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Immunoglobulins in the Lung

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Immunoglobulins in the Lung Thorax: first published as 10.1136/thx.41.5.337 on 1 May 1986. Downloaded from Thorax 1986;41:337-344 Editorial Immunoglobulins in the lung The lungs are continually exposed to a vast range of meable membrane with respect to proteins in solu- antigenic material. The immunoglobulins of the lung tion. The transudation rate of a protein, and hence therefore have an important role in the neutralisation the secretion concentration, will depend on three fac- of antigens, which leads to cellular processing and tors: the "resistance" of the tissues to protein removal. The lung is undoubtedly a major "immu- diffusion, the plasma concentration of the protein, nological organ" since it contains a considerable and the effective size of the protein. We do not know amount of lymphoid tissue, with the ability to syn- whether the diffusion rate of proteins across the lung thesise immunoglobulins. The analysis of immuno- varies in different anatomical areas, although local globulins in the secretions of the lung has clarified our inflammation undoubtedly results in increased tran- understanding of their origins in this organ but the sudation.' Several proteins in lung secretions are details of the functions of immunoglobulins in the derived exclusively by diffusion from the blood. For lung are not well understood. Nevertheless, the secre- these proteins a correlation is observed between tions lining the airways are likely to be the site where the secretion:serum concentration ratios and their lung immunoglobulin function as a front line of effective sizes (expressed as Stokes' radius).1 Con- defence is most important. For this reason we can be sequently, if the secretion concentration of a protein fairly confident that studies of immunoglobulins in (relative to that in the serum) is higher than predicted lung secretions will be relevant to their significance for this size, simple transduration from the blood is in vivo. not the only source. The second possible source of a protein in the lung Origins of immunoglobulins in lung secretions secretions is local production by cells within lung tis- sues. Synthesis might be effected by cells actually So far our knowledge of the origins of the immuno- within the secretions. Alternatively, proteins may be http://thorax.bmj.com/ globulins in lung secretions has resulted almost synthesised by the epithelium or cells in the lamina entirely from the development of antisera that are propria and then either diffuse or become actively specific for the immunoglobulins and their discrete transported across the epithelium. subpopulations, such as the structural forms of IgA There is now evidence to suggest that, apart from and the immunoglobulin subclasses. These antisera IgD, for which no data are yet available, all the have been used for immunohistochemical studies, immunoglobulins enter the lung secretions by all of which have shown the presence of immunoglobulin these mechanisms. bearing plasma cells in the bronchial mucosa and in the secretions of the airways, thus confirming that IgA on September 26, 2021 by guest. Protected copyright. local synthesis of immunoglobulins does occur at IgA is the predominant immunoglobulin class in lung these sites. Furthermore, the development of specific secretions in contrast to blood plasma, where IgG is and sensitive immunological assays has allowed the found at higher concentrations. Most of the IgA in immunoglobulin composition of lung secretions to be the blood (about 90%) is monomer (mIgA),2 whereas studied in some detail. in lung secretions about halfthe IgA is dimeric (dIgA) In essence, there are two major sources of immu- and most of this is in the form of secretory IgA noglobulins in the lung secretions: (sIgA).3 Two subclasses of IgA, IgAl and IgA2, have Firstly, all the immunoglobulin classes are repre- been distinguished in serum and secretions by the use sented in the blood plasma. Thus a proportion of of specific antibodies. In the blood IgA2 comprises these proteins in lung secretions will be derived from 10-20% of the total IgA but in bronchoalveolar the vascular compartment by diffusion (transudation) lavage fluid samples it represents about 30%.4 These across the lung tissue, which behaves as a semiper- differences in the IgA composition of serum and lung secretions reflect the considerable local synthesis of IgA within the lung, although a proportion of the IgA Address for reprint requests: Dr D Burnett, Lung Immuno- in lung secretions is still derived from the blood by biochemical Research Laboratory, Clinical Teaching Block, General transudation. I Hospital, Birmingham B46NH. Dimeric IgA (dIgA), which is produced by plasma 337 Thorax: first published as 10.1136/thx.41.5.337 on 1 May 1986. Downloaded from 338 cells in the lamina propria, comprises two IgA mole- Since most of the blood IgA is monomeric, a large cules linked by another protein, J chain, which is also proportion of mIgA in lung secretions should, the- synthesised by plasma cells. The dIgA is bound by a oretically, be derived from the plasma by transuda- receptor, secretory component (SC), which is a pro- tion. Nevertheless, lung secretion concentrations of tein inserted in the plasma membrane on the baso- mIgA are also higher than would be predicted if the lateral surfaces of some mucosal epithelial cells. The protein were derived only from the blood.3'1 This dIgA-SC complex on the epithelial plasma membrane suggests that most of the mIgA in bronchoalveolar is thought to be endocytosed, transported in vesicles lavage fluid and sputum is locally synthesised by across the cell, and released at the luminal surface as plasma cells within the lamina propria, although, in sIgA.' contrast to dIgA, monomer is not transported across This SC mediated transport of dIgA has been the epithelium by the SC mediated mechanism. defined mainly in studies of the gut mucosa. The high Immunoglobulin secreting cells are also located in the concentrations of sIgA in lung secretions support the mucosal secretions lining respiratory epithelium but hypothesis that this mechanism also operates in the one study of these cells, obtained by bronchoalveolar lung. Furthermore, immunohistochemical studies lavage, suggested that they do not contribute appre- have shown that SC and IgA are both present on the ciably to the IgA found in secretions.'2 epithelial surface, within vesicles ofbronchial glandu- Further evidence for local IgA synthesis in the lung lar epithelial cells and in the glandular lumen. In con- has been obtained from studies of the IgA subclasses. trast, cilated epithelium stains only faintly for SC and The proportion of IgA present as IgA2 is higher in is negative for IgA.6 This evidence supports the con- lung secretions than in blood plasma.4 This suggests cept of SC mediated transport of dIgA, as sIgA, that the proportion of IgA2 producing plasma cells of across the glandular epithelium of bronchi. Secretory the lung should be higher than that of non-mucosal component and IgA associated with J chain (sug- lymphoid tissue. Immunohistochemical studies using gesting that the IgA is dimeric) have also been located antisera specific for IgAI or IgA2 confirm this predic- on the plasma membrane and within pinocytic invag- tion. In bone marrow, tonsil, and peripheral lymph inations and vesicles of bronchiolar non-cilated epi- nodes 10-20% of the IgA plasma cells produce thelium and type II alveolar cells.7 These results IgA2.13 14 By comparison, 26-33% of the IgA showed that SC mediated transport of dIgA could plasma cells in bronchial mucosa produce IgA2.'3 also contribute appreciably to sIgA in the lower The proportion of IgA2 in blood or lung secretionshttp://thorax.bmj.com/ respiratory tract. therefore reflects the proportion of IgA2 producing IgA producing plasma cells are more abundant in plasma cells in non-mucosal lymphoid tissue and the glands and lamina propria of major bronchi than bronchial mucosa respectively. in the small bronchi, bronchioles, or alveolar sep- tae.78 These observations suggest that most sIgA IgG production should occur in the upper respiratory IgG is the predominant immunoglobulin class in tract. This is supported by a study in dogs that blood and some of the lung IgG is derived from the showed that sIgA concentrations were highest in plasma by transudation. Four subclasses of IgG have secretions from the upper respiratory tract.9 Another been described and each has been detected in bron- on September 26, 2021 by guest. Protected copyright. investigation,'0 which compared the IgA components choalveolar lavage fluid samples from normal sub- in sputum, bronchial washings, and bronchoalveolar jects.'5 In that study IgG subclass concentrations lavage fluid from patients with chronic bronchitis, were related to albumin measurements and the IgG highlighted the major problem with this kind of subclass:albumin ratios in the bronchoalveolar lavage study. The differential dilution of secretions, caused fluid and serum samples were compared. It was con- by sampling techniques, makes comparison ofprotein cluded that IgGI and IgG2 were derived wholly from concentrations in secretions from different levels of the blood because the IgG:albumin ratios were simi- the bronchial tree complicated. lar in serum and lavage samples. This result, however, Plasma cells in the lamina propria are not the exclu- would actually argue in favour of an appreciable sive source of sIgA in the upper or lower respiratory degree of local production of IgGI and IgG2 within tract. About 10% of plasma IgA is dimeric and Hai- the lung since it does not take into account the moto et al7 showed that IgA is present in endocytic different diffusion rates of albumin and IgG through vesicles of capillary endothelial cells, in the inter- biological tissues. Albumin, which has a Stokes radius cellular spaces adjoining endothelial cells, and on (Rs) of 3.5 nm, is smaller than IgG (Rs = 5.1 nm) and basement membrane.
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