Editorial Immunoglobulins in thelungThe concentrations of this immunoglobulin in bronchoalveolar lavage fluid suggested appreciable local synthesis, probably by IgE producing plasma

Thorax 1986;41:337-344

Editorial

Immunoglobulins in the lung

The lungs are continually exposed to a vast range ofantigenic material. The immunoglobulins of the lungtherefore have an important role in the neutralisationof antigens, which leads to cellular processing andremoval. The lung is undoubtedly a major "immu-nological organ" since it contains a considerableamount of lymphoid tissue, with the ability to syn-thesise immunoglobulins. The analysis of immuno-globulins in the secretions of the lung has clarified ourunderstanding of their origins in this organ but thedetails of the functions of immunoglobulins in thelung are not well understood. Nevertheless, the secre-tions lining the airways are likely to be the site wherelung immunoglobulin function as a front line ofdefence is most important. For this reason we can befairly confident that studies of immunoglobulins inlung secretions will be relevant to their significancein vivo.

Origins of immunoglobulins in lung secretions

So far our knowledge of the origins of the immuno-globulins in lung secretions has resulted almostentirely from the development of antisera that arespecific for the immunoglobulins and their discretesubpopulations, such as the structural forms of IgAand the immunoglobulin subclasses. These antiserahave been used for immunohistochemical studies,which have shown the presence of immunoglobulinbearing plasma cells in the bronchial mucosa and inthe secretions of the airways, thus confirming thatlocal synthesis of immunoglobulins does occur atthese sites. Furthermore, the development of specificand sensitive immunological assays has allowed theimmunoglobulin composition of lung secretions to bestudied in some detail.

In essence, there are two major sources of immu-noglobulins in the lung secretions:

Firstly, all the immunoglobulin classes are repre-sented in the blood plasma. Thus a proportion ofthese proteins in lung secretions will be derived fromthe vascular compartment by diffusion (transudation)across the lung tissue, which behaves as a semiper-

Address for reprint requests: Dr D Burnett, Lung Immuno-biochemical Research Laboratory, Clinical Teaching Block, GeneralHospital, Birmingham B46NH.

meable membrane with respect to proteins in solu-tion. The transudation rate of a protein, and hencethe secretion concentration, will depend on three fac-tors: the "resistance" of the tissues to proteindiffusion, the plasma concentration of the protein,and the effective size of the protein. We do not knowwhether the diffusion rate of proteins across the lungvaries in different anatomical areas, although localinflammation undoubtedly results in increased tran-sudation.' Several proteins in lung secretions arederived exclusively by diffusion from the blood. Forthese proteins a correlation is observed betweenthe secretion:serum concentration ratios and theireffective sizes (expressed as Stokes' radius).1 Con-sequently, if the secretion concentration of a protein(relative to that in the serum) is higher than predictedfor this size, simple transduration from the blood isnot the only source.The second possible source of a protein in the lung

secretions is local production by cells within lung tis-sues. Synthesis might be effected by cells actuallywithin the secretions. Alternatively, proteins may besynthesised by the epithelium or cells in the laminapropria and then either diffuse or become activelytransported across the epithelium.There is now evidence to suggest that, apart from

IgD, for which no data are yet available, all theimmunoglobulins enter the lung secretions by all ofthese mechanisms.

IgAIgA is the predominant immunoglobulin class in lungsecretions in contrast to blood plasma, where IgG isfound at higher concentrations. Most of the IgA inthe blood (about 90%) is monomer (mIgA),2 whereasin lung secretions about half the IgA is dimeric (dIgA)and most of this is in the form of secretory IgA(sIgA).3 Two subclasses of IgA, IgAl and IgA2, havebeen distinguished in serum and secretions by the useof specific antibodies. In the blood IgA2 comprises10-20% of the total IgA but in bronchoalveolarlavage fluid samples it represents about 30%.4 Thesedifferences in the IgA composition of serum and lungsecretions reflect the considerable local synthesis ofIgA within the lung, although a proportion of the IgAin lung secretions is still derived from the blood bytransudation. I

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cells in the lamina propria, comprises two IgA mole-cules linked by another protein, J chain, which is alsosynthesised by plasma cells. The dIgA is bound by areceptor, secretory component (SC), which is a pro-tein inserted in the plasma membrane on the baso-lateral surfaces of some mucosal epithelial cells. ThedIgA-SC complex on the epithelial plasma membraneis thought to be endocytosed, transported in vesiclesacross the cell, and released at the luminal surface assIgA.'

This SC mediated transport of dIgA has beendefined mainly in studies of the gut mucosa. The highconcentrations of sIgA in lung secretions support thehypothesis that this mechanism also operates in thelung. Furthermore, immunohistochemical studieshave shown that SC and IgA are both present on theepithelial surface, within vesicles of bronchial glandu-lar epithelial cells and in the glandular lumen. In con-trast, cilated epithelium stains only faintly for SC andis negative for IgA.6 This evidence supports the con-cept of SC mediated transport of dIgA, as sIgA,across the glandular epithelium of bronchi. Secretorycomponent and IgA associated with J chain (sug-gesting that the IgA is dimeric) have also been locatedon the plasma membrane and within pinocytic invag-inations and vesicles of bronchiolar non-cilated epi-thelium and type II alveolar cells.7 These resultsshowed that SC mediated transport of dIgA couldalso contribute appreciably to sIgA in the lowerrespiratory tract.IgA producing plasma cells are more abundant in

the glands and lamina propria of major bronchi thanin the small bronchi, bronchioles, or alveolar sep-tae.78 These observations suggest that most sIgAproduction should occur in the upper respiratorytract. This is supported by a study in dogs thatshowed that sIgA concentrations were highest insecretions from the upper respiratory tract.9 Anotherinvestigation,'0 which compared the IgA componentsin sputum, bronchial washings, and bronchoalveolarlavage fluid from patients with chronic bronchitis,highlighted the major problem with this kind ofstudy. The differential dilution of secretions, causedby sampling techniques, makes comparison of proteinconcentrations in secretions from different levels ofthe bronchial tree complicated.Plasma cells in the lamina propria are not the exclu-

sive source of sIgA in the upper or lower respiratorytract. About 10% of plasma IgA is dimeric and Hai-moto et al7 showed that IgA is present in endocyticvesicles of capillary endothelial cells, in the inter-cellular spaces adjoining endothelial cells, and onbasement membrane. Some of this IgA was dimericsince J chain was also located in these areas. Theseresults suggested that dIgA in capillary blood mightbe transported by SC into lung secretions.

Since most of the blood IgA is monomeric, a largeproportion of mIgA in lung secretions should, the-oretically, be derived from the plasma by transuda-tion. Nevertheless, lung secretion concentrations ofmIgA are also higher than would be predicted if theprotein were derived only from the blood.3'1 Thissuggests that most of the mIgA in bronchoalveolarlavage fluid and sputum is locally synthesised byplasma cells within the lamina propria, although, incontrast to dIgA, monomer is not transported acrossthe epithelium by the SC mediated mechanism.Immunoglobulin secreting cells are also located in themucosal secretions lining respiratory epithelium butone study of these cells, obtained by bronchoalveolarlavage, suggested that they do not contribute appre-ciably to the IgA found in secretions.'2

Further evidence for local IgA synthesis in the lunghas been obtained from studies of the IgA subclasses.The proportion of IgA present as IgA2 is higher inlung secretions than in blood plasma.4 This suggeststhat the proportion of IgA2 producing plasma cells ofthe lung should be higher than that of non-mucosallymphoid tissue. Immunohistochemical studies usingantisera specific for IgA I or IgA2 confirm this predic-tion. In bone marrow, tonsil, and peripheral lymphnodes 10-20% of the IgA plasma cells produceIgA2.13 14 By comparison, 26-33% of the IgAplasma cells in bronchial mucosa produce IgA2.'3The proportion of IgA2 in blood or lung secretionstherefore reflects the proportion of IgA2 producingplasma cells in non-mucosal lymphoid tissue andbronchial mucosa respectively.

IgGIgG is the predominant immunoglobulin class inblood and some of the lung IgG is derived from theplasma by transudation. Four subclasses of IgG havebeen described and each has been detected in bron-choalveolar lavage fluid samples from normal sub-jects.'5 In that study IgG subclass concentrationswere related to albumin measurements and the IgGsubclass:albumin ratios in the bronchoalveolar lavagefluid and serum samples were compared. It was con-cluded that IgGI and IgG2 were derived wholly fromthe blood because the IgG:albumin ratios were simi-lar in serum and lavage samples. This result, however,would actually argue in favour of an appreciabledegree of local production of IgGI and IgG2 withinthe lung since it does not take into account thedifferent diffusion rates of albumin and IgG throughbiological tissues. Albumin, which has a Stokes radius(Rs) of 3.5 nm, is smaller than IgG (Rs = 5.1 nm) andcan therefore diffuse more easily from blood to secre-tions. Indeed, it has been shown that if IgG werederived exclusively from the blood, the secre-tion:serum concentration ratio relative to that for



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albumin would have a value of 0.5.1 Any valuegreater than 0.5 therefore indicates a degree of localproduction. The secretion:serum ratio of IgGI andIgG2, relative to albumin, reported by Merrill etal'approached 1.0, confirming significantly higher con-centrations in bronchoalveolar lavage fluid thancould be accounted for by transudation from theblood. The results reported for IgG3 and IgG4 indi-cated that these subclasses are also locally producedin the lung but to a relatively greater degree thanIgGI and IgG2.Plasma cells producing IgG have been located in

bronchial mucosa8 16 and these are likely to be thesource of the locally produced IgG, since IgG pro-ducing cells isolated from secretions obtained bybronchoalveolar lavage probably do not normallycontribute appreciably to the concentrations of thisimmunoglobulin in secretions.'2 IgG synthesised byplasma cells in the bronchial mucosa will not, how-ever, be actively transported by SC and its movementacross the epithelium probably still relies on passivediffusion.

Local production of IgG3 and IgG4 is relativelygreater than that of IgGI and IgG2'5 and thereforeplasma cells producing IgG3 and IgG4 are also likelyto be relatively more frequent in the bronchialmucosa. Such a finding would support the idea ofselective production of these subclasses. No data areyet available, however, regarding IgG subclass pro-ducing plasma cells within the lung. Further studieswill be necessary to test this possibility and clarify themechanism for IgG production in pulmonary tissues.

IgMIgM is composed of five immunoglobulin subunitslinked by a J chain and is consequently a large protein(molecular weight 900 000). Diffusion of 1gM intolung secretions from the blood is greatly restricted byits large size. Nevertheless, the concentrations of IgMin bronchoalveolar lavage samples from normalsubjects and sputum from bronchitic subjects are

higher than can be explained by simple diffusion fromthe blood.'"' As an illustration, in bronchoalveolarlavage fluid the concentrations of IgM (relative toalbumin) are higher than those of the smaller proteina2 macroglobulin."IIgM producing plasma cells arepresent in the bronchial mucosa, though less fre-quently than IgG or IgA producing cells.'6 IgM isbound and transported across epithelial cells by SCand this mechanism is therefore likely to contributeappreciably to concentrations of this protein in lungsecretions.

IgEIgE is present at low concentrations in serum andbronchoalveolar lavage fluid from normal subjects.' s

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The concentrations of this immunoglobulin inbronchoalveolar lavage fluid suggested appreciablelocal synthesis, probably by IgE producing plasmacells in the bronchial mucosa.16

Immunoglobulin functions in the lung

The primary function of all immunoglobulins is therecognition and binding of specific antigenic deter-minants, whether soluble (including toxins), particu-late, or cellular, such as pathogens. The consequencesof immunoglobulin binding depend on the nature ofthe antigen and, at its simplest, may be the physicalprevention of antigen penetration through the epi-thelium. The secondary effects may include com-plement activation with target cell lysis, opsonisationresulting in enhanced phagocytosis, or antibodydependent cell mediated cytotoxicity by a variety ofeffector cells. The ability to intiate these secondaryeffects, however, varies with the immunoglobulinclass and subclass concerned.

Functions of IgAThe presence of high concentrations of IgA in lungsecretion suggests that this immunoglobulin classshould have an important role in the neutralisation ofinhaled antigens or pathogens and their toxic prod-ucts. The complex structure of secretory IgA (sIgA)may in itself confer advantages on this immuno-globulin. Firstly, since sIgA has four antigen bindingsites, it may be an effective agglutinating antibody,preventing bacterial growth'7 and bacterial adher-ence to the epithelium.'8 Secondly, secretory com-ponent has the ability to stabilise the genetic variantAm2 of the IgA2 subclass. The Am2 form is unstablesince it lacks disulphide bridges between the heavyand light chains but human SC has been shown tobind dimeric and monomeric IgAm2 molecules, thuspreventing their dissociation.'9 It was shown that thestabilisation of IgAm2 required an excess of SC in thereaction mixture. Free SC is present in lungsecretions20 and this mechanism might thereforeoccur in vivo.The structural integrity of immunoglobulins in the

lung secretions is an important requirement for theirantibody activity. Lung infection and inflammationare often associated with the presence of proteinasesderived from leucocytes and bacteria. It has beenshown that the opsonic effect of IgG antibodies toPseudomonas aeruginosa was reduced in broncho-alveolar lavage samples from patients with cysticfibrosis.2' This inactivity of the IgG antibodies wasattributed to the presence of proteinases that frag-mented the immunoglobulin molecules. The conceptof proteinase mediated damage to immunoglobulins



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340may have relevance to the presence of high concen-trations of IgA2 in the lung secretions. IgAl is sus-ceptible to hydrolysis by proteinases produced bymany pathogenic bacteria, cleavage of the IgAloccurring at a Pro-Thr bond in the hinge region of theheavy chain.22 IgA2 has a 13 amino acid deletionincluding the susceptible Pro-Thr residues. IgA2 istherefore resistant to proteolytic cleavage and itsfunction in lung secretions would be better main-tained in the presence of potentially damagingenzymes.The ability of IgA to activate complement has been

the subject of controversy. Several studies haveshown that, under appropriate conditions, in vitro,IgA may be effective in activating complement by theclassical or alternative pathways. The significance ofthese effects in vivo is, however, still unresolved andfurther studies are required. Similarly, there havebeen conflicting results regarding the opsonisingability of IgA antibodies. Secretory IgA has beenshown to enhance phagocytosis by mouse alveolarmacrophages,23 but IgA antibodies to Haemophilusinfluenzae from bronchoalveolar lavage samples werealso shown to block the opsonising activity of IgGantibodies.24 Furthermore, although sIgA antibodiesalone may not induce antibody dependent cell medi-ated cytotoxicity by effector cells, they have beenshown to synergise with IgG in stimulating this mech-anism of target cell lysis.25 Clearly, the opsonisingability of IgA may be dependent on experimentalconditions in vitro and factors such as the presenceof other immunoglobulins and effector cellsubpopulations should be considered. Further studiesinvestigating the biological significance of IgA underconditions occurring in vivo may clarify our under-standing of its function.

Functions ofIgGThe biological effects of IgG vary considerably withthe subclass concerned. Whereas IgGI, IgG2, andIgG3 can activate complement via the classical path-way, IgG4 is ineffective. The opsonising activity of anantibody will depend largely on the presence of rele-vant Fc receptors on effector cells. Naegel etal26showed that about 25% of human alveolar macro-phages could bind IgG3 and 10% bound IgG4,whereas no significant binding of IgGI or IgG2 wasobserved. These results suggest therefore that IgG3and IgG4 may be the most important subclassesconcerned in the opsonisation of pathogens foralveolar macrophages and may explain the relativelyhigh degree of local synthesis of these proteins.Further studies will be necessary to clarify the role ofIgG in inducing opsonisation by other effector cellpopulations in lung secretions.

Another factor to be considered is the class or sub-

class specific response to stimulation by particularantigens. Polysaccharide antigens appear to evoke apredominantly IgG2 response systemically,27whereas protein antigens favour the production ofIgGI and IgG3 antibodies.28The biological effects of IgG antibodies in the lung

are far from understood. Many factors, including thenature of the stimulating agents, antigen presentingcell populations, and cooperating T-cells within thelung will influence the type of antibody response. Inturn, the effects of the antibodies produced willdepend in part on the effector cell populationspresent. Since many of these cells are now recognisedas being phenotypically variable in different tissues,future studies may be more rewarding if the experi-ments investigate appropriate human lung material.

Functions ofIgMIgM is the most effective complement fixing immuno-globulin class and the 10 antigen binding sites on thepentameric structure ensure that it is a good aggluti-nating antibody. IgM is the first immunoglobulin tobe detected in the blood during the primary andsecondary antibody responses and its main role isgenerally considered to be the neutralisation ofpathogens, especially viruses, in the vascular com-partment. The role of IgM in the lung secretions isless well understood, although its ability to activatecomplement and opsonise pathogens is likely to be ofmajor importance. It is thought that IgM may benecessary in replacing the functions of IgA in subjectswith selective IgA deficiency. This conclusion is basedon the observation that IgM producing plasma cellsand IgM concentrations in secretions were shown tobe raised in the intestine of patients with IgAdeficiency.29 The relevance of these observations tothe lung is not known.

Functions of IgEIgE is bound by Fc receptors on mast cells. Crossbridging of the cell bound IgE with specific antigenresults in the release of several active substances fromthe mast cell, including histamine and slow reactingsubstance of anaphylaxis (leukotrienes C4, D4, andE4), which result in bronchiolar smooth musclecontraction and increased blood vessel permeability.The mast cells also release potent enzymes, includingelastase, cathepsin G, and kininogenase.3031 Fur-thermore, other cells are recruited to the inflam-matory process through the release of neutrophil andeosinophil chemotactic factors and platelet activatingfactor. This IgE mediated inflammatory response ismost evident in type 1 hypersensitivity reactions suchas occur in allergic asthma, but it has been proposedthat this mechanism has an important role in the hostdefence against metazoan parasites.32 In addition,



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IgE may itself interact with other inflammatory cells.For instance, IgE has been shown to bind to receptorson alveolar macrophages causing the release oflysosomal enzymes.32The factors responsible for high IgE antibody

concentrations in atopic individuals are not known,although defects in T cell function have beensuggested.33

Disease and lung immunoglobulins

The immunoglobulin composition of the lung may beinfluenced by many factors. In some diseases, how-ever, the aetiology or progression of the conditionappears to be directly related to abnormal immuno-globulin production or function. Thus autoantibodiesmay be an important feature in Goodpastures's dis-ease and atopy is often associated with excessive IgEsynthesis. The present discussion, however, will beconfined to two groups of lung diseases, the inter-stitial and obstructive lung conditions.

Interstitial lung diseasesThe interstitial lung diseases are characterised byinfiltration of the interstitium by inflammatory cellsand the development of alveolitis, fibrotic changes,and granulomas. There appears to be a significant"immunological" component to the pathogenesisof these diseases, indicated by the presence ofactivated T lymphocytes and a polyclonal stimulationof immunoglobulin synthesis, including auto-antibodies.34 Sarcoidosis is associated with asignificant increase in serum concentrations of IgAand a significant, though small, increase in serumIgG.12The most striking changes in immunoglobulin

production in interstitial diseases are revealed by theanalysis of lung secretions from patients with theseconditions. Several studies have shown greater IgGand IgA concentrations in bronchoalveolar lavagefluid samples from patients with sarcoidosis than insamples from healthy controls." 12 35 The concen-tration of IgM in lavage fluid in sarcoidosis was alsoshown to be increased in two of these studies"1 35 butwas reported to be similar to that in lavage fluid fromcontrols by Rankin etaL.'2 The increased immuno-globulin concentrations in lavage fluid were related todisease activity since they were observed only inpatients with high intensity alveolitis, l " and clinicalimprovement after corticosteroid treatment was asso-ciated with reduced immunoglobulin concentrationsin lavage fluid.35

Idiopathic pulmonary fibrosis, fibrosing alveolitis,and chronic hypersensitivity pneumonitis were alsoreported to be associated with increased concen-

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trations of IgG and IgA in lavage fluid.36 IgM wasalso increased in chronic hypersensitivity pneu-monitis but no significant increase in IgE concen-trations in lavage fluid were observed. This study alsoshowed a significant reduction in IgG in lavage fluidafter corticosteroid treatment.The increased immunoglobulin concentrations in

the lung secretions of patients with interstitial lungdisease would appear to occur for two reasons. Thefirst is an increase in the transudation of protein fromthe blood, presumably because of inflammationwithin the lung. This conclusion is based on the obser-vation that albumin concentrations in lavage fluid arealso frequently increased in sarcoidosis, "1 12 althoughnot in idiopathic pulmonary fibrosis.36 Secondly,local synthesis of immunoglobulins is likely to resultfrom an increase in synthesis by plasma cells in thelung, including cells within the secretions lining theairways. Although no significant relationship wasobserved between the number of immunoglobulinsecreting cells and immunoglobulin levels inbronchoalveolar lavage fluid from normal subjects, acorrelation was reported for IgG (but not IgA orIgM) in lavage fluid from patients with sarcoidosis. 12Other studies have reported an increase in IgG secret-ing cells in lavage samples from patients withsarcoidosis34 37 and idiopathic pulmonary fibrosis.37The results were not conclusive for other immuno-globulins since Hunninghake and Crystal34 observedan increase in IgM producing cells in lavage samplesfrom patients with sarcoidosis but Lawrence etat37reported no difference in comparison with controls.No increase in IgA secreting cells were found. Inter-estingly, successful corticosteroid treatment reducedthe numbers of IgG producing cells in lavage samplesfrom the patients with sarcoidosis.37 The increasedimmunoglobulin concentrations in lung secretionsfrom patients with interstitial lung disease clearlyresult mainly from local synthesis by plasma cells and,by contrast with the normal lung, a considerable pro-portion of this protein is derived from cells lining theairways. The source of these cells is not known. Thepredominant form (80%) of IgA in bronchoalveolarlavage fluid from subjects with sarcoidosis, however,is monomer."1 Since this represents a higher propor-tion ofmonomer than is present in the normal lung, itwas suggested that the plasma cells responsible forIgA synthesis in the sarcoid lung were recruited fromthe blood." Alternatively, subpopulations of B lym-phocytes already within the lung could be stimulatedin these diseases. This explanation seems less likely inview of the polyclonal nature of the immunoglobulinsproduced.34The reasons for the increased synthesis of immuno-

globulins in patients with interstitial lung diseasesremains obscure. The phenomenon appears to be



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localised specifically to the lung. This is supported bythe observed increase in immunoglobulin concentra-tion and number of immunoglobulin producing cellsin bronchoalveolar lavage fluid samples and by theincrease in numbers ofT helper cells in the lung secre-tions obtained from patients with interstitial lung dis-eases. Furthermore, T cell numbers correlated withimmunoglobulin concentrations and number ofimmunoglobulin producing plasma cells and withdisease activity.3435 Perhaps most important was theobservation that these T cells could induce immuno-globulin synthesis in otherwise unstimulated B cellsfrom the blood of normal individuals.34 The evidenceso far therefore suggests that T cell mediated syn-thesis of immunoglobulins within the lung is a centralfeature of interstitial lung diseases. The mechanismsleading on to lung damage are not yet clear. Furtheridentification of the subpopulations of the immuno-globulins produced in these conditions would beinteresting. This might help to establish whether thereis a functional association between the immuno-globulins, effector cells, and pathological changesseen in the lungs.

Infections and obstructive lung diseaseImmunoglobulin deficiencies are often associatedwith chronic or recurrent pulmonary infections andseveral studies have investigated the immunoglobulinclass or subclass deficiencies in the serum of patientswith these respiratory problems. The frequency ofobserved immunoglobulin deficiencies in thesepatients differ considerably from study to study andwill reflect the groups of patient selected. Forinstance, the frequency of selective serum IgAdeficiency (<50mg/1) in caucasians is 1/300-1/2000but in the Japanese population it is much rarer,having an incidence of only 1/18 000.38 Furthermore,the specificity of the assays used will dictate whetheran immunoglobulin deficiency is detected. Serumdeficiencies of IgG clearly are often overlooked unlessthe IgG subclasses are quantified. For instance,Umetsu et at39 studied 20 children with recurrentsinopulmonary infections who had normal totalserum IgG concentrations. All of these children were,however, deficient in one or more IgG subclass and15% were deficient in IgA. The most frequent IgGsubclass deficiency was IgG2, and this was possiblythe reason for the observed low titres of antibody tothe capsular polysaccharide of Haemophilusinfluenzae in these patients.

Studies in other groups of patients have detectedlower frequencies of immunoglobulin deficiencies inthe serum of patients with recurrent and chronic chestinfections.40 Furthermore, in some patients immuno-globulin concentrations were increased in response to

the microbial antigen challenge.Several factors may explain why immunoglobulin

deficiency has not been detected in many patients withchronic or recurrent infections. Firstly, the recognisedincidence of immunoglobulin deficiency has increasedsince assays for IgG subclasses were introduced.More specific assays for the measurement of IgAsubclasses and antigen specific antibodies mightreveal further causes of infection. Secondly, despitenormal immunoglobulin concentrations, deficienciesin effector cell function may be present in a propor-tion of patients. Thirdly, and relevant to all of thesepossibilities, is the need to quantify the componentsof the immune system in the lungs of these patientsrather than in the serum. Infections are often confinedto the lungs, and thus deficiencies in local immuno-globulin synthesis alone may be a key aetiological fac-tor. For instance, specific sIgA deficiency has beendescribed in patients with normal serum IgA concen-trations.20 The secretory IgA system may therefore beindependent of the systemic IgA system, and thismight also be the case for other immunoglobulins. Atpresent little is known about how the immuno-globulin composition of the lung secretions ofpatients with recurrent or chronic respiratory infec-tions compares with that of normal individuals.The IgA system has been studied in sputum sam-

ples obtained from patients with chronic bronchitis.In those who were not apparently IgA deficient thepresence of a clinical pulmonary infection was associ-ated with significantly increased sputum mIgA anddIgA.3 An appreciable amount of the IgA (bothmonomer and dimer) was locally synthesised, pre-sumably in response to the infecting organisms. Theseresults suggest that the lungs of most patients withchronic bronchitis are capable of mounting an IgAimmune response to infecting organisms, although nocomparison with the healthy lung is yet possible.

Soutar8 reported that patients who had died fromchronic obstructive bronchitis were deficient in IgAproducing plasma cells throughout the respiratorytract, whereas patients with bronchitis who had diedof other causes were normal, which suggests that fatalbronchitis was associated with a deficiency of lungIgA plasma cells. A more recent study reportedincreased IgA plasma cells in the bronchi of patientswith chronic bronchitis.4" The plasma cells were ofboth IgA subclasses but the increase was mainly in theplasma cells producing IgAl. Clearly these differentresults may be explained in part by the study ofdifferent groups of patients. Further studies arerequired, quantifying the IgA and IgG subclasses inbronchoalveolar lavage fluid from patients withchronic obstructive lung disease and comparing theconcentrations with those of normal individuals.Such comparisons will clarify whether immuno-



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globulin deficiencies have a role in the aetiology ofchronic obstructive lung disease.

D BURNETTUniversity Department of Immunology

and Lung Immunobiochemical ResearchLaboratory, General Hospital

Birmingham B4 6NH

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Documents

Editorial Immunoglobulins in thelungThe concentrations of this immunoglobulin in bronchoalveolar lavage fluid suggested appreciable local synthesis, probably by IgE producing plasma