lung mucosal immunity iga revisited

7/31/2019 Lung Mucosal Immunity IgA Revisited

1/18

SERIES 0LUNG INFECTION AND LUNG IMMUNITY 0

Edited by M. Spiteri and L.P. Nicod Number 1 in this Series

Lung mucosal immunity: immunoglobulin-A revisited

C. Pilette, Y. Ouadrhiri, V. Godding, J-P. Vaerman, Y. Sibille

Lung mucosal immunity: immunoglobulin-A revisited. C. Pilette, Y. Ouadrhiri, V.Godding, J-P. Vaerman, Y. Sibille. # ERS Journals Ltd 2001.ABSTRACT: Mucosal defence mechanisms are critical in preventing colonization of the respiratory tract by pathogens and penetration of antigens through the epithelialbarrier. Recent research has now illustrated the active contribution of the respiratoryepithelium to the exclusion of microbes and particles, but also to the control of theinammatory and immune responses in the airways and in the alveoli. Epithelial cellsalso mediate the active transport of polymeric immunoglobulin-A from the laminapropria to the airway lumen through the polymeric immunoglobulin receptor. The roleof IgA in the defence of mucosal surfaces has now expanded from a limited role of scavenger of exogenous material to a broader protective function with potentialapplications in immunotherapy. In addition, the recent identication of receptors forIgA on the surface of blood leukocytes and alveolar macrophages provides an additionalmechanism of interaction between the cellular and humoral immune systems at the levelof the respiratory tract.Eur Respir J 2001; 18: 571588.

Unit of Experimental Medicine, Chris-tian de Duve Institute of CellularPathology (ICP), University of Lou-vain, Brussels, Belgium.

Correspondence: Y. Sibille, Unite deMedecine experimentale, 74 avenueHippocrate BP 7430, 1200 Bruxelles,Belgique.Fax: 32 81423352

Keywords: Fc a Rimmunoglobulin-Amucosal immunitypolymeric immunoglobulin receptor

Received: March 22 2001Accepted after revision May 8 2001

C. Pilette is currently Aspirant of theFonds National de la Recherche Scien-tique (Belgium) and Y. Ouadrhiri issupported by the Fondation Lancardis(Switzerland).

Each breath carries in the inhaled air thousands of micro-organisms and microparticles into the respira-tory tract. This exposure appears well tolerated by thehost, which rarely reacts to this continuous stimu-lation. Thus, in normal conditions, the respiratorytract appears to be well equipped to efciently elimi-nate exogenous material without generating a majorinammatory or immune response. The defence of therespiratory tract against pathogens relies on twodistinct mechanisms, located in the airways (upperand lower) and the alveolar space, respectively. In theairways, mechanical defence appears to predominateand includes the deposition on the nasal and oro-pharyngeal surfaces and elimination through cough,sneezing, and mucociliary clearance. In contrast, thealveolar epithelium lacks mucociliary properties andtherefore relies mostly on the alveolar macrophages toremove particles and micro-organisms reaching thealveolar space [1]. In addition, the respiratory tractcan also call on several protective mechanismswhenever required (table 1). For example, the con-tribution of polymorphonuclear neutrophils (PMNs)to the defence of the lung against bacterial infection iswell recognized [2], and recent research has elucidatedimportant mechanisms of recruitment and activationof PMNs at sites of infection. Another area of

research where major progress has been madeconcerns the epithelial cells. Thus, the bronchialepithelial cell which has long been recognized as akey element of the mucociliary system is now alsoconsidered as a pivotal cell in the control of inammatory and immune responses against patho-gens and biotoxics. The respiratory epithelium is ableto initiate and perpetuate an inammatory reactionin response to a variety of stimuli. In particular,bronchial epithelial cells produce interleukin (IL)-5,IL-8, regulated on activation, normal T-cell expressedand secreted (RANTES), and growth factors such asgranulocyte macrophage-colony stimulating factor(GM-CSF), all implicated in attraction and/or activa-tion of inammatory cells [3]. Interestingly, IL-8, themost potent neutrophil chemoattractant, is releasedby bronchial epithelial cells in response to bacterialproducts [4]. In addition, the epithelium can proba-bly participate in the immune response at an earlystage after antigen deposition. This participation canoccur since epithelial cells are recognized as antigen-presenting cells, both in the respiratory and digestivemucosa. Also, while it is well accepted that inam-matory mediators such as oxidants and proteases candamage the airways, conversely, it is likely thatremodelling of the bronchial structures (as observed

Eur Respir J 2001; 18: 571588Printed in UK all rights reserved

Copyright # ERS Journals Ltd 2001European Respiratory Journal

ISSN 0903-1936


2/18

in chronic disorders such as asthma, chronic bron-

chitis or cystic brosis) could modify the response of the host against inhaled pathogens and toxins.Although lymphocytes are scarce in the normal

airway and alveolar lumen, they are detected in thesubmucosa of the bronchi and when they areabundant, such as in some pathologies, they are some-times organized in lymphoid tissue called bronchus-associated lymphoid tissue (BALT). A part of theirrole is related to the mucosal humoral immuneresponse and more specically to the production of immunoglobulin (Ig)-A. The defence mechanisms of the bronchial tree and lung parenchyma againstinfection, often associated with an inammatory orimmune response, have been the topic of extensivereviews and of several workshops [5]. However, themost recent information on the role of the mucosalhumoral immune system (namely the secretory IgAsystem) has rarely been addressed in the literaturedevoted to the lung. Therefore, the present review willfocus on the secretory IgA system, considering boththe properties shared with other mucosa and thosemore specic to the respiratory tract. This appears tobe of great importance when considering that IgA, themost abundant Ig in the mucosal uids, can alsointeract with phagocytic cells. The rst part willdiscuss the different steps and mechanisms of IgAproduction, transport, and activity, while a secondpart will consider more specically the functions of

IgA in mucosal tissues. The last part will be devotedto the putative roles of the mucosal IgA systemin respiratory disorders, both considering pathophy-siological aspects and potential therapeutical inter-ventions.

Organization of the mucosal immunoglobulin-Asystem

Immunoglobulin-A structure and distribution

IgA [6] not only represents the predominant Ig insecretions, but has unique characteristics notably dueto its association with a " transport piece " [7]. IgA ismuch less abundant in serum than IgG, but itscatabolism is four-eight-fold faster (considering,respectively, monomeric and polymeric IgA). Thus,homeostasis of serum IgA requires a synthesis ratequite similar to that of IgG (21 mg ? kg -1 ? day -1 for IgAversus 30 mg ? kg -1 ? day -1 for IgG). By contrast, inthe various mucosa and exocrine glands, IgA produc-tion is much higher than IgG and, considering bothvascular and mucosal compartments, the daily IgAproduction appears thus quantitatively much moreimportant than its IgG counterpart [8]. The secretoryIg system is characterized by a close cooperationbetween the mucosal lymphoid tissue, which assumesa continuous and adaptive production of Ig (mainlypolymeric IgA) and the epithelium, which allows thetransport of polymeric Ig (pIg) within the mucosallumen through the polymeric Ig receptor (pIgR) [9].Thus, the majority of polymeric IgA (pIgA) and IgM(pIgM) produced at these sites is transported acrossepithelia into the luminal environment, where secre-tory Ig is thought to inhibit adherence of noxious

micro-organisms and antigens to the epithelium,performing a so-called " immune exclusion " . Similarly,innocuous antigens seem ignored by the immunesystem through unclear mechanisms related to a" mucosal tolerance " . These mechanisms provide anefcient " rst-line " of defence of the 400 m 2 surfacearea of mucosa (100 m 2 for the lung, excluding thebronchial tree), preventing the development of apotentially damaging inammatory response.

The molecular heterogeneity of IgA in serum andsecretions (reviewed in [10]) is mainly related to itspolymerization state. Serum IgA in humans andprimates consists mostly of monomeric IgA (88%),which is produced by bone marrow plasma cells, and

its concentration in serum is about ve-fold lowerthan that of IgG. By contrast, mucosal plasma cellsproduce mostly pIgA (80%, mainly dimeric), which isthe predominant form of IgA in secretions. Themajority of pIgA in secretions is associated with thesecretory component (SC) from epithelial origin toform secretory IgA (SIgA). Another differencebetween the serum and secretory pools of IgA is arelative increase of the IgA2 isotypic form in secre-tions (especially in the large bowel, but also in thebronchi) as compared to serum. IgA2 lacks most of the hinge region and therefore appears less susceptibleto degradation by bacterial IgA-proteases (see later).Finally, IgA2 has two allotypic variants, namely

Table 1. Defence mechanisms of the respiratory tract

Upper respiratory tract (nose, oropharynx, larynx)Mechanical

Nasal hairs and sneezingNasal, oropharyngal and sinusal ciliated epitheliumSaliva, mucusVocal cords

Innate immunityComplementProteasesLactoferrin

Acquired humoral immunitySecretory immunoglobulin (Ig-A and IgM

Lower respiratory tract (tracheobronchial tree)Mechanical

Mucociliary clearanceCough and impaction on bronchial branching

Acquired cellular immunityBronchial-associated lymphoid tissue (BALT)

Humoral immunitySecretory IgA and IgM

Lung parenchyma (alveoli and lung interstitium)Surfactant products (SP-A, SP-B, SP-D)Phagocytic cellular mechanisms

Resident alveolar macrophagesPhagocytosisOxygen and nitrogen metabolitesLysozyme, acid hydrolases

Recruited polymorphonuclear neutrophils(from pulmonary microvessels)PhagocytosisOxygen and nitrogen metabolitesLactoferrin, defensins (human neutrophil

peptides 14)Bacterial/permeability increasing proteinCationic antimicrobial protein (CAP/azurocidin)

572 C. PILETTE ET AL.


3/18

IgA2m(1) and IgA2m(2), predominating in Cauca-sians and Africans, respectively. A third IgA2 isotypicform possibly exists on a genetic basis, but this proteinhas not yet been isolated.

Monomeric IgA (mIgA) is constituted by two lightchains ( k or l ), common with other Igs, associatedcovalently with two specic heavy chains ( a chains).An exception is constituted by IgA2m(1), in whichlight chains form a covalent dimer, noncovalentlylinked to the heavy chains. The a chain comprises fourdomains, as for IgG or IgD, and a unique 18 aminoacid (aa) carboxyl terminal polypeptide called secre-tory tail piece ( a tp). This tp includes a penultimatecysteine involved in disulphide bonding with thehomologous cysteine of the other a chain, or with acysteine residue of nonimmunological proteins suchas albumin or a 1-antitrypsin. Monomeric IgA has amolecular weight of 160 kDa and a sedimentationcoefcient of 7S. pIgs are characterized by a highvalency of antigen binding sites ( 4), which lead to agreat agglutinating capacity of micro-organisms, andby the association with a small 15 kDa polypeptidecalled the joining chain (J-chain) produced concomi-tantly with pIgs by mucosal plasma cells. This J-chainincludes cysteine residues implicated in IgA (and IgM)polymerization, and is necessary for the transepithelialtransport of pIgs. More specically, the J-chain is notmandatory for polymer formation, but regulates theirquaternary structure ( " tail-to-tail " model for IgAand ring structure for IgM), which appears to be adeterminant for the binding to the epithelial pIgR[1113]. pIgA is mainly represented by dimeric IgA(335 kDa and 9.5S), whereas higher aggregation states(trimers and tetramers) are also found, usually insmaller proportions. In dimeric IgA, two moleculesof IgA are thus linked " tail-to-tail " by the J-chain that

bridges one tp of each IgA molecule, while theremaining tps are directly disulphide bound [14].These disulphide bonds involve the penultimatecysteines located in position 495 in the a tp, whichplays an important role in the intrinsic tendency of IgA to polymerize. pIgM (900 kDa and 18S) [15]represents the main form of IgM, in which vemolecules of IgM are linked in a ring structure viathe J-chain that bridges the rst to the fth monomer.However, larger polymers of IgM that are devoid of aJ-chain also exist. The heavy chain of IgM ( m chain)also includes a tail piece ( mtp), which is highly similarto that of IgA.

Secretory Igs (SIgs) are formed by the association

of pIgs produced by mucosal plasma cells with theepithelial SC. This association, elaborated duringtransepithelial transport, remains noncovalent forIgM, while a disulphide link is usually formed betweenpIgA (cys 309 , or sometimes denoted cys 311 ) and SC(cys 467 ) [16]. This association with SC was shown toprotect SIgA from proteolytic degradation, althoughthe latter is much less pronounced in the respiratorytract than in the large bowel [17]. In addition,nonsecretory Igs such as mIgA, IgG, IgD or IgE canalso reach secretions, mostly by passive diffusionthrough the endothelial and epithelial tight junctionsfrom submucosal blood capillaries, or from locallyinltrating plasma cells producing these monomeric

Igs. Moreover, these monomeric Igs might be cotrans-ported via the pIgR, concomitantly with an immunecomplex involving at least one pIg.

In the gut, an abundant commensal bacterialmicroora supports a relatively high proteolyticactivity. SIgs and especially SIgA appear moreresistant to proteolysis than the other Ig isotypes bytheir unique structure. Nevertheless, virulent strains of Streptococcus pneumoniae or Haemophilus inuenzaecan produce bacterial IgA-specic proteases thatspecically cleave the hinge region of IgA1 to produceantigen-binding and crystalline fragments (Fab andFc, respectively) [18], and this could facilitate thedevelopment of infections including in the respiratorytract. Other less classical enzymes, notably from Gramnegative bacteria such as some Pseudomonas andProteus spp., can cleave serum and secretory IgA1 andIgA2 outside the hinge region. These latter proteaseshave a broader specicity, sometimes also cleavingIgG. Importantly, these bacterial IgA1-proteases areresistant to inhibition by plasma protease inhibitors(such as a 1-antitrypsin or a 2-macroglobulin), butsome can be inactivated by specic neutralizingantibodies present in serum and/or secretions.

Immunoglobulin-A production

Mucosal lymphoid organization. Mucosa-associatedlymphoid tissues (MALTs) are organized lymphoidtissues in close relationship with surface and glandularepithelia to constitute both inductive and effector sitesof mucosal immune responses. Inductive sites (tonsils,adenoids as nasal-associated lymphoid tissue (NALT),BALT, and Peyer 9 s patches and appendix/colonic-

rectal solitary follicles as gut-associated lymphoidtissues (GALT)) are characterized by several follicleswhere B-cells are preferentially found and contain,after antigenic stimulation, secondary germinal centres.These follicles are surrounded by more diffuse lym-phoid tissue (extra-follicular area or T-cell zone) andtheir luminal side (often called " dome " ) is covered bythe so-called follicle-associated epithelium, which con-tains microfold cells (M-cells) sampling the antigenicluminal content. MALTs lack afferent lymphatics,which are replaced by specialized high endothelialvenules. Conversely, effector sites are represented bythe diffuse lamina propria of the different mucosa andexocrine glands, also in striking relationship with the

epithelium. Although mucosal and systemic immunesystems do not appear totally segregated, MALT hassome specic features such as a large predominance of IgA-producing immunocytes.

Several characteristics of the MALT were demon-strated in studies mainly related to the gut, althoughmost of them probably also apply to the respiratorytract. However, a major difference between the airwayand digestive mucosa is that MALT and M-cells arevirtually absent from the normal respiratory tract [19].Thus, the organization of the MALT, includingM-cell epithelial differentiation is probably inducedonly when airway and lung tissues are exposed to anincreased antigenic load.

573MUCOSAL IMMUNITY IN THE RESPIRATORY TRACT


4/18

B-cell priming in inductive sites. Naive B-lymphocytesenter through high endothelial venules by a multistepprocess of extravasation into inductive sites (reviewedin [20]). There, they are primed in extra-follicular areasby local CD4 z T-cells, which are activated byinterdigitating antigen-presenting cells (APCs) thathave processed a luminal antigen [21]. The surface (s)IgD z IgM z CD38 z (where z represents positive ex-pression of a given marker) B-cells, primed via theseinteractions referred to as " rst signals " , produce anunmutated IgM which can bind the antigen with a lowafnity, generating soluble immune complexes that,in contact with follicular dendritic cells, are thoughtto maintain B-cell memory [22]. Surface IgD z IgM z -CD38 z primed B-cells migrate specically in the darkzone of germinal centres where they proliferate as" founder " Ki-67 z centroblasts. These " founder cells "

are characterized by somatic hypermutation of their Igvariable region genes. This process of hypermutationleads to the expression of an IgM of high afnity for theantigen that rescues these cells from CD95-inducedapoptosis by cognate interactions with folliculardendritic cells expressing the processed antigen. More-over, via this high afnity IgM, centroblasts can pickup the antigen and present it to follicular CD4 z T-cells.This interaction requires an additional CD40-CD40ligand interaction. Finally, activated centroblasts giverise to B-cells that will lead to Ig-producing cells, after aterminal differentiation phase occurring in secretoryeffector tissues.

B-cell terminal differentiation. Antigen-specic B-cellseither lead to memory B-cells (sIgD -IgM z CD38 -B7z

B-cells) or initiate isotype switching of their heavychain constant region (C H ) gene from C m todownstream isotypes. This isotype switching, which

is associated with high CD38 expression and clonalproliferation, constitutes the terminal phase of B-cellmaturation into Ig-producing immunocytes. The" second signals " inducing these events remain poorlydened, but are probably provided by micro-environmental factors such as cytokines released byepithelial or mononuclear cells, and/or cell-to-cellinteractions with dendritic cells, as well as topicalantigenic exposure (especially in the colon or con- junctiva). Thus, the presence of commensal bacteriaplays an important role, since intestinal (and probablybronchial) mucosa from germ-free mice is almostdevoid from IgA-producing immunocytes [23]. Assupported by the partial IgA deciency observed in

TGF b1-decient mice [24], TGF- b has been shown tobe a crucial cytokine for IgA switching ( " switchfactor " ), whereas IL-2, IL-5, and especially IL-10 areimportant (in humans) for clonal proliferation of activated B-cells and terminal differentiation into Ig-producing cells. However, the precise reason why IgA-producing immunocytes represent the predominantmucosal mature plasma cell [25] remains obscure.Moreover, whereas IgA1 represents the predominantisotype, a relativeincrease of IgA2expression character-izes mucosal as compared to systemic Ig-producingcells. Alternatively, for IgG-producing mucosal cells(representing about 3 and 20% of the Ig-producing cellsin the gut and bronchi, respectively), the predominant

isotype is IgG1. Moreover, IgG3 z cells are morefrequent than IgG2 z cells in the upper airways, incontrast with the distal gut. IgE-producing plasma cellsare virtually absent, except in the mucosa from someallergic patients. Precursors of IgD-producing cells aregenerated from activated centroblasts characterizedb y a C H gene deletion of C a and C m, leading toSIgD z IgM -CD38 z cells. This particular subset of centroblasts is frequently found in the upper aero-digestive tract, possibly related to the presence at thislevel of bacteria such as H. inuenzae or Branhamellacatarrhalis producing an IgD-binding protein that cancross-link SIgD. Interestingly, since 90% of IgA z (andmost IgM z ), as well as 40100% of IgG z and IgD z

mucosal immunocytes are also J-chain z , J-chainexpression represents a relatively early marker of MALT-specic B-cells and thus appears closely relatedto the homing within the mucosal B-cell system.

Lymphoid recirculation and mucosal homing. Lymphoidrecirculation and mucosal homing is reviewed in [26]and [27]. The majority of IgA plasma cells have a half-life of 5 days (as shown in the mouse gut); therefore acontinuous supply must be guaranteed by a dailymigration and maturation of B-cells into mucosaltissues. Repopulationstudies have clearly indicatedthatmucosal effector immunocytes are largely derived fromB-cells initially induced in MALTs. Moreover, aregional specicity characterizes this mucosal homing,since primed B-cells migrate preferentially into effectortissues corresponding to the inductive site where theyhave been initially stimulated [28]. Further studiesestablished that this specic mucosal homing issupported by specic cell-to-cell interactions betweenB-cells and endothelial cells in venules of the para-follicular areas (inductive sites) or of the lamina propria

(effector sites). The interaction between a 4b7 integrinexpressed by mucosal B- and T-cells and mucosaladdressincellularadhesionmolecule-1 (MadCAM-1, or" mucosal homing receptor " ), expressed by mucosalendothelial cells from high endothelial venules [29], hasbeen shown to support in the gut, both the attractionof naive B-cells in inductive sites and emigration of primed B-cells in effector tissues. More specically, theformer is characterized by the interaction betweena 4b7 integrin associated with L-selectin (CD62 ligand)and a MadCAM-1 molecule with a modiedO-glycosylation pattern (g. 1), while the latter invol-ves the interaction between a 4b7 integrin (withoutL-selectin) with unmodied MadCAM-1. Othergeneral

leukocyte-endothelium interactions might also beimplicated, such as those between leukocyte functionassociated molecule (LFA)-1 ( a L b2 integrin, CD11a/CD18) and intercellular adhesion molecule (ICAM)-1or -2,or between very late antigen (VLA)-4 andvascularcell adhesion molecule (VCAM)-1. The molecularinteractions underlining the specicity of B-cellmigration to the airway and lung mucosa remainunprecised, since a 4b7 is well expressed in the airways,but MadCAM-1 is only very weakly expressed by thebronchial endothelium.

Different chemokines released by resident cellsregulate the cell trafcking in mucosal tissues. Afterextravasation, immune cells are directed towards the



5/18

different lymphoid microcompartments by specicchemoattractants such as B-lymphocyte chemoattrac-tant (BCA)-1, a CXC chemokine attracting B-cells,and secondary lymphoid tissue chemokine (SLC, orExodus-2), a CC chemokine mainly for T-cells [30]that upregulates the binding of a 4b7 integrin zlymphocytes to MadCAM-1 z endothelial cells, asshown in the gut. Several other mediators have beenimplicated in the attraction of naive immunocompe-tent cells into mucosal tissues, such as macrophageinammatory protein (MIP)-3 a (Exodus-1) and 3 b(Exodus-3) or stromal cells derived factor (SDF)-1 a .Emigration of activated B-cells from germinal centresis probably directed by Ebstein-Barr Virus (EBV)-induced molecule-1 ligand chemokine (ELC) [31].These molecules act on receptors expressed at thesurface of B-cells (or T-cells), such as CXCR-5 forBCA-1 and CCR-7 for SLC. CXCR-5 (and CCR-4)is upregulated on activated CD4 z T-cells, T-helper(Th)1 cells preferentially expressing CCR-5 andCXCR-3 while Th2 preferentially express CCR-3 (oreotaxin R). CD8 z T-cells are probably directed intomucosal tissues by similar signals. Finally, extracel-lular matrix proteins such as bronectin, as well as theorientation of reticular bres, could also play animportant role notably through interactions with a 4b7(or a 4b1) integrins.

In addition to the regional specialization, themucosal homing of activated B-cells is character-ized by a dichotomy between the upper aerodigestivetract and the gut, since the migration of NALT- orBALT-induced B-cells to the gut is negligible in terms

of generating SIgA antibodies [32]. This dichotomycould be related to differences in the adhesionmolecules or chemokine proles mentioned above. A" non-intestinal " homing receptor prole might thusallow the selectivity of homing to the airways (and/orto the urogenital tract), such as interaction of a 4b7integrin with VCAM-1 or L-selectin with its counter-receptor. It is likely that future studies will addressand hopefully unravel the mechanisms associated withthe lymphocyte homing into the respiratory mucosa.

Putative roles of the epithelium in mucosal immunoglobulin production. The epithelial surfaces representthe putative site of initial antigen encounter. Solubleluminal antigens are probably picked up through theepithelium and further removed from the laminapropria by poorly stimulating dendritic cells. In thegut, luminal particles are preferentially taken up by

specialized follicle-associated epithelial M-cells, whichare in striking contact with APCs. By contrast, sinceM-cells have not been identied in the normalrespiratory mucosa, the fate of antigens in the air-way lumen remains unknown. In addition, both in theairways and in the gut, epithelial cells can provide" second signals " promoting terminal differentiation of B-cells oriented towards IgA production since they canproduce different cytokines involved in this processsuch as TGF- b , IL-5 or IL-10 [33]. In this regard,T-cells are probably not the main source of the cyto-kines regulating IgA-commitment since IgA productionhas been shown to be CD4-independent. The epithe-lium seems thus implicated in most of the different

Endothelial cells

High endothelialvenule

CXCR5 CCR-7

Lymphocyte

LFA-1L-selectin

Mad CAM-1

4 7 integrin

BCA-1 SLC/6CK

ICAM-1, 2

Fig. 1. Lymphocyte-endothelial cell interactions in high endothelial venules, as identied in gut-associated lymphoid tissues (Peyer 9 spatch). Interaction between a 4b7 integrin associated with L-selectin and mucosal addressin cellular adhesion molecule (MadCAM)-1 isrequired for the mucosal homing of naive lymphocytes in the gut. The other leukointegrin, leukocyte function associated molecule (LFA)-1, interacts with intracellular adhesion molecule (ICAM)-1 or -2 on endothelial cells. The B-lymphocyte chemoattractant (BCA)-1chemokine attracts in mucosal lymphoid tissues CXCR-5-expressing B-cells, while secondary lymphoid tissue chemokine (SLC)/6CKattracts T-cells through activation of the CCR-7 chemokine receptor.



6/18

processes of the mucosal defence including thehumoral immune response. Similarly, recent data,including that from studies of the respiratory tract,suggest that the epithelium plays a key role inthe pathogenesis of various inammatory mucosaldisorders [33].

Immunoglobulin-A transport

The receptor for pIgs (namely pIgA and IgM) isexpressed by mucosal epithelial cells and was initiallyidentied in its soluble form in secretions, hence called" transport piece " and more recently SC. Several linesof evidence indicate, both directly and indirectly, thatpIgR, identical to transmembrane SC [9], mediates thetransport of pIgs produced in the lamina propriaacross epithelium into the mucosal lumen. This repre-sents the most active and widespread transcellularprotein transport system in the body.

Polymeric immunoglobulin receptor expression. ThepIgR is expressed on the basolateral pole of epithe-lial cells, mainly of the serous type in the gut [34],whereas mucous and ciliated cells also express thissurface receptor in bronchi, although to a lesser extentthan the serous phenotype [35, 36]. The human pIgR/SC consists in a 100 kDa heavily glycosylated proteinof 693 aa which comprises a 18 aa N-terminal signalpeptide (encoded by two exons), ve Ig-like domainsD1D5 (encoded by four exons), and a sixth extra-cellular domain, followed by a membrane-spanningsegment (23 aa) and a highly conserved cytoplasmictail (103 aa), all encoded by 5 exons [37] (g. 2). The19-kb human pIgR gene, which thus includes 11 exons,

is located in chromosome 1 (single locus 1q31q41)and gives rise to a 3.8 kb messenger ribonucleic acid(mRNA) transcript without alternative splicing. ThepIgR promoter region has also been characterized [38,39] and includes putative binding sites for transcriptionfactors such as interferon (IFN)- c stimulation responseelements (ISREs), binding sites for activating protein(AP)-1 and nuclear factor (NF)- kB, as well as forsteroid hormones. The constitutive expression of pIgRappears dependent on a composite site formed by anE-box associated to a partially overlapping invertedrepeat sequence. Three types of deoxyribonucleicacid (DNA) response elements in the pIgR gene areinvolved in the pIgR expression inducible by cyto-

kines: three ISREs (two in the upstream region andone in exon 1) implicated in the response to IFN- c[39] as well as more weakly to TNF- a [40], a 570 bpregion in intron 1 as response element to IL-4 andTNF- a [41], and steroid response element(s) in exon 1for glucocorticoids and androgens.

The epithelial expression of pIgR appears thusupregulated in vitro by different cytokines, especiallyby IFN- c both on intestinal epithelial cell lines [42]and the bronchial epithelial cell line Calu-3 [43], as wellas on primary bronchial epithelial cells [44], by inter-acting with specic receptors expressed restrictivelyon the basolateral pole of these cells. Synergisticallywith IFN- c , IL-4 upregulates SC expression on HT-29

colon carcinoma cells [42] and Calu-3 cells [45], whilethe effects of these cytokines appeared additive on IgAtransport. TNF- a and IL-1 b also enhance SC expres-sion, but to a lesser extent than IFN- c. Although forsome authors [46], the increased SC expression is onlypartially ascribed to IFN- c , the observation that SCupregulation is abolished by blocking IFN- c activityin supernatants from stimulated intestinal mono-nuclear cells suggests that IFN- c is the predominantupregulator of pIgR/SC expression [47]. The mechan-ism of pIgR upregulation by IFN- c , which is trans-criptional and also dependent on de novo proteinsynthesis, has been clearly elucidated (reviewed in[48]). IFN- c recruits via its membrane receptor SignalTransducer and Activator of Transcription (STAT)-1that once phosphorylated and dimerized, stimulatesthe transcription of IFN- c regulatory factor (IRF)-1that binds to the ISRE in exon 1 of the pIgR gene topromote its transcription. The drastic decrease of SCexpression in intestine from IRF-1 decient mice [49]is consistent with the important role of IRF-1 inmediating the stimulatory effect of IFN- c on SC genetranscription. Although IRF-1 is also induced byTNF- a , this cytokine exerts its effect mainly througha response element in intron 1 of the pIgR gene.Moreover, conversely with the observations of BLANCH et al. [49], ACKERMAN et al. [50] found thatthe level of IL-4- or IFN- c-induced IRF-1, correlatedonly weakly with that of SC mRNA, indicating that

D3

D2

D1

D4

D5Extracellular

* Site cleavage(arg585) *

Cell membrane

Intracellular

Basolateral targetingSer655

COOH

NH2 s s

s s

s s

s s

s s s s

s s

s s s s

s s

Fig. 2. Schematic structure of the human polymeric immuno-globulin (pIg) receptor (pIgR)/secretory component (SC) protein.The extracellular part of the pIgR consists in ve domains(D1D5) with Ig-like loops formed via disulphide bonds (-S-S-).Additional disulphide bonds are found within the different loops,except in D2. The binding of pIgA implicates the rst extracellulardomain (D1), while D5 is involved in the covalent bridge withpIgA. SC is the released product of pIgR, the cleavage of pIgRoccurring just upstream of the transmembrane segment after anarginine (in position 585), which thus constitutes the last carboxy-terminal amino acid of SC. The cytoplasmic tail includes aphosphorylated serine (in position 655) regulating the basolateraltargeting of the pIgR (adapted from [48]). COOH: carboxylic acid.



7/18

IRF-1 independent pathways may be involved in theregulation of pIgR gene transcription by cytokines.

Mechanisms and regulation of transcytosis. The mecha-nisms and regulation of transcytosis are reviewed in[48] and [51]. After pIgR is synthesized in roughendoplasmic reticulum as a 90100 kDa precursorprotein, it matures to 100120 kDa after glycosylationin the Golgi complex. A basolateral targeting sequencedirects its delivery from the TransGolgi Network to thebasolateral membrane where it can eventually bind aJ-chain-containing pIg. This sequence is representedby 17 aa comprising a serine (ser 655 , in human pIgR)which inhibits the basolateral targeting when phos-phorylated [52]. The binding of pIgA to pIgR isinitiated by a noncovalent interaction between a loopregion of the third constant domain of IgA (C a 3) and aconserved sequence in D1 of the pIgR [53]. In contrastwith IgM, a covalent disulphide bond is formed duringtranscytosis and stabilizes the pIgA/pIgR complex(cys 311 in C a 2 andcys 467 in D5 of pIgR) [16]. The pIgR,either unbound or complexed with a pIg, is endo-cytozed, since two tyrosine-based signals direct it toclathrin-coated pits [54], and delivered to basal earlyendosomes. Under resting conditions, nearly half of the receptor pool is recycled to the basolateral mem-brane, while 30% is transcytozed in microtubularstructures and trapped in apical vesicles withoutbasolateral recycling, to reach the apical membrane.There, the pIgR is released as the SC by a leupeptin-sensitive proteolytic cleavage [55] just upstream fromthe membrane-spanning segment (after arg 585 ) [56], butthe identity of the implicated protease(s) remainsunknown. The cleavage releases J-chain-containingpIgA, covalently linked to SC to generate SIgA,whereas IgM is noncovalently complexed to SC to

form SIgM. Moreover, since some uncomplexed pIgRsare transcytozed and released, unbound (free) SC isalso found in secretions (g. 3).

The transport of pIgs may be upregulated by anincrease of the pIgR transcytotic rate, independentlyof the level of pIgR expression. Activation of phos-pholipase C (PLC)-dependent intracellular signals,such as intracellular calcium increase or protein kinaseC (PKC) activation, can lead to stimulation of pIgRtranscytosis and SC release. Thus, phorbol-myristate-acetate (PMA)-induced translocation of PKC a (ande) stimulates the pIgR transcytosis and its apicalrecycling and cleavage in pIgR-expressing MadinDarby Canine Kidney (MDCK) cells [57], and this

effect is independent of Ser655

phosphorylation.Transcellular routing of pIgR can also be enhancedby calmodulin that binds, in the presence of calcium,to the basolateral targeting signal of pIgR [58]. Otherintracellular pathways may also be implicated, such asthe phosphatidyl-inositol 3 kinase (PI-3K) pathway,since wortmannin, a PI-3K inhibitor, downregulatespIgR transcytosis by increasing its basolateral recy-cling after endocytosis. Finally, in contrast withhuman pIgR, the rabbit pIgR complexed with itsligand appears transcytozed faster than the unoccu-pied receptor. A stimulation of the rabbit pIgRdelivery from apical endosomes to apical membranemediates this ligand-induced upregulation of pIgR

transcytosis, through an intracellular calcium in-crease, dependent on a tyrosine kinase (TK), furtheridentied as p62 yes tk [59], a nonreceptor TK of thesarcoma (src) family.

Immunoglobulin-A leukocyte receptor

Identication and characterization of immunoglobulin-Aleukocyte receptor. In addition to their importantdirect role of antigen binding in humoral immunityagainst infectious agents such as bacteria and parasites,Igs can also initiate and regulate the development of myeloid immune responses through isotype specic Igreceptors, designated FcR. Twenty years ago, surfacereceptors for IgA designated Fc a R were identied onmyeloid cells. Fc a R, like Fc cR (IgG receptors), Fc eR(IgE receptors), Fc mR (IgM receptors), and Fc dR (IgD

receptors), are involved in antigen-antibody complexrecognition by various cells of the immune system.Fc a R recognizes the Fc portion of IgA and trigger cellresponses, which, under appropriate conditions, usethe same transduction pathways as antigen receptors[60]. In contrast to Fc cRs and until now, only oneFc a R called CD89 has been cloned from the humanmonocytic cell line U937 [61] and its cellulardistribution has been characterized by the use of mono-clonal antibodies against the CD89 cluster [62]. Fun-ctional but heterogenous Fc a Rs have been describedto be expressed on monocytes/macrophages [6366],myeloid cell lines [66, 67], neutrophils [68, 69],eosinophils [70], mesangial cells [71], and probably

Transcytosedvesicle

Endocytosis

plg receptorplgA plasma cell

RER

GOLGI

SIgASC

Fig. 3. Polymeric immunoglobulin (pIg) receptor (pIgR)-mediated transcytosis of pIgA. The epithelial receptor for pIgs,synthesized in the rough endoplasmic reticulum (RER) andheavily glycosylated in the Golgi apparatus, is directed to thebasolateral membrane where it can bind its ligand (mostly pIgA).The pIgR/ligand complex is endocytozed in clathrin-coated vesi-cles. While a signicant pool of pIgR is recycled to the cell mem-brane (not shown), about 30% of the pIgR pool is transcytozed inbasal conditions by a microtubular-dependent mechanism towardsapical vesicles. The pIgR/pIgA complex is released after cleavagefrom the apical membrane into the mucosal lumen as secretoryimmunoglobulin-A (SIgA), while free secretory component (SC) isgenerated from the constitutive transcytosis of uncomplexed pIgR.



8/18

on certain lymphocyte populations [72]. The dataconcerning the expression of Fc a R on lymphocytesand on mesangial cells are somewhat contradictory.K ERR et al. [72] have demonstrated that B- but notT-lymphocytes bind IgA. An IgA receptor could,however, be induced on T-lymphocytes by mitogen orantigen stimulus. Nevertheless, this receptor is dif-ferent from the CD89 myeloid receptor, as none of themonoclonal antibodies recognizing CD89 bind toT-lymphocytes [72] and recently, P HILLIPS QUAGLIATAet al. [73] demonstrated the presence on T-lymphocytesof an IgA receptor that is more related to the epithelialpIgR than to the CD89 myeloid Fc a R. For mesangialcells, the presence of an IgA receptor and Fc a R mRNAhas also been reported [71]. However, the lack of sur-face expression of CD89 on cultured mesangial cells,theinhibition of IgA binding by galactose, and the sizeof this stained protein receptor on sodium dodecylsulphate-polyacrylamide gel electrophoresis appear torule out Fc a R [7476]. Finally, while Fc a Rs appearmostly expressed in PMN, eosinophils and mono-nuclear phagocytes, these receptors have also beenreported to be expressed on mouse hepatic cells [77].

The CD89 gene is localized on chromosome 19(q13.4) [78] and consists of y 12 Kb [79]. The CD89complementary DNA (cDNA) codes for an apparent30 kDa protein with two extracellular Ig-likedomains, a single transmembrane domain and a shortcytoplasmic tail with no known signalling motifs.Fc a Rs are heavily, but variably glycosylated proteinswith apparent molecular masses of 5575 kDa on mono-cytes, macrophages, neutrophils, and 70100 kDa oneosinophils [69, 70]. Enzymatic removal of N-linkedcarbohydrate groups allows the identication of themature CD89 protein,which has a core structure of either 32 or 36 kDa in monocytes, neutrophils and

U937 cells, while only the 32 kDa protein is observedin eosinophils [62, 69]. In human alveolar macro-phages, a core protein of 28 kDa has been described[80]. Thus, human alveolar macrophages seem toexpress an Fc a R different from that of monocytes andgenerated by an alternative splicing of the CD89primary transcript [80]. Indeed, several isoforms of CD89, lacking different parts of the extracellular ortransmembrane/intracellular domain and produced byalternative splicing of Fc a R transcript, have beendescribed in several cells of the myeloid lineage:macrophages [80], neutrophils [81], and eosinophils[82]. However, the surface expression of a differentisoform has only been observed so far in human

alveolar macrophages.Fc a R binds all forms of IgA (monomeric, poly-meric and secretory IgA of both IgA1 and IgA2subclasses). Considering the high level of SIgA insecretory uids, binding of SIgA to Fc a R on phago-cytic cells is of particular interest with respect to thedefence of mucosal surfaces [63]. In addition to Fc a R,SIgA has been shown to bind to an unidentied IgAreceptor on human monocytes and that binding isblocked by galactose [83]. Moreover, a 15 kDa recep-tor for secretory component (SC) and thus also forSIgA has been identied on eosinophils but not onneutrophils [84]. Using different CD89 transfectantcell models, several studies have reported that pIgA

binds more efciently to Fc a R than mIgA [85]. Thesedata suggest that Fc a R probably plays an importantrole in mucosal as compared to systemic immunity,and notably in the clearance of pIgA immunecomplexes, phagocytozed by alveolar macrophagesand/or hepatic Kupffer cells, while it seems very likelythat the clearance of mIgA from the blood occursthrough other mechanisms [72]. The spliced variantsof CD89, which exhibit different characteristics forIgA binding, may contribute to mIgA binding andclearance by phagocytes.

Association of immunoglobulin-A leukocyte receptorwith signalling immunoglobulin leukocyte receptorc -chain. Fc a Rs are expressed on the cell surface inassociation with the FcR c-chain homodimer [8688]which is also associated with the Fc eRI, the T-cellreceptor complex (CD3), the Fc cRI (CD64), and someisoforms of Fc cRII (CD32) and Fc cRIII (CD16) [89].The FcR c-chain is associated to the 19 aa trans-membrane domain of Fc a R where the single positivelycharged arginine residue at position 209 is necessaryfor this physical association [88]. FcR c-chain is neitheressential for the binding of IgA to Fc a R [85] nor toFc a R expression in transfectants [88, 90]. However, theFcR c-chain is essential for Fc a R-mediated recycling(but not endocytosis), and for triggering the increase of intracellular calcium ions (Ca 2z ), antigen presentationand cytokine production [91]. The FcR c-chain alsoplays an important role in targeting Fc a R-bound IgAinto endolysosomal compartments, leading thereforeto its degradation, while c-less Fc a R-expressing cells,including monocytes and neutrophils, recycle theinternalized IgA towards the cell surface. Thisrecycling mechanism could have a physiological

signicance in regard to the homeostasis of serumIgA concentration by decreasing IgA catabolism [92].Although the FcR c-chain is necessary for IgA-induced" outside-in " signal transduction in leukocytes, it is notrequired for cytokine-induced IgA binding toeosinophils. Thus, the binding of IgA to IL-5-primedeosinophils occurs via the intracellular domain of Fc a R, independently of its interaction with the FcRc-chain, through a PI-3K mediated " inside-out "

signalling [93].The FcR c-chain, but not the Fc a R, contains in its

cytoplasmic domain, immunoreceptor tyrosine-basedactivation motifs (ITAMs) that are phosphorylated ontyrosine residues subsequently to Fc a R cross-linking

[88, 94]. Phosphorylation of ITAMs correlates withthe activation of several sets of cytoplasmic proteintyrosine kinases (PTKs) [60]. Src family phosphotyr-osine kinases are the rst set of these PTKs and incontrast to Fc cR, only p56 Lyn kinase seems implicatedin Fc a R/c-chain signal transduction [95]. Phospho-rylation of Src kinases results in the recruitment of p72 Syk family member and Bruton tyrosine kinase(Btk) to the Fc a R/FcR c-chain complex [95, 96]. Thisprocess leads to the phosphorylation and thereforethe activation of further downstream proteins suchas PKC, PLC c [97] and mitogen activated proteinkinases (MAPK). Tyrosine kinases could phosphory-late other intracellular proteins such as phospholipid



9/18

kinases and phospholipases [71]. Signals triggeredfollowing phosphorylation of ITAMs could join thebiochemical pathways generated by other antigenreceptors [60]. These include increased concentrationof intracellular Ca 2z , activation of PKC and raspathways that at the end phosphorylate MAPKs,which activate transcription factors regulating geneexpression (g. 4).

Immunoglobulin-A leukocyte receptor expression and regulation. Different mechanisms regulate Fc a Rexpression according to the type of myeloid cell. Forexample, PMA enhances the expression of Fc a R onmonocytic cell lines, but not on eosinophils, while aCa 2z -ionophore upregulates Fc a R on eosinophilswithout modulating that on monocytes [70]. Several

studies have reported that the expression of Fc a R onleukocytes can be either up- or down-regulated byeither Th1 or Th2 cytokines and endotoxins, but alsoby different agents such as phorbol esters, calcitriol,and ionomycin. Chemotactic peptides such as formyl-methionyl leucyl phenylalanine also increase theexpression of Fc a R on neutrophils, suggesting that

this receptor is stored in intracellular pools on themembrane of secretory vesicles [98]. Cross-linking of Fc a R with IgA upregulates Fc a R expression itself [69,99]. Table 2 summarizes the modulation of Fc a Rexpression in leukocytes [100107].

Several molecules involved in the signal transduc-tion pathways subsequent to Fc a R activation are nowwell recognized. Interestingly, the regulation of Fc a Rexpression can also be modulated by an " inside-out "

signalling which results in either an increased numberof Fc a R on the cell surface and/or a higher afnityfor their ligands. PI-3K and p38 MAPK, but notMAPKinase/ERKinaseKinase (MEK) kinases, playfor example a critical role in the binding of IgA to

IL-4- and IL-5-primed eosinophils [108]. The mechan-isms by which PI-3K and p38 MAPK activate Fc a Rare unknown. However, it is important to outline thatthese two kinases regulate the cytoskeletal reorganiza-tion [109, 110] suggesting, therefore, that cytoskeletalorganization may be determinant for Fc a R activation.Indeed, cytochalasin D-treated eosinophils fail to bindIgA complexes [93].

In addition to its membrane-bound form, Fc a Rexists also in soluble forms [111]. These solublemolecules are produced by alternative splicing of theFc a R primary transcript or by proteolysis of themembrane-associated full length receptor. Recent datasuggest that monocytes could be the major source for

soluble Fc a R as PMN do not release it in vitro [111].Soluble Fc a R can downregulate Fc a R signalling bycompeting for IgA. This strongly suggests that solubleFc a R is biologically active with a potentially bene-cial effect in cases where Fc a R/IgA complexes inducecytotoxicity. Soluble Fc a R may, therefore, have poten-tial therapeutic effects in IgA-mediated disorders.

FcR Cross-linking by IgAImmune complexes

Out

In

NH2FcR (CD89)

COOHITAMs

Fc chain

PhagocytosisRespiratory burstDegranulationCytokine releaseADCC

Outside-in signaling Inside-out signaling

TGF-IL-4IL-5TNF-CD89 expression

Signaling pathway:

?

PI-3K

+p38MAPKPKC

++

ERK1/2 MAPK?

CD89 expression

Ca++

PTKPKCPLCYMAPK ?

+++

Fig. 4. Schematic representation of the leukocyte immunoglobu-lin-A (IgA) crystallisable fragment (Fc) receptor (Fc a R) associatedwith crystallisable fragment receptor FcR c-chain, and the out-side-in and inside-out signalling pathways that regulate functionalaspects of Fc a R and its expression, respectively ( w : increase, v :decrease, : activation). NH 2: amino group; IL: interleukin;TNF- a : tumour necrosis factor- a ; ERK: extracellular signal-regulated kinase; TGF- b: transforming growth factor- b; Cazz :calcium ions; PKC: protein kinase-C; ADCC: antibody-dependentcell-mediated cytotoxicity; COOH: carboxylic acid; Fc c: crystal-lizable fragment- c.

Table 2. Distribution and modulation of the CD89 surface expression on leukocytes

Fc a RCells

Upregulation Downregulation

First author [ref. no.]

Monocytes/macrophages TNF- a , IL-1 b SHEN [100]GM-CSF, LPS S HEN [100]

PMA M ONTERIO [69]Calcitriol, IL-3 B OLTZ -N ITULESCU [101]

IFN- c , suramin S CHILLER [102]TGF- b R ETERINK [104]

PMN GM-CSF W EISBART [105]TNF- a G ESSL [103]

IL-8 H OSTOFFER [98]f-MLP S IBILLE [106]

Eosinophils IL-4, IL-5, GM-CSF B RACKE [107]

Fc a R: leukocyte immunoglobulin-A receptor; TNF- a : tumour necrosis factor- a ; IL: interleukin; GM-CSF: granulocytemacrophage-colony stimulating factor; LPS: lipopolysaccharide; PMA: phorbol-myristate-acetate; IFN: interferon; TGF- b:transforming growth factor- b ; f-MLP: formyl-methionyl leucyl phenylalanine.



10/18

Functions of the mucosal immunoglobulin-A system

The 400 m 2 surface area (300 m 2 and 100 m 2 for thedigestive and lung surfaces, respectively) of mucosacontinuously in contact with both innocuous andpotentially noxious micro-organisms and antigensrepresent a major challenge for the defence system.IgA-dependent immunity is suggested by several linesof evidence to t these particular conditions byproviding, in cooperation with nonspecic innatefactors such as mucociliary clearance, an efcient" rst-line " of defence against external agents withoutinducing a potentially deleterious inammatory res-ponse. The following observations indirectly supportthe fact that SIgs (mainly SIgA) make a largecontribution to this " rst-line " mucosal defence byperforming a so-called " immune exclusion " of infec-tious agents from mucosal tissues. The structure itself of SIgA appears to be a compromise between the highcross-linking capacity of pentameric IgM and thegreat tissue diffusion ability of monomeric IgG. Inaddition, and especially when the rst-line of defenceis encompassed, IgA may recruit the inammatorysystem by activating Fc a R-expressing mucosal leuko-cytes. On the other hand, an immune tolerance isdeveloped towards innocuous antigens encounteringmucosal surfaces.

Protective effects of immunoglobulin-A against infect-ious agents

Several groups have reported an inhibition of theadherence of bacteria such as Escherichia coli to theepithelium by SIgA specic antibodies [112], as well asby free SC. In this respect, it has been shown that

SIgA antibodies have a broader specicity thancomparable serum antibodies, as supported by dele-tions and insertions in the complementary determin-ing regions of Ig variable region genes from mucosalimmunocytes [113]. The relatively high level of polyreactive " natural " SIgA antibodies is probablydesigned to assume immediate protection before anadaptive response is elicited, and thus participates toinnate immunity [114]. SIgA (as well as free SC) hasalso been shown to bind to S. pneumoniae through abacterial surface protein called S. pneumoniae surfaceprotein A: SpsA [115]. Interestingly, Z HANG et al. [116]recently illustrated that the interaction of SpsA withthe pIgR on nasopharyngeal epithelial cells mimics

the infectious process since it initiates adherence andinternalisation of S. pneumoniae and its transcytosistowards the basolateral pole were the bacteria arereleased. This might represent an example of deviationby a pathogen of a mucosal defence mechanism.However, IgA, which was not present in this in vitrosystem might interfere with this process of invasionthrough its binding to the pIgR.

In addition to the putative luminal exclusion of bacteria performed by SIgA, a specic intraepithelialneutralization of viruses (such as inuenza or rota-virus) through interferences with their assemblingprocesses has been demonstrated in pIgR-expressingMDCK cells [117]. Furthermore, it has also been

shown that pIgA present in immune complexes ( i.e.dimeric (d)IgA against dinitrophenyl/bovine serumalbumin complex) can be excreted from the basal intoapical compartment by conuent monolayers of pIgR-expressing MDCK cells. Thus, IgA appears tobe able to neutralize infectious agents or antigens atthe three levels of the mucosal tissues: into the lumen(" exclusion " of bacteria), inside the epithelial cell(" neutralization " of viruses), and in the lamina propria(" excretion " of immune complexes). Other anti-infectious properties of SIgA include induction of aloss of bacterial plasmids encoding molecules relatedto adherence or antibiotic resistance, as well asinterference with growth factors (such as iron) orenzymes required for pathogen growth and invasion.It is probably through these different benecialmechanisms identied in vitro that SIgA antibodieshave been shown in vivo to confer protection to naivemice against oral challenge with Taenia taeniaeformis[118], or that many states of resistance to infection arecorrelated with titres of specic SIgA antibodies [119].

Immunoglobulin-A leukocyte receptor-mediated leuko-cyte response

In addition to the role of neutralization performedin the mucosa by IgA through its Fab fragment, IgA-containing immune complexes also initiate immuneresponses that could play a crucial role in hostdefence, but also in inammatory diseases. Like theother FcRs associated to ITAMs, cross-linking of Fc a R via Fc fragments of IgA triggers several bio-logical responses which seem to be dependent on thecell type in the myeloid lineage. These responses,which are generally mediated by Ca 2z mobilization

and PKC activation [97], include phagocytosis of IgAimmune complexes [120, 121], antibody-dependentcell-mediated cytotoxicity [120], killing of IgA-opsonized bacteria and parasites [122124], and pro-duction of reactive oxygen intermediates [64, 125,126], inammatory mediators and cytokines [127], aswell as leukotrienes and prostaglandins [128]. Cross-linking of Fc a R by IgA complexes on monocytesinduces an increased production of TNF- a , IL-1 b andIL-6 [99, 128130]. Activation of Fc a R may, thus,result in enhanced production of cytokines, whichcould modulate inammatory immune responses andtissue inltration by PMN. The interaction of IgA,and in particular SIgA, with Fc a R is also of critical

importance in the protection of the epithelial immunebarrier. Human IgA can mediate both phagocytosisand postphagocytic intracellular events. This is a rele-vant effect, especially at mucosal surfaces where theinammatory response and released cytokines follow-ing bacterial adherence and/or invasion can stimulateboth Fc a R expression and phagocytosis of IgA-opsonized particles by PMN [131]. Fc a R also playsan important role in eosinophil degranulation [132]and killing of parasites such as schistosomes [124]. Inaddition, eosinophils may also bind SIgA via a specicreceptor for SC and therefore constitute potential can-didates in host mucosal defence against parasite inva-sion. Moreover, it was also shown that SIgA induces



11/18

the degranulation of human basophils after primingwith IL-3 [133], although no receptor for IgA has beencharacterized so far on basophils or mast cells.

The triggering of Fc a R by IgA is not exclusivelyassociated with the activation of proinammatoryprocesses such as cytokine release and oxidativemetabolism. Several studies have shown that IgAdownregulates the oxidative burst and the release of inammatory cytokines such as TNF- a and IL-6 byactivated monocytes [134]. Moreover, in contrast withIgM or IgG, IgA immune complexes exhibit a limitedcapacity of complement (C) activation. This occursthrough the alternate pathway ( via C3b binding),since IgA complexes fail to activate the C classicalpathway [135]. Furthermore, specic IgA can com-petitively block the IgG-mediated C activation [136].These Fc a R-mediated anti-inammatory effects are of critical importance in controlling both mucosal andsystemic inammation, protecting host tissues frominjury [137, 138]. Indeed, excessive production of cytotoxic oxygen metabolites and inammatory med-iators are often associated with chronic inammatorydiseases such as asthma, chronic obstructive pulmo-nary disease (COPD), or brosing alveolitis. It is,however, important to outline that this Fc a R-mediated down-regulation is dependent both on thetype of co-stimulatory signals and on the type of effector cell triggered. In this context, the demonstra-tion of spliced variants of Fc a R on the surface of thealveolar macrophages is interesting. Although the roleof these receptors remains to be dened, they arelikely to provide additional regulatory mechanisms of phagocytic and inammatory responses [80].

Mucosal tolerance

In contrast to the immune response elicited bynoxious antigens, probably taken up by efcientM-cells, an inammatory response against innocuousagents is avoided, particularly in the gut, continuouslyin contact with food and microora bacterial antigens.This so-called " oral tolerance " (reviewed in [139]) isrecognized as a form of peripheral tolerance in whichmature tissue lymphocytes are rendered nonfunctionalor hyporesponsive by prior oral administration of antigen. This immune tolerance is also effective in thenasal or bronchial mucosa. Nevertheless, the mechan-isms supporting this tolerance towards innocuous andself antigens, which are probably abrogated in coeliac

disease as well as in chronic inammatory disorders of the bowel or the airways, remain poorly understood.They probably involve multiple pathways such asrapid removal of luminal soluble antigens from themucosa by poorly activating or " tolerogenic " APCs(dendritic cells, naive B-cells, or alveolar macrophageslacking co-stimulatory molecules CD80/CD86 orICAM-1) [140]. While several studies indicated thatCD4 z , rather than CD8 z , T-cells are required fortolerance induction, CD8 z T-cells primed throughhuman leukocyte antigen (HLA) class I (or CD1)-restricted presentation by epithelial cells have beeninitially suggested to be the effectors of oral tolerance.Moreover, T-cell receptor (TCR) cd -expressing CD8 z

T-cells have been shown to play an important role,since IgE responses to inhaled antigens in rodentmodels of nasal or bronchial induced tolerance couldbe suppressed by the transfer of antigen-specic cdz

T-cells [141]. Similarly, in vivo treatment with specicanti-TCR cd antibodies inhibited the induction of oraltolerance in ovalbumin-fed mice [142]. Conversely,F UJIHASHI et al. [143] reported an abrogation of oraltolerance by cd - T-cells from the gut epithelium. TheTh-cell balance might also be implicated, since oral ornasal tolerance induction is associated with anupregulation of Th2 and a downregulation of Th1cell activation. However, the subsequent tolerancedoes not require IL-4 [144]. An active cellularregulation by some particular Th subsets, such asTh3 cells producing mainly TGF- b or IL-10 depen-dent TGF- b-secreting regulatory T-cells (Tr1 cells),has been implicated, especially after administrationof low doses of antigen. Conversely, activated CD4 zT-cells expressing cytotoxic T-lymphocyte-associatedmolecule (CTLA-4), in contrast to CD28-expressingcells, might provide negative signals leading to T-cellapoptosis, anergy, and down-regulation of Th-cellresponses following higher doses of antigen adminis-tration [145]. Despite that, the mechanisms under-lining both active and anergic immune tolerance havenot been completely elucidated, the mucosal route toaccess a major part of the immune system appearsextremely attractive from a clinical standpoint, andshould hasten the development of mucosally adminis-tered antigens for the treatment of diseases includingthose of the respiratory tract.

Mucosal immunity in respiratory diseases

Immunoglobulin-A deciencyA selective IgA deciency, dened by a serum IgA

concentration v 0.05 mg ? mL -1 with normal levels of other immunoglobulin classes, is frequently observedin serum from healthy blood donors with a prevalenceof 0.1250.2%. This inheritable humoral deciency isnot due to defects in the different genes encodinga -chains, but in those regulating the isotype switching.The mucosa from these subjects appears devoid of IgA-producing cells, while an increase of IgG andespecially IgM-producing cells is observed with nor-mal migration and maturation of J-chain-expressingB-cells [146]. Although most of these IgA-decient

individuals are healthy, this immunodeciency isassociated with an increased prevalence of atopy[147], or food antigen sensitization [148], as well asrecurrent infections (notably in childhood), neoplasticand auto-immune disorders. It is intriguing that aller-gic and infectious diseases associated with IgAdeciency are mainly located to the respiratory tract.This could be related to the less efcient compensationby IgM observed in the respiratory mucosa as com-pared to the gut, and/or to a putative proinammatoryactivity of IgD, which is predominant in the upperairways. Similarly to IgA-decient subjects, pIgR-decient mice, characterized by a total absence of SIgs, appear relatively healthy. However, these mice



12/18

exhibit increased concentrations of mIgA and albuminin secretions associated with a plasma leakage andincreased concentration of IgG in serum includingIgG antibodies against their own E. coli , probablyrelated to a decient epithelial barrier [149]. More-over, their susceptibility to pathogens and allergens isso far unknown.

Immunoglobulin-A response in chronic airway inam-matory diseases

In contrast to the permanent genetic IgA deciency,acquired and transient defects of secretory immunitycan also occur. Thus, a decrease of IgA z plasma cellswas observed in the bronchial mucosa from patientswho died from COPD as compared with COPDpatients who died from other causes, as well as adecrease of IgA in bronchial secretions from heavysmokers [150]. However, variable levels of IgA and SChave been described in airway secretions fromsmokers and COPD patients, possibly related to thedifferent methods of titration used, or to the potentialrole of infection. Thus, an increased concentration of sputum IgA in chronic bronchitis was associated withthe presence of a clinical respiratory infection [151]. Arecent study showed that patients with severe COPDare characterized by a reduced pIgR bronchialexpression that correlates with airow limitation andPMN inltration [36]. Although consequences of thesendings remain hypothetical, it could be speculatedthat in this acquired deciency the mechanisms of compensation are not present or inappropriate whenthe inammatory response is elicited. Thus, in somesusceptible smokers, it is possible that a persistentimpairment of the production and transport of

secretory Igs, secondary to a decreased pIgR expres-sion, might promote bacterial colonization andthereby PMN inltration of the airways. The perpe-tuation of this process could contribute to theprogressive remodelling of the bronchial structuresas observed in COPD. Moreover, bacteria and PMNare both capable of degrading IgA by proteolyticcleavage [119], leading to a vicious circle of impairedsecretory immunity combined with an ampliedinammatory response. Similarly, in patients withcystic brosis, a decrease of SIgA in saliva andbronchial secretions has been observed [152]. Thisobservation is in agreement with a study showing thatSC expression by the bronchial epithelium from

patients transplanted for cystic brosis, is stronglydecreased as compared with control patients trans-planted for primary pulmonary hypertension [153].However, no signicant correlation was foundbetween SC expression and functional parameters inthese patients. Thus, secretory immunity seems clearlyimpaired in COPD and cystic brosis, both character-ized by chronic obstruction, PMN inltration, andbacterial colonization of the airways. The epithelialdamage associated with these disorders further sup-ports an inefcient rst-line of defence with decreasedmucociliary clearance and IgA secretion.

The implication of secretory immunity in thepathogenesis of asthma remains more controversial.

While the level of SC appeared decreased in thebronchoalveolar uid from asthmatics [154], manystudies observed an increase of IgA production inairway secretions from these patients, possibly relatedto the release of cytokines such as IL-4 and IL-5known to upregulate IgA production and transport.In addition, an increased concentration of specic IgAantibodies to both Dermatophagoides farinae and S. pneumoniae was observed in sputum from D. farinae -sensitized asthmatics as compared to controls [155]. Inthis respect, it has been shown that IgA antibodies topollen allergens in tears from asthmatics are directedagainst epitope determinants different from thoseeliciting IgE synthesis [156]. In asthma and in a widevariety of inammatory diseases, granulocyte activa-tion is thought to represent a driving force. SinceFc a R is largely distributed on granulocytes, IgA couldinuence the fate of inammatory diseases such as inmacrophage-dependent lung injury [157], dermatitisherpetiformis [158], IgA-nephropathy [159], viralinfection through Fc a R-mediated uptake of IgA-coated viruses [160], and asthma where eosinophils,particularly in the activated stage [161], could becontrolled by IgA-dependent mechanisms. In asthma,IgA, which is present in abundance on mucosalsurfaces, is thus able to induce eosinophil degranula-tion [132], leading to the destruction and/or damage of the respiratory epithelium. Moreover, Fc a R expres-sion is increased on eosinophils from allergic indi-viduals [70] and in contrast to healthy donors,eosinophils from asthmatic patients do not needadditional cytokine-priming to bind IgA in vitro[162]. TNF- a , which has been reported to beimplicated in eosinophil-mediated cytotoxicity [163],is abundantly produced in allergic inammatorydiseases [164] and high levels of TNF- a are detected

in the bronchoalveolar uid from asthmatic patients[165]. This is of interest, since TNF- a -primed eosino-phils from asthmatic patients bind more IgA thanprimed eosinophils from normal donors [162]. More-over, sputum IgA levels from asthmatic patientscorrelated signicantly with eosinophil cationic pro-tein levels [155], suggesting a contribution of IgA toeosinophil activation in asthma. Several other groupsfocussed their interest on IgA nephropathy, which ischaracterized by the deposition of IgA (mostly pIgA1)in the renal glomerular mesangial area where recep-tors for IgA have been reported to be expressed onhuman mesangial cells [71]. Patients with IgA-nephropathy present delayed plasma clearance of

IgA immune complexes and impaired Fc a R endocy-tosis [166]. It has been shown that IgA from thesepatients is undergalactosylated [167], and this couldexplain the impaired catabolism of IgA. In the kidneyglomerular mesangium, IgA deposition is oftenassociated with IgG, IgM and complement, andresults in renal tissue damage. It is not clear whetherthe production of pro-inammatory cytokines, mainlyTNF- a and IL-6, subsequent to IgA binding tomesangial cells may participate in the amplicationof human renal injury. Indeed, and in contrast to therat model, local inammation is not associated withincreased proliferation of the human mesangial cellsinduced by IL-6 [168].



13/18

Therapeutic applications

Passive immunization with secretory immunoglobulin-Aantibodies. Several experimental models have shownthat passive immunization with specic pIgA or SIgAcan protect animals against various infections, andclinical studies have now been performed [169]. First,IgA puried from human serum, as well as hyper-immune bovine colostrum, which contains, however,mostly IgG antibodies, in addition to SIgA, gave someprotection against infections in immunocompromisedpatients. A promising approach consists of takingadvantage of the fact that both J-chain-containingpIgA and SC, in recombinant secretory antibodies,may be produced in the same cell if the appropriategene transfections have been performed, and thatthe specicity may be selected by cloning Ig variableregion genes from murine monoclonal antibodies.Recombinant anti- Streptococcus mutans chimericSIgA/IgG antibodies produced in plant cells havethus been shown to provide a long-lasting protectionagainst recolonization when applied to tooth surfacesfrom volunteers [170].

Active mucosal vaccination. In contrast with parti-culate or replicating antigens, which often induceactive mucosal immunity, oral tolerance can poten-tially be induced by all thymus-dependent solubleantigens, a feature that has hampered the successfuldevelopment of oral vaccines, notably for autoimmunediseases. Some adjuvants have been shown to promotetolerance, such as conjugation to the B subunit of cholera toxin. Moreover, the possibility to tolerateeven a sensitized host has been demonstrated in vivo[171]. However, variable results have been obtained sofar in clinical trials for disorders such as rhumatoid

arthritis, systemic sclerosis or food allergies, notablyrelated to dose-dependent effects.

Polymeric immunoglobulin receptor-targeted gene or protein delivery. Expression plasmids, encoding forexample the cystic brosis transmembrane regulator(CFTR), complexed to polylysine-linked Fab frag-ments of antibodies directed against SC,are specicallyand efciently incorporated into pIgR-expressingepithelial cells. This observation has evolved as a poten-tial method of introducing normal copies of the CFTRgene into respiratory cells from patients with cysticbrosis [172]. However, problems related to the vari-able level of gene expression or to the route of admini-

stration exist for this pIgR-targeted gene therapy, sincethe plasmids need to be injected in the blood to reachthe basolateral pole of the respiratory epithelium andthus cross the endothelial barrier. More recently, afusion protein consisting of an anti-SC single chainvariable fragment (Fv) linked to human a 1antitrypsinhas been shown to be efciently transported in vitroacross respiratory epithelial cells [173]. In addition toits potential application in a 1antitrypsin-decient pati-ents, this fusion protein might provide a potentialstrategy of delivery of a 1antitrypsin into the bronchialepithelial lining uid from patients with cystic bro-sis, to neutralize neutrophil elastase activity, whichprobably contributes to the progression of the disease.

Conclusion

A complex network of cells and mediators isrequired to protect the respiratory tract againstvarious insults, including infection. Immunoglobulin-Awas discovered over 40 years ago and was soonidentied as the major immunoglobulin in mucosalsecretions, at least quantitatively. Despite this, andin contrast with immunoglobulin-G, very little wasknown about the specic role of immunoglobulin-A inthe mucosa. Extensive research has highlighted uniquefeatures of the immunoglobulin-A system, particularlyrelated to the protection of mucosal surfaces andthe mechanisms regulating immunoglobulin-A activetransport at the level of epithelial cells. Together withthe recent identication of the immunoglobulin-Aleukocyte receptor on phagocytes including alveolarmacrophages, increased knowledge of the immuno-globulin-A biology has opened new perspectives forboth basic and clinical research that will hopefully leadto the development of novel therapeutic modalitiestargeted to respiratory disorders.

References

1. Sibille Y, Reynolds HY. Macrophages and poly-morphonuclear neutrophils in lung defence andinjury . Am Rev Respir Dis 1990; 141: 471501.

2. Sibille Y, Marchandise FX. Pulmonary immune cellsin health and disease: polymorphonuclear neutrophils .Eur Respir J 1993; 6: 15291543.

3. Polito AJ, Proud D. Epithelial cells as regulators of airway inammation . J Allergy Clin Immunol 1998;102: 714718.

4. Massion PP, Inoue H, Richman-Eisenstat J, et al.Novel Pseudomonas product stimulates interleukin-8production in airway epithelial cells in vitro. J ClinInvest 1994; 93: 2632.

5. Crapo JD, Harmsen AG, Sherman MP, Musson RA.Pulmonary immunobiology and inammation inpulmonary diseases. NHLBI Workshop Summary .Am J Respir Crit Care Med 2000; 162: 19831986.

6. Heremans JF, Heremans M-Th, Schultze HE. Isola-tion and description of a few properties of the b2A -globulin of human serum . Clinica Chimica Acta 1959;4: 96102.

7. Tomasi TB Jr, Tan EM, Solomon A, Prendergast RA.Characterization of an immune system common to cer-tain external secretions . J Exp Med 1965; 121: 101124.

8. Conley ME, Delacroix DL. Intravascular and mucosalIgA: two separate but related systems of immunedefence? Ann Intern Med 1987; 106: 892899.

9. Mostov KE, Blobel G. A transmembrane precursor of secretory component, the receptor for transcellulartransport of secretory immunoglobulins . J Biol Chem1982; 257: 1181611821.

10. Kerr MA. The structure and function of human IgA .Biochem J 1990; 271: 285296.

11. Brandtzaeg P, Prydz H. Direct evidence for an integ-rated function of J chain and secretory component inepithelial transport of immunoglobulins . Nature 1984;311: 7173.

12. Vaerman JP, Langendries A, Giffroy D, BrandtzaegP, Kobayashi K. Lack of SC/pIgR-mediated epithelial



14/18

transport of a human polymeric IgA devoid of J chain:in vitro and in vivo studies . Immunol 1998; 95: 9096.

13. Vaerman JP, Langendries AE, Giffroy DA, et al.Antibody against the human J chain inhibits polymericIg-receptor mediated biliary and epithelial transportof human polymeric IgA . Eur J Immunol 1998; 28:171182.

14. Johansen F, Braathen R, Brandtzaeg P. Role of J

chain in secretory immunoglobulin formation . Scand J Immunol 2000; 52: 240248.

15. Reddy PS, Corley RB. The contribution of ER qualitycontrol to the biologic functions of secretory IgM .Immunol Today 1999; 20: 582588.

16. Fallgreen-Gebauer E, Gebauer W, Bastian A, et al.The covalent linkage of secretory component to IgA.Structure of SIgA . Biol Chem Hoppe Seyler 1993; 374:10231028.

17. Mbawuike IN, Pacheco S, Acuna CL, Switzer KC,Zhang Y, Harriman GR. Mucosal immunity toinuenza without IgA: An IgA knockout mousemodel . J Immunol 1999; 162: 25302537.

18. Killian M, Reinholdt J, Lomholt H, Poulsen K,Frandsen EV. Biological signicance of IgA1 pro-teases in bacterial colonization and pathogenesis:critical evaluation and experimental evidence .APMIS 1996; 104: 321338.

19. Pabst R. Is bronchus-associated lymphoid tissue amajor component of the human lung immune system?Immunol Today 1992; 13: 119122.

20. Brandtzaeg P, Baekkevold ES, Farstad IN, et al.Regional specialization in the mucosal immunesystem: what happens in the microcompartments?Immunol Today 1999; 20: 141151.

21. Garside P, Ingulli E, Merica RR, Johnson JG, NoelleRJ, Jenkins MK. Visualization of specic B and Tlymphocyte interactions in the lymph node . Science1998; 281: 9699.

22. Ahmed R, Gray D. Immunological memory andprotective immunity: understanding their relation .Science 1996; 272: 5460.

23. Crabbe PA, Bazin H, Eyssen H, Heremans JF. Thenormal microbial ora as a major stimulus forproliferation of plasma cells synthesizing IgA in thegut. The germ-free intestinal tract . J Exp Med 1969;130: 723744.

24. Van Ginkel FW, Wahl SM, Kearney JF, et al. PartialIgA-deciency with increased Th2-type cytokines inTGF- b1knockoutmice .JImmunol 1999;163:19511957.

25. Crabbe PA, Carbonara AO, Heremans JF. Thenormal human intestinal mucosa as a major sourceof plasma cells containing A-immunoglobulin . LabInvest 1965; 14: 235248.

26. Brandtzaeg P, Farstad IN, Haraldsen G. Regionalspecialization in the mucosal immune system: primedcells do not always home along the same tract .Immunol Today 1999; 20: 267277.

27. Von Andrian UH, Mackay CR. T-cell function andmigration. Two sides of the same coin . New Engl J Med 2000; 343: 10201037.

28. Butcher EC, Picker LJ. Lymphocyte homing andhomeostasis . Science 1996; 272: 6066.

29. Streeter PR, Berg EL, Rouse BT, Bargatze RF,Butcher EC. A tissue-specic endothelial cell moleculeinvolvedin lymphocyte homing . Nature 1988;331: 4146.

30. Gunn MD, Ngo VN, Ansel KM, Eckland EH, CysterJG, Williams LT. A B-cell-homing chemokine made

in lymphoid follicles acivates Burkitt 9 s lymphomareceptor-1 . Nature 1998; 391: 799803.

31. Ngo VN, Tang HL, Cyster JG. Epstein-Barr virus-induced molecule 1 ligand chemokine is expressed bydendritic cells in lymphoid tissues and stronglyattracts naive T cells and activated B cells . J ExpMed 1998; 188: 181191.

32. Nadal D, Albini B, Chen CY, Schlapfer E, Berstein

JM, Ogra PL. Distribution and engraftment patternsof human tonsillar mononuclear cells and immuno-globulin-secreting cells in mice with severe combinedimmunodeciency: role of the Epstein-Barr virus . IntArch Allergy Appl Immunol 1991; 95: 341351.

33. Salvi S, Holgate ST. Could the airway epithelium playan important role in mucosal IgA production? ClinExp Allergy 1999; 29: 15971605.

34. Brandtzaeg P. Immunohistochemical studies on vari-ous aspects of glandular immunoglobulin transport inman . Histochem J 1977; 9: 553572.

35. Goodman MR, Link DW, Brown WR, Nakane PK.Ultrastructural evidence of transport of secretory IgAacross bronchial epithelium . Am Rev Respir Dis 1981;123: 115119.

36. Pilette C, Godding V, Kiss R, et al. Reduced epithelialexpression of secretory component in small airwayscorrelates with airow obstruction in COPD . Am J Respir Crit Care Med 2001; 163: 185194.

37. Krajci P, Kvale D, Tasken K, Brandtzaeg P.Molecular cloning and exon-intron mapping of thegene encoding human transmembrane secretory com-ponent (the poly-Ig receptor) . Eur J Immunol 1992; 22:23092315.

38. Verrijdt G, Swinnen J, Peeters B, Vehoeven G,Rombauts W, Claessens F. Characterization of thehuman secretory component gene promoter . BiochimBiophys Acta 1997; 1350: 147154.

39. Piskurich JF, Youngman KR, Phillips KM, et al.Transcriptional regulation of the human polymericimmunoglobulin receptor gene by interferon- c . MolecImmunol 1997; 34: 7591.

40. Kaetzel CS, Blanch VJ, Hempen PM, Phillips KM,Piskurich JF, Youngman KR. The polymeric immuno-globulin receptor: structure and synthesis . BiochemSoc Trans 1997; 25: 475480.

41. Schjerven H, Nilsen EM, Brandtzaeg P, Johansen FE.IL-4 and TNF- a enhance the expression of humanpIg-receptor through DNA elements in the rstintron. 29 th Ann Meeting of SSI, abstract 36 . Scand J Immunol 1998; 47: 623.

42. Phillips JO, Everson MP, Moldoveanu Z, Cummins L,Mestecky J. Synergistic effect of IL-4 and IFN- c onthe expression of polymeric Ig receptor (secretorycomponent) and IgA binding by human epithelialcells. J Immunol 1990; 145: 17401744.

43. Loman S, Radl J, Jansen HM, Out TA, Lutter R.Vectorial transcytosis of dimeric IgA by the Calu-3human lung epithelial cell line: upregulation by IFN- c.Am J Physiol 1997; 272: L951L958.

44. Godding V, Sibille Y, Massion PP, et al. Secretorycomponent production by human bronchial epithelialcells is upregulated by interferon gamma . Eur Respir J 1998; 11: 10431052.

45. Loman S, Jansen HM, Out TA, Lutter R. Interleukin-4 and interferon- c synerstically increase secretory com-ponent gene expression, but are additive in stimulatingsecretory immunoglobulin-A release by Calu-3 airwayepithelial cells . Immunol 1999; 96: 537543.



15/18

46. Nilsen EM, Lundin KE, Krajci P, Scott H, Sollid LM,Brandtzaeg P. Gluten specic, HLA-DQ restricted Tcells from coeliac mucosa produce cytokines with Th1or Th0 prole dominated by interferon gamma . Gut1995; 37: 766776.

47. Youngman KR, Fiocchi C, Kaetzel CS. Inhibitionof IFN-gamma activity in supernatants from stimu-lated human intestinal mononuclear cells prevents

up-regulation of the polymeric Ig receptor in anintestinal epithelial cell line . J Immunol 1994; 153: 675 681.

48. Norderhaug IN, JohansenFE,SchjervenH, BrandtzaegP. Regulation of the formation and external transportof secretory immunoglobulins . Crit Rev Immunol 1999; 19: 481508.

49. Blanch VJ, Piskurich JF, Kaetzel CS. Cutting edge:Coordinate regulation of IFN regulatory factor-1 andthe polymeric Ig receptor by proinammatory cyto-kines . J Immunol 1999; 162: 12321235.

50. Ackerman LW, Wollenweber LA, Denning GM. IL-4and IFN- c increase steady state levels of polymeric Igreceptor mRNA in human airway and intestinalepithelial cells . J Immunol 1999; 162: 51125118.

51. Mostov KE, Kaetzel CS. Immunoglobulin transportand the polymeric immunoglobulin receptor. MucosalImmunology. San Diego, CA, Academic Press, 1999;pp. 181214.

52. Casanova JE, Breitfeld PP, Ross SA, Mostov KE.Phosphorylation of the polymeric immunoglobulinrecetor required for its efcient transcytosis . Science1990; 248: 742745.

53. Hexham JM, White KD, Carayannopoulos LN, et al.A human immunoglobulin (Ig)A C a 3 domain motif directs polymeric Ig receptor-mediated secretion . J Exp Med 1999; 189: 747752.

54. Okamoto CT, Shia SP, Bird C, Mostov K, Roth MG.The cytoplasmic domain of the polymeric immuno-globulin receptor contains two internalization signalsthat are distinct from its basolateral sorting signal . J Biol Chem 1992; 267: 99259932.

55. Musil LS, Baenziger JU. Cleavage of membranesecretory component to soluble secretory componentoccurs on the cell surface of rat hepatocyte mono-layers . J Cell Biol 1987; 104: 17251733.

56. Hughes GJ, Frutiger S, Savoy LA, Reason AJ, MorrisHR, Jaton JC. Human free secretory component iscomposed of the rst 585 amino acid residues of thepolymeric immunoglobulin receptor . FEBS Letters1997; 410: 443446.

57. Cardone MH, Smith BL, Song W, Mochly-Rosen D,Mostov KE. Phorbol myristate acetate-mediatedstimulation of transcytosis and apical recycling inMDCK cells . J Cell Biol 1994; 124: 717727.

58. Chapin SJ, Enrich C, Aroeti B, Havel RJ, Mostov KE.Calmodulin binds to the basolateral targeting signal of the polymeric immunoglobulin receptor . J Biol Chem1996; 271: 13361342.

59. Luton F, Verges M, Vaerman JP, Sudol M, MostovKE. The SRC family protein tyrosine kinase p62 yes

controls polymeric IgA transcytosis in vivo. Molec Cell 1999; 4: 627632.

60. Daeron M. Fc receptors biology . Annu Rev Immunol 1997; 15: 203234.

61. Maliszewski CR, March CJ, Schoenborn MA, GimpelS, Shen L. Expression cloning of a human Fc receptorsfor IgA . J Exp Med 1990; 172: 16651672.

62. Monteiro RC, Cooper MD, Kubagawa H. Molecular

heterogeneity of Falpha receptors detected by receptor-specic monoclonal antibodies . J Immunol 1992; 148:17641770.

63. Fanger MW, Shen L, Pugh J, Bernier GM. Sub-populations of human peripheral granulocytes andmonocytes express receptors for IgA . Proc Natl Acad Sci USA 1980; 77: 36403644.

64. Shen L, Lasser R, Fanger MW. My 43, a monoclonal

antibody that reacts with human myeloid cells inhibitsmonocyte IgA binding and triggers functions . J Immunol 1989; 143: 41174122.

65. Sibille Y, Chatelain B, Staquet P, Merrill WW,Delacroix DL, Vaerman JP. Surface IgA and Fc-alpha receptors on human alveolar macrophages fromnormal subjects and from patients with sarcoidosis .Am Rev Respir Dis 1989; 139: 740747.

66. Sibille Y, Depelchin S, Staquet P, et al. Fc alpha-receptor expression on the myelomonocytic cell lineTHP-1: comparison with human alveolar macro-phages . Eur Respir J 1994; 7: 11111119.

67. Maliszewski CR, Shen L, Fanger MW. The expres-sion of receptors for IgA on human monocytes andcalcitriol-treated HL-60 cells . J Immunol 1985; 135:

38783881.68. Albrechtsen M, Yeamn GR, Kerr MA. Character-

ization of the IgA receptor from human polymorpho-nuclear neutrophils . Immunology 1988; 64: 201205.

69. Monteiro RC, Kubagawa H, Cooper MD. Cellulardistribution, regulation, and biochemical nature of anFc a receptor in humans . J Exp Med 1990; 171: 597613.

70. Monteiro RC, Hostoffer RW, Cooper MD, BonnerJR, Gartland GL, Kubagawa H. Denition of immunoglobulin-A receptors on eosinophils andtheir enhanced expression in allergic individuals . J Clin Invest 1993; 92: 16811685.

71. Gomez-Guerrero C, Gonzalez E, Egido J. Evidencefor a specic IgA receptor in rat and human mesangialcells. J Immunol 1993; 151: 71727181.

72. Kerr MA, Stewart WW, Bonner BC, Greer MR,MacKenzie SJ, Steele MG. The diversity of leucocyteIgA receptors . Contrib Nephrol 1995; 111: 6064.

73. Phillips-Quagliata JM, Patel S, Han JK, et al. The IgA/IgM receptor expressed on a murine B cell lymphoma ispoly-Ig receptor . J Immunol 2000; 165: 25442555.

74. Diven SC, Caisch CR, Hammond DK, Weigel PH,Oka JA, Goldblum RM. IgA induced activation of human mesangial cells: independent of Fc alphaRI(CD 89) . Kidney Int 1998; 54: 837847.

75. Barratt J, Greer MR, Pawluczyk IZ, et al. Identica-tion of a novel Fc alpha receptor expressed by humanmesangial cells . Kidney Int 2000; 57: 19361948.

76. Leung JC, Tsang AW, Chan DT, Lai KN. Absenceof CD89, polymeric immunoglobulin receptor, andasialoglycoprotein receptor on human mesangial cells .J Am Soc Nephrol 2000; 11: 241249.

77. Sancho J, Gonzalez E, Egido J. The importance of theFc receptors for IgA in the recognition of IgA bymouse liver cells: its comparison with carbohydrateand secretory component receptors . Immunology 1986;57: 3742.

78. Kremer EJ, Kalatzis V, Baker E, Callen DF,Sutherland GR, Maliszewski CR. The gene for theimmune IgA Fc receptor maps to 19q13.4 . Hum Genet1992; 89: 107108.

79. De Wit TPM, Morton HC, Capel PJA, van de WinkelJGJ. Structure of the gene for the human myeloid IgAFc receptor (CD89) . J Immunol 1995; 155: 12031209.



16/18

80. Patry C, Sibille Y, Lehuen A, Monteiro RC.Identication of Fc a receptor (CD89) isoformsgenerated by alternative splicing that differentiallyexpressed between blood monocytes and alveolarmacrophages . J Immunol 1996; 156: 44424448.

81. Morton HC, Schiel AE, Janssen SWJ, van de WinkelJGJ. Alternatively spliced forms of the human myeloidFc a receptor (CD89) in neutrophils . Immunogen 1996;

43: 246247.82. Van Dijk TB, Brake M, Caldenhoven E, et al. Cloningand characterisation of Fc a Rb novel Fc a -receptor(CD89) isoform expressed in eosinophils and neutro-phils . Blood 1996; 88: 42294238.

83. Keidan I, Laufer J, Shor R, Farzam N, Gitel S,Passwell JH. Activation of monocytes via their Fcalpha R increases procoagulant activity . J Lab ClinMed 1995; 125: 7278.

84. Lamkhioued B, Gounni AS, Gruart V, Pierce A,Capron A, Capron M. Human eosinophils express areceptor for secretory component. Role in secretoryIgA-dependent activation . Eur J Immunol 1995; 25:117125.

85. Reterink TJ, van Zandbergen G, van Egmond M, et al.

Size-dependent effect of IgA on the IgA Fc receptor(CD89) . Eur J Immunol 1997; 27: 22192224.

86. Weissman AM, Hou D, Orloff DG, et al. Molecularcloning and chromosomal localization of the humanT-

lung mucosal immunity iga revisited

Documents