. +ecurrent sinopulmonary infections are an important clue to all these syndromes. The physician should be prepared to examine such a patient thoroughly. * detailed history will immediately provide important information about affected siblings, infertility, or a stri#ing change in respiratory health that ma#es an ac"uired abnormality li#ely. /reliminary screening tests are a complete blood count and "uantitative serum immunoglobulins, and perhaps pulmonary function tests, even if the chest radiograph is normal in appearance> also indicated may be microbial cultures of respiratory secretions and analysis of the electrolytes contained in a sample of sweat or nasal potential difference measurements. !ucoid strains of Pseudomonas aeru+inosa and elevated sweat chloride values can be noted in cystic fibrosis. ;ther useful secondary-level screening tests are "uantitation of subclasses of Ig.> secretory Ig* as sampled in parotid fluid or nasal wash samples> subtyping of blood lymphocytes> measurement of antibody responses to protein and7or polysaccharide antigens> search for genetic mutations of the cystic fibrosis transmembrane conductance regulator %$)T+(> assessment of ciliary clearance with an aerosoli ed, isotopic tracer> nasalmucosal biopsy for electron-microscopic ultrastructural analysis of cilia> sperm motility in males of appropriate age> and documentation of bronchiectasis by high-resolution computed tomographic scans of the chest. * thorough evaluation by an otolaryngologist is also often helpful because of the recurrent sinusitis, otitis media, and nasal polyps that might be present.

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*lternatively, certain forms of pneumonia point to possible deficiencies in lung cells such as alveolar macrophages, lymphocytes, or /!0s. *s opsoni ation of certain encapsulated bacteria is necessary for optimal phagocytosis by macrophages and /!0s, the lac# of appropriate Ig. antibodies against pneumococci, Haemophilus species, 4le.siella pneumoniae$ and staphylococci may contribute to infections with these common bacteria.:owever, other causes of pneumonia may reflect abnormal lymphocyte function and cellmediated immunity. Infection with 5e+ionella bacteria is an example. *fter an infection with 5. pneumophila$ the host develops specific Ig! and Ig. serum antibodies. These antibodies, in the presence of complement, do not create a lytic state that is sufficient to #ill the bacteria.:owever, they do behave as opsonins to ensure that the 5e+ionella organisms can attach and be ingested by various phagocytic cells, including /!0s, blood monocytes, and alveolar macrophages. ;nce inside the phagocytes, 5e+ionellamultiply and eventually can #ill and disrupt the host cells.&hen alveolar macrophages are activated with I)0-B these stimulated phagocytes will inhibit the growth of the bacteria. This may be the result of the ability of I)0-B to down-regulate the transferrin receptors on these cells, thereby limiting the accumulation of intracellular iron which is an essential metabolite for 5e+ionella. 2upport for this concept comes from experiments with an experimental 5e+ionella pulmonary infection rat model, in which administration of intratracheal I)0-B reduced intrapulmonary replication of the bacteria, improving host defenses. *nother example of defects at the level of the lymphocyte is *I92, in which the human host is infected with human immunodeficiency virus %:IO( that destroys $9F T: lymphocytes. These patients experience recurrent respiratory infections with diverse organisms, including viruses %cytomegalovirus or herpes simplex(, Pneumo)ystis )arinii$ My)o.a)terium tu.er)ulosis$ M. a6ium-intra)ellulare$ fungi such asCrypto)o))us species, and7o8oplasma +ondii and5e+ionella. These infectious agents have a common feature of residing in macrophages or similar cells as facultative intracellular organisms. ;ne reason why a patient with *I92 has trouble with this group of infections relates to the relative imbalance of lymphocytes found in the alveoli, as sampled by ,*1 of the lung.0ormal values for T lymphocytes have been given in Table -A--. )rom subjects with *I92, the recoverable alveolar lymphocytes reflect a decrease in the $9F T: cells from :IO infection, offset by an increase in the suppressor-cytotoxic species of T lymphocytes. *lthough alveolar macrophages normally exist in an environment where they can be activated sufficiently to #ill or control microbes of this sort, the $9F deficiency 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 Pneumo)ystis or mycobacterial species.

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1<$TD+<+2 = -. /rof. dr. <ddy !art 2alim, 2p/9, C-*I 4. dr. !asdianto !usai, 2p/9 6. dr. 0ova Curniati, 2p/9

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