ANSWER
Mucosal defense mechanisms are critical in preventing pathogen colonization of the respiratory tract and antigen penetration through the epithelial barrier. Recent research has shown that the respiratory epithelium actively contributes to the exclusion of microbes and particles and to controlling inflammatory and immune responses in the airways and alveoli. Through the polymeric immunoglobulin receptor, epithelial cells also mediate the active transport of polymeric immunoglobulin-A from the lamina propria to the airway lumen. IgA’s role in mucosal surface defense has evolved from a limited role as a scavenger of exogenous material to a broader protective function with potential applications in immunotherapy. Furthermore, the recent discovery of IgA receptors on the surface of blood leukocytes and alveolar macrophages provides an additional interaction mechanism between the cellular and humoral immune systems at the respiratory tract level.

Polymeric immunoglobulin receptor for FcRimmunoglobulin-Amucosal immunity
C. Pilette is currently a Fonds National de la Recherche Scientifique (Belgium) Aspirant, and Y. Ouadrhiri is supported by the Foundation Lancardis (Switzerland).
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Each breath introduces thousands of microorganisms and microparticles into the respiratory tract via inhaled air. The host tolerates this exposure well, as it rarely reacts to this continuous stimulation. Thus, under normal conditions, the respiratory tract can eliminate exogenous material efficiently without eliciting a significant inflammatory or immune response. The respiratory tract’s defense against pathogens is based on two distinct mechanisms: the airways (upper and lower) and the alveolar space. Mechanical defense appears to predominate in the airways, with deposition on the nasal and oropharyngeal surfaces and elimination via cough, sneezing, and mucociliary clearance. The alveolar epithelium, on the other hand, lacks mucociliary properties and thus relies heavily on alveolar macrophages to remove particles and microorganisms that enter the alveolar space 1. Furthermore, when necessary, the respiratory tract can activate several protective mechanisms (table 1). The contribution of polymorphonuclear neutrophils (PMNs) to lung defense against bacterial infection, for example, is well recognized 2, and recent research has elucidated important mechanisms of recruitment and activation of PMNs at infection sites. Another area of research where significant progress has been made is with epithelial cells. Thus, the bronchial epithelial cell, which has long been recognized as an important component of the mucociliary system, is now a key cell in controlling inflammatory and immune responses against pathogens and biotoxins. The respiratory epithelium can initiate and sustain an inflammatory response in response to various stimuli. Bronchial epithelial cells, in particular, produce interleukin (IL)-5, IL-8, RANTES (regulated on activation, normal T-cell expressed and secreted), and growth factors such as granulocyte macrophage-colony stimulating factor (GM-CSF), all of which are implicated in the attraction or activation of inflammatory cells. 3. Interestingly, bronchial epithelial cells release IL-8, the most potent neutrophil chemoattractant, in response to bacterial products. 4. Furthermore, the epithelium will likely participate in the immune response shortly after antigen deposition. Because epithelial cells are recognized as antigen-presenting cells in both the respiratory and digestive mucosa, this participation is possible. Furthermore, while it is widely accepted that inflammatory mediators such as oxidants and proteases can cause damage to the airways, likely, remodeling of the bronchial structures (as seen in chronic disorders such as asthma, chronic bronchitis, or cystic fibrosis) can alter the host’s response to inhaled pathogens and toxins.

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Table 1: Respiratory tract defense mechanisms

Although lymphocytes are rare in the normal airway and alveolar lumen, they are found in the bronchial submucosa. When they are abundant, as in some pathologies, they are sometimes organized in lymphoid tissue, known as bronchus-associated lymphoid tissue (BALT). They play a role in the mucosal humoral immune response, specifically in the production of immunoglobulin (Ig)-A. The bronchial tree and lung parenchyma’s defense mechanisms against infection, which are frequently associated with an inflammatory or immune response, have been the subject of extensive reviews and several workshops 5. However, the most recent information on the role of the mucosal humoral immune system (specifically, the secretory IgA system) in the lung has yet to be addressed in the lung literature. As a result, the current review will concentrate on the secretory IgA system, considering both properties shared with other mucosa and those unique to the respiratory tract. This is crucial, given that IgA, the most abundant Ig in mucosal fluids, can also interact with phagocytic cells. The first section will cover the various steps and mechanisms of IgA production, transport, and activity. In contrast, the second section will go over the functions of IgA in mucosal tissues in greater detail. The final section will focus on the potential roles of the mucosal IgA system in respiratory disorders, taking into account both pathophysiological aspects and potential therapeutic interventions.

The mucosal immunoglobulin-A system is organized.
Structure and distribution of immunoglobulin A
IgA 6 is the most common Ig in secretions and has distinct properties due to its association with a “transport piece.” 7. Although IgA is much less abundant in serum than IgG, its catabolism is four-eight times faster (considering, respectively, monomeric and polymeric IgA). Thus, serum IgA homeostasis necessitates a synthesis rate comparable to that of IgG (21 mgkg1day1 for IgA versus 30 mgkg1day1 for IgG). In contrast, IgA production in the various mucosa and exocrine glands is much higher than IgG. When both vascular and mucosal compartments are considered, daily IgA production is much more important than its IgG counterpart 8. A close collaboration distinguishes the secretory Ig system between the mucosal lymphoid tissue, which produces Ig (primarily polymeric IgA) on a continuous and adaptive basis, and the epithelium, which allows the transport of polymeric Ig (pIg) within the mucosal lumen via the polymeric Ig receptor (pIgR) 9. Thus, the majority of polymeric IgA (pIgA) and IgM (pIgM) produced at these sites is transported across epithelia into the luminal environment, where secretory Ig is thought to inhibit adherence of harmful microorganisms and antigens to the epithelium, a process known as “immune exclusion.” Similarly, innocuous antigens seem ignored by the immune system through unclear mechanisms related to “mucosal tolerance.” These mechanisms provide an effective “first-line” of defense for the mucosa’s 400 m2 surface area (100 m2 for the lung, excluding the bronchial tree), preventing the development of a potentially harmful inflammatory response.

The polymerization state of IgA in serum and secretions (reviewed in 10) is primarily responsible for its molecular heterogeneity. In humans and primates, serum IgA primarily comprises monomeric IgA (88%) produced by bone marrow plasma cells. Its serum concentration is approximately five times lower than that of IgG. Mucosal plasma cells, on the other hand, produce mostly pIgA (80%, mostly dimeric), which is the predominant form of IgA in secretions. The secretory component (SC) from the epithelial origin is associated with most pIgA in secretions to form secretory IgA. (SIgA). Another distinction between serum and secretory IgA pools is a relative increase in the IgA2 isotypic form in secretions (particularly in the large bowel and the bronchi) compared to serum. Because IgA2 lacks most of the hinge region, it appears less susceptible to degradation by bacterial IgA-proteases (see later). Finally, IgA2 has two allotypic variants predominant in Caucasians and Africans. A third IgA2 isotypic form may exist genetically, but this protein has yet to be isolated.

Monomeric IgA (mIgA) is made up of two light chains (or) that, like other Igs, are covalently linked to two specific heavy chains (chains). IgA2m(1) is an exception, in which the light chains form a covalent dimer that is noncovalently linked to the heavy chains. The chain comprises four domains, similar to IgG or IgD, and a unique 18 amino acid (aa) carboxyl-terminal polypeptide known as the secretory tailpiece (tp). This tp contains a penultimate cysteine that forms a disulfide bond with the homologous cysteine of the other chain or a cysteine residue of a nonimmunological protein like albumin or 1-antitrypsin. The molecular weight of monomeric IgA is 160 kDa, and the sedimentation coefficient is 7S. Pigs are distinguished by a high valency of antigen-binding sites (4), which results in a high agglutinating capacity of microorganisms, as well as by their association with a small 15 kDa polypeptide known as the joining chain (J-chain), which is produced concurrently with pIgs by mucosal plasma cells. This J-chain contains cysteine residues involved in IgA (and IgM) polymerization and is required for pIg transepithelial transport. The J-chain, in particular, is not required for polymer formation but regulates their quaternary structure (“tail-to-tail” model for IgA and ring structure for IgM), which appears to be a determinant for binding to epithelial pIgR 11-13. pIgA is primarily represented by dimeric IgA (335 kDa and 9.5S), but higher aggregation states (trimers and tetramers) are also present, albeit in smaller amounts. The J-chain that bridges one tp of each IgA molecule connects two molecules of IgA “tail-to-tail” in dimeric IgA, while the remaining tps are directly disulfide bound 14. These disulfide bonds involve the penultimate cysteines in position 495 of the top, which is important in the intrinsic polymerization tendency of IgA. The main form of IgM is pIgM (900 kDa and 18S) 15, in which five molecules of IgM are linked in a ring structure via the J-chain that connects the first to the fifth monomer. There are, however, larger polymers of IgM that lack a J-chain. IgM’s heavy chain (chain) includes a tailpiece (tp), which is very similar to IgA’s.

Secretory Igs (SIgs) are formed when mucosal plasma cells associate with epithelial SC to produce pigs. This association remains noncovalent for IgM during transepithelial transport, whereas a disulfide link is usually formed between pIgA (cys309, or sometimes cys311) and SC (cys467) 16. This interaction with SC has been shown to protect SIgA from proteolytic degradation, though this is much less pronounced in the respiratory tract than in the large bowel 17. Nonsecretory Igs such as IgA, IgG, IgD, and IgE can also reach secretions, primarily through passive diffusion through endothelial and tight endothelial junctions from submucosal blood capillaries or locally infiltrating plasma cells that produce these monomeric Igs. Furthermore, these monomeric Igs may be transported via the pIgR alongside an immune complex containing at least one pIg.

The gut’s abundant commensal bacterial microflora supports a relatively high proteolytic activity. Because of their unique structure, SIgs, particularly SIgA, appear more resistant to proteolysis than the other Ig isotypes. Nonetheless, virulent strains of Streptococcus pneumoniae or Haemophilus influenzae can produce bacterial IgA-specific proteases that cleave the hinge region of IgA1 to produce antigen-binding and crystalline fragments (Fab and Fc, respectively), which could aid in the development of infections, including those of the respiratory tract 18. Other enzymes, particularly those from Gram-negative bacteria such as Pseudomonas and Proteus spp., can cleave serum and secretory IgA1 and IgA2 outside the hinge region. These latter proteases have a broader specificity, occasionally cleaving IgG as well. These bacterial IgA1-proteases are resistant to inhibition by plasma protease inhibitors (such as 1-antitrypsin or 2-macroglobulin), but some can be inactivated by specific neutralizing antibodies found in serum and secretions.

Production of immunoglobulin A
Organization of mucosal lymphoid cells
Mucosa-associated lymphoid tissues (MALTs) are lymphoid tissues organized close to the surface and glandular epithelia and serve as both inductive and effector sites of mucosal immune responses. Tonsils, adenoids as nasal-associated lymphoid tissue (NALT), BALT, Peyer’s patches, and appendix/colonic-rectal solitary follicles as gut-associated lymphoid tissues (GALT) are inductive sites that contain secondary germinal centers after antigenic stimulation. These follicles are surrounded by more diffuse lymphoid tissue (extra-follicular area or T-cell zone), and their luminal side (often referred to as the “dome”) is covered by follicle-associated epithelium, which includes microfold cells (M-cells) that sample the antigenic luminal content. Afferent lymphatics are absent in MALTs and are replaced by specialized high endothelial venules. In contrast, effector sites are represented by the diffuse lamina propria of the various mucosa and exocrine glands, which are also close to the epithelium. Although the mucosal and systemic immune systems are not completely separated, MALT has some distinct characteristics, such as a large predominance of IgA-producing immunocytes.

Several MALT characteristics have been demonstrated in studies primarily focused on the gut, though most are likely to apply to the respiratory tract. The absence of MALT and M-cells in the normal respiratory tract is a significant difference between the airway and digestive mucosa 19. Thus, MALT organization, including M-cell epithelial differentiation, is likely to be induced only when airway and lung tissues are subjected to an increased antigenic load.

B-cell priming in inductive environments
Naive B-lymphocytes enter inductive sites via high endothelial venules via a multistep extravasation process (reviewed in 20). Local CD4+ T-cells prime them in extra-follicular areas, activated by interdigitating antigen-presenting cells (APCs) that have processed luminal antigens 21. Surface (s) IgD+IgM+CD38+ (where + represents the positive expression of a given marker) B-cells primed by these interactions, known as “first signals,” produce an unmutated IgM that can bind the antigen with low affinity, generating soluble immune complexes that are thought to maintain B-cell memory 22. Surface IgD+IgM+CD38+ primed B-cells migrate to the germinal center’s dark zone, where they increase as “founder” Ki-67+ centroblasts. These “founder cells” are distinguished by somatic hypermutation of Ig variable region genes. This hypermutation process produces an IgM with a high affinity for the antigen, which protects these cells from CD95-induced apoptosis via cognate interactions with follicular dendritic cells expressing the processed antigen.
Furthermore, centroblasts can pick up the antigen and present it to follicular CD4+ T-cells via this high-affinity IgM. This interaction necessitates another CD40-CD40 ligand interaction. Finally, activated centroblasts differentiate into B-cells, which differentiate into Ig-producing cells after a terminal differentiation phase in secretory effector tissues.

Terminal differentiation of B cells
Antigen-specific B-cells either differentiate into memory B-cells (sIgDIgM+CD38B7+ B-cells) or switch their heavy chain constant region (CH) gene from C to downstream isotypes. This isotype switching, accompanied by increased CD38 expression and clonal proliferation, represents the final stage of B-cell maturation into Ig-producing immunocytes. The “second signals” that trigger these events are still unknown. Still, they are most likely provided by microenvironmental factors such as cytokines released by epithelial or mononuclear cells, cell-to-cell interactions with dendritic cells, or topical antigenic exposure (especially in the colon or conjunctiva). Thus, the presence of commensal bacteria is important because the intestinal (and probably bronchial) mucosa of germ-free mice is nearly devoid of IgA-producing immunocytes 23. TGF- is a crucial cytokine for IgA switching (“switch factor”), as supported by the partial IgA deficiency observed in TGF1-deficient mice 24, whereas IL-2, IL-5, and especially IL-10 are important (in humans) for the clonal proliferation of activated B-cells and terminal differentiation into Ig-producing cells. However, the precise reason why IgA-producing immunocytes constitute most mucosal mature plasma cells 25 is unknown.
Furthermore, while IgA1 is the predominant isotype, mucosal Ig-producing cells exhibit a relative increase in IgA2 expression compared to systemic Ig-producing cells. Alternatively, the predominant isotype for IgG-producing mucosal cells (representing about 3 and 20% of Ig-producing cells in the gut and bronchi, respectively) is IgG1. Furthermore, in the upper airways, IgG3+ cells outnumber IgG2+ cells, in contrast to the distal gut. Except in the mucosa of some allergic patients, IgE-producing plasma cells are almost non-existent. IgD-producing cells are generated from activated centroblasts with a CH gene deletion of C and C, resulting in SIgD+IgMCD38+ cells. This subset of centroblasts is frequently found in the upper aerodigestive tract, which may be due to the presence of bacteria such as H. influenzae or Branhamella catarrhalis producing an IgD-binding protein that can cross-link SIgD at this level. Interestingly, because 90% of IgA+ (and most IgM+) mucosal immunocytes are also J-chain+, as are 40-100% of IgG+ and IgD+ mucosal immunocytes, J-chain expression represents a relatively early marker of MALT-specific B-cells and thus appears to be closely related to homing within the mucosal B-cell system.

Recirculation of lymphocytes and mucosal homing
Lymphoid recirculation and mucosal homing are discussed in chapters 26 and 27. Because most IgA plasma cells have a half-life of 5 days (as demonstrated in the mouse gut), a continuous supply must be ensured by daily B-cell migration and maturation into mucosal tissues. According to repopulation studies, mucosal effector immunocytes are largely derived from B-cells initially induced in MALTs. Furthermore, this mucosal homing is characterized by regional specificity, as primed B-cells migrate preferentially into effector tissues corresponding to the inductive site where they were initially stimulated 28. Further research revealed that specific cell-to-cell interactions between B-cells and endothelial cells in venules of the parafollicular areas (inductive sites) or the lamina propria support this specific mucosal homing (effector sites). The interaction between α4β7 integrin expressed by mucosal B- and T-cells and mucosal addressin cellular adhesion molecule-1 (MadCAM-1, or “mucosal homing receptor”), expressed by mucosal endothelial cells from high endothelial venules 29, has been shown to support in the gut, both the attraction of naive B-cells in inductive sites and emigration of primed B-cells in effector tissues. The former is distinguished by the interaction of 47 integrins with L-selectin (CD62 ligand) and a MadCAM-1 molecule with a modified O-glycosylation pattern (fig. 1), whereas the latter is distinguished by the interaction of 47 integrins (without L-selectin) with unmodified MadCAM-1. Other general leukocyte-endothelium interactions, such as those between LFA-1 (L2 integrin, CD11a/CD18) and intercellular adhesion molecule (ICAM)-1 or -2, or between the very late antigen (VLA)-4 and vascular cell adhesion molecule (VCAM)-1, could also be involved. Because 47 is well expressed in the airways but MadCAM-1 is only very weakly expressed by the bronchial endothelium, the molecular interactions underlying the specificity of B-cell migration to the airway and lung mucosa remain unknown.

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Fig. 1.—
Interactions between lymphocytes and endothelial cells in high endothelial venules, as seen in gut-associated lymphoid tissues (Peyer’s patch). The interaction of 47 integrins associated with L-selectin and mucosal addressin cellular adhesion molecule (MadCAM)-1 is required for naive lymphocyte mucosal homing in the gut. The other leukointegrin, leukocyte function-associated molecule (LFA)-1, interacts with endothelial cells via intracellular adhesion molecule (ICAM)-1 or -2. B-lymphocyte chemoattractant (BCA)-1 chemokine attracts CXCR-5-expressing B-cells in mucosal lymphoid tissues, whereas secondary lymphoid tissue chemokine (SLC)/6CK attracts T-cells via activation of the CCR-7 chemokine receptor.

Cell trafficking in mucosal tissues is regulated by various chemokines released by resident cells. Specific chemoattractants, such as B-lymphocyte chemoattractant (BCA)-1, a CXC chemokine attracts B-cells, and secondary lymphoid tissue chemokine (SLC, or Exodus-2). This CC chemokine primarily attracts T-cells 30, directing immune cells to the different lymphoid microcompartments after extravasation. Several other mediators, such as macrophage inflammatory protein (MIP)-3 (Exodus-1) and 3 (Exodus-3) or stromal cells derived factor (SDF)-1, have been implicated in the attraction of naive immunocompetent cells into mucosal tissues. Ebstein-Barr virus (EBV)-induced molecule-1 ligand chemokine (ELC) 31 is likely to direct the emigration of activated B-cells from germinal centers. These molecules bind to B-cell (or T-cell) surface receptors such as CXCR-5 for BCA-1 and CCR-7 for SLC. CXCR-5 (and CCR-4) is upregulated on activated CD4+ T-cells, with Th1 cells preferentially expressing CCR-5 and CXCR-3 and Th2 cells preferentially expressing CCR-3 (or eotaxin R). Similar signals are likely to direct CD8+ T-cells into mucosal tissues. Finally, extracellular matrix proteins such as fibronectin and reticular fiber orientation may play an important role, particularly through interactions with 47 (or 41) integrins.

In addition to regional specialization, the mucosal homing of activated B-cells is distinguished by a distinction between the upper aerodigestive tract and the gut because the migration of NALT- or BALT-induced B-cells to the gut is insignificant in terms of SIgA antibody production 32. This dichotomy could be attributed to differences in the adhesion mentioned above molecules or chemokine profiles. A “non-intestinal” homing receptor profile, such as the interaction of 47 integrins with VCAM-1 or L-selectin with its counter-receptor, may thus allow selectivity of homing to the airways (and to the urogenital tract). Future research will likely address and, hopefully, unravel the mechanisms underlying lymphocyte homing into the respiratory mucosa.

The epithelium’s potential roles in mucosal immunoglobulin production
The epithelial surfaces are considered the site of the first antigen encounter. Soluble luminal antigens are most likely taken up by the epithelium and removed from the lamina propria by poorly stimulated dendritic cells. Specialized follicle-associated epithelial M-cells preferentially take up luminal particles in the gut, which are close to APCs. In contrast, the fate of antigens in the airway lumen is unknown because M-cells have not been identified in the normal respiratory mucosa. Furthermore, epithelial cells in the airways and the gut can provide “second signals” promoting terminal differentiation of B-cells oriented toward IgA production because they can produce different cytokines involved in this process, such as TGF-, IL-5, or IL-10 33. T-cells are most likely not the primary source of the cytokines that regulate IgA commitment because IgA production is CD4-independent. Thus, the epithelium is involved in the majority of the different processes of mucosal defense, including the humoral immune response. Similarly, recent data from respiratory tract studies indicate that the epithelium plays an important role in the pathogenesis of various inflammatory mucosal disorders 33.

Transport of immunoglobulin A
The receptor for pIgs (specifically pIgA and IgM) is expressed by mucosal epithelial cells. It was first identified in secretions in its soluble form, hence the names “transport piece” and, more recently, SC. Several lines of evidence suggest that pIgR, identical to transmembrane SC 9, mediates the transport of pigs produced in the lamina propria across the epithelium and into the mucosal lumen. This is the body’s most active and widespread transcellular protein transport system.

Expression of polymeric immunoglobulin receptors
In the gut, the pIgR is expressed on the basolateral pole of epithelial cells, primarily of the serous type 34. In contrast, mucous and ciliated cells express this surface receptor in the bronchi, albeit to a lesser extent than the serous phenotype 35, 36. The human pIgR/SC consists of a 100 kDa heavily glycosylated protein of 693 aa which comprises an 18 aa N-terminal signal peptide (encoded by two exons), five Ig-like domains D1-D5 (encoded by four exons). A sixth extracellular domain, followed by a membrane-spanning segment (23 aa) and a highly conserved cytoplasmic tail (103 aa), all encoded by five exons 37 (fig. 2⇓). The 19-kb human pIgR gene, which contains 11 exons, is found on chromosome 1 (single locus 1q31-q41) and produces a 3.8 kb messenger ribonucleic acid (mRNA) transcript with no alternative splicing. The pIgR promoter region has also been studied 38, 39, and it contains putative binding sites for transcription factors such as interferon (IFN)-stimulated response elements (ISREs), activating protein (AP)-1, nuclear factor (NF)-B, and steroid hormones. pIgR constitutive expression depends on a composite site formed by an E-box linked to a partially overlapping inverted repeat sequence. Three types of deoxyribonucleic acid (DNA) response elements in the pIgR gene are involved in cytokine-induced pIgR expression:
Three ISREs (two in the upstream region and one in exon 1)
A 570 bp region in intron one as a response element to IL-4 and TNF- 41
Steroid response element(s) in exon 1 for glucocorticoids and androgens

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Figure 2: The human polymeric immunoglobulin (pIg) receptor (pIgR)/secretory component (SC) protein structure. The extracellular portion of the pIgR is made up of five domains (D1-D5) that contain Ig-like loops formed by disulfide bonds (-S-S-). Except in D2, additional disulfide bonds can be found within the various loops. The first extracellular domain (D1) is involved in pIgA binding, while D5 is involved in the covalent bridge with pIgA. SC is the released product of pIgR, with pIgR cleavage occurring upstream of the transmembrane segment after an arginine (in position 585), forming the last carboxy-terminal amino acid of SC. The cytoplasmic tail contains a phosphorylated serine (at position 655) that regulates the pIgR’s basolateral targeting (adapted from 48). COOH stands for carboxylic acid.

Different cytokines, particularly IFN-, appear to upregulate pIgR epithelial expression in vitro on intestinal epithelial cell lines 42 and the bronchial epithelial cell line Calu-3 43 and on primary bronchial epithelial cells 44 by interacting with specific receptors expressed restrictively on the basolateral pole of these cells. IL-4 upregulates SC expression on HT-29 colon carcinoma cells 42 and Calu-3 cells 45 in a synergistic manner with IFN-, while the effects of these cytokines appeared additive on IgA transport. TNF- and IL-1 increase SC expression, though to a lesser extent than IFN-. Although some authors 46 attribute only a portion of the increased SC expression to IFN-, the observation that blocking IFN- activity in supernatants from stimulated intestinal mononuclear cells abolishes SC upregulation suggests that IFN- is the primary regulator of pIgR/SC expression 47. The mechanism of IFN—induced pIgR upregulation, which is transcriptional and dependent on de novo protein synthesis, has been clearly defined (reviewed in 48). IFN- recruits via its membrane receptor STAT-1, which, once phosphorylated and dimerized, stimulates the transcription of IFN- regulatory factor (IRF)-1, which binds to the ISRE in exon 1 of the pIgR gene to promote its transcription. The dramatic reduction in SC expression in the intestines of IRF-1 deficient mice 49 is consistent with IRF-1’s critical role in mediating the stimulatory effect of IFN- on SC gene transcription. Although TNF- also induces IRF-1, this cytokine works primarily through a response element in intron 1 of the pIgR gene. Furthermore, Ackerman et al. Fifty discovered that the IL-4- or IFN—induced IRF-1 correlated only weakly with that of SC mRNA, indicating that IRF-1 independent pathways may be involved in the regulation of pIgR gene transcription by cytokines.

Transcytosis mechanisms and regulation
48 and 51 discuss the mechanisms and regulation of transcytosis. After being synthesized as a 90-100 kDa precursor protein in the rough endoplasmic reticulum, pIgR matures to 100-120 kDa after glycosylation in the Golgi complex. A basolateral targeting sequence directs the delivery of a J-chain-containing pIg from the TransGolgi Network to the basolateral membrane. This sequence consists of 17 amino acids, one of which is a serine (ser655, in human pIgR) that inhibits basolateral targeting when phosphorylated 52. A noncovalent interaction between a loop region of the third constant domain of IgA (C3) and a conserved sequence in D1 of the pIgR 53 initiates the binding of pIgA to pIgR. During transcytosis, a covalent disulfide bond is formed, stabilizing the pIgA/pIgR complex (cys311 in C2 and cys467 in D5 of pIgR) 16. Endocytosis of pIgR, whether unbound or complexed with a pIg, is mediated by two tyrosine-based signals that direct it to clathrin-coated pits 54 and delivery to early basal endosomes. Nearly half of the receptor pool is recycled to the resting basolateral membrane. At the same time, the remaining 30% is transcytosis in microtubular structures and trapped in apical vesicles without basolateral recycling to reach the apical membrane. There, a leupeptin-sensitive proteolytic cleavage 55 just upstream from the membrane-spanning segment (after arg585) 56 releases the pIgR as the SC, but the identity of the implicated protease(s) is unknown. The cleavage produces J-chain-containing pIgA, covalently linked to SC to form SIgA, whereas IgM is complexed to SC noncovalently to form SIgM. Furthermore, because some uncomplicated pIgRs are transcytosis and released, unbound (free) SC can be found in secretions (fig. 3).

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Fig. 3.—
Transcytosis of polymeric immunoglobulin (pIg) receptor (pIgR)-mediated pIgA. The epithelial receptor for pIgs is synthesized in the RER and heavily glycosylated in the Golgi apparatus before being directed to the basolateral membrane to bind its ligand (mostly pIgA). Endocytosis of the pIgR/ligand complex occurs in clathrin-coated vesicles. While a significant pool of pIgR is recycled to the cell membrane (not shown), approximately 30% of the pIgR pool is transcytosis towards apical vesicles in basal conditions via a microtubular-dependent mechanism. After cleavage from the apical membrane, the pIgR/pIgA complex is released into the mucosal lumen as secretory immunoglobulin-A (SIgA). In contrast, the free secretory component (SC) is produced by constitutive transcytosis of uncomplexed pIgR.

The transport of pigs may increase the pIgR transcytotic rate, regardless of the pIgR expression level. Activating phospholipase C (PLC)-dependent intracellular signals, such as increased intracellular calcium or protein kinase C (PKC), can stimulate pIgR transcytosis and SC release. Thus, PKC (and)-induced translocation stimulates pIgR transcytosis, apical recycling, and cleavage in pIgR-expressing Madin Darby Canine Kidney (MDCK) cells 57, and this effect is independent of Ser655 phosphorylation. Calmodulin, which binds to the basolateral targeting signal of pIgR 58 in the presence of calcium, can also improve the transcellular routing of pIgR. Other intracellular pathways, such as the phosphatidyl-inositol three kinases (PI-3K) pathway, may also be involved because wortmannin, a PI-3K inhibitor, inhibits pIgR transcytosis by increasing basolateral recycling after endocytosis. Finally, unlike human pIgR, rabbit pIgR complexed with ligand appears to be transcoded faster than the unoccupied receptor. This ligand-induced upregulation of pIgR transcytosis is mediated by a stimulation of rabbit pIgR delivery from apical endosomes to the apical membrane, which is dependent on a tyrosine kinase (TK), identified as p62yes tk 59, a nonreceptor TK of the sarcoma (src) family.

Leukocyte immunoglobulin-A receptor
The immunoglobulin-A leukocyte receptor has been identified and characterized.
In addition to their direct role in humoral immunity against infectious agents such as bacteria and parasites, Igs can also initiate and regulate the development of myeloid immune responses via isotype-specific Ig receptors known as FcR. FcR surface receptors for IgA were discovered on myeloid cells 20 years ago. FcR, like FcR (IgG receptors), FcR (IgE receptors), FcR (IgM receptors), and FcR (IgD receptors), plays a role in antigen-antibody complex recognition by immune system cells. FcR recognizes the Fc portion of IgA and initiates cell responses using the same transduction pathways as antigen receptors 60. In contrast to FcRs, only one FcR, CD89, has been cloned from the human monocytic cell line U937 61, and its cellular distribution has been characterized using monoclonal antibodies against the CD89 cluster 62. FcRs are expressed on monocytes/macrophages 63-66, myeloid cell lines 66, 67, neutrophils 68, 69, eosinophils 70, mesangial cells 71, and possibly on certain lymphocyte populations 72. The data on FcR expression in lymphocytes and mesangial cells are somewhat contradictory. Kerr et al. 72 discovered that B-lymphocytes, but not T-lymphocytes, bind to IgA. However, a mitogen or antigen stimulus could induce the expression of an IgA receptor on T-lymphocytes. However, this receptor differs from the CD89 myeloid receptor because none of the monoclonal antibodies that recognize CD89 bind to T-lymphocytes. 72, and Phillips-Quagliata et al. 73 recently demonstrated the presence of an IgA receptor on T-lymphocytes that is more similar to the epithelial pIgR than to the CD89 myeloid FcR. The presence of an IgA receptor and FcR mRNA in mesangial cells has also been reported 71. The lack of surface expression of CD89 on cultured mesangial cells, galactose inhibition of IgA binding, and the size of this stained protein receptor on sodium dodecyl sulfate-polyacrylamide gel electrophoresis appear to rule out FcR 74-76. Finally, while FcRs are most commonly found in PMN, eosinophils, and mononuclear phagocytes, they have also been found in mouse hepatic cells 77.

The CD89 gene is found on chromosome 19 (q13.4) 78 and spans 12 Kb 79. The CD89 complementary DNA (cDNA) encodes a protein of approximately 30 kDa with two extracellular Ig-like domains, a single transmembrane domain, and a short cytoplasmic tail with no known signaling motifs. FcRs are glycosylated proteins with apparent molecular masses of 55-75 kDa on monocytes, macrophages, and neutrophils and 70-100 kDa on eosinophils 69, 70. Enzymatic removal of N-linked carbohydrate groups enables the identification of the mature CD89 protein, which has a core structure of 32 or 36 kDa in monocytes, neutrophils, and U937 cells, but only the 32 kDa protein in eosinophils 62, 69. A core protein of 28 kDa has been identified in human alveolar macrophages 80. Thus, human alveolar macrophages seem to express a FcαR different from that of monocytes and generated by alternative splicing of the CD89 primary transcript 80. Indeed, several isoforms of CD89, lacking different parts of the extracellular or transmembrane/intracellular domain and produced by alternative splicing of FcαR transcript, have been described in several cells of the myeloid lineage: macrophages 80, neutrophils 81, and eosinophils 82. However, the surface expression of a different isoform has only been observed so far in human alveolar macrophages.

FcαR binds all forms of IgA (monomeric, polymeric and secretory IgA of both IgA1 and IgA2 subclasses) (monomeric, polymeric and secretory IgA of both IgA1 and IgA2 subclasses). Considering the high level of SIgA in secretory fluids, the binding of SIgA to FcαR on phagocytic cells is of particular interest concerning the defense of mucosal surfaces 63. In addition to FcαR, SIgA has been shown to bind to an unidentified IgA receptor on human monocytes, and that binding is blocked by galactose 83. Moreover, a 15 kDa receptor for secretory component (SC) and thus also for SIgA has been identified on eosinophils but not on neutrophils 84. Using different CD89 transfectant cell models, several studies have reported that pIgA binds more efficiently to FcαR than mIgA 85. These data suggest that FcαR probably plays an important role in mucosal compared to systemic immunity and notably in the clearance of pIgA immune complexes, phagocytosed by alveolar macrophages and hepatic Kupffer cells. At the same time, it seems very likely that the clearance of mIgA from the blood occurs through other mechanisms 72. The spliced variants of CD89, which exhibit different characteristics for IgA binding, may contribute to mIgA binding and clearance by phagocytes.

Association of immunoglobulin-A leukocyte receptor with signaling immunoglobulin leukocyte receptor γ-chain
FcαRs are expressed on the cell surface in association with the FcR γ-chain homodimer 86–88, which is also associated with the FcεRI, the T-cell receptor complex (CD3), the FcγRI (CD64), and some isoforms of FcγRII (CD32) and FcγRIII (CD16) 89. The FcR γ-chain is associated with the 19 aa transmembrane domain of FcαR, where the single positively charged arginine residue at position 209 is necessary for this physical association 88. FcR γ-chain is neither essential for binding IgA to FcαR 85 nor FcαR expression in transfectants 88, 90. However, the FcR γ-chain is essential for FcαR-mediated recycling (but not endocytosis) and for triggering the increase of intracellular calcium ions (Ca2+), antigen presentation, and cytokine production 91. The FcR γ-chain also plays an important role in targeting FcαR-bound IgA into endolysosomal compartments, leading, therefore, to its degradation, while γ-less FcαR-expressing cells, including monocytes and metabolism 92. Although the FcR γ-chain is necessary for IgA-induced “outside-in” signal transduction in leukocytes, it is not required for cytokine-induced IgA binding to eosinophils. Thus, the binding of IgA to IL-5-primed eosinophils occurs via the intracellular domain of FcαR, independently of its interaction with the FcR γ-chain, through a PI-3K mediated “inside-out” signaling 93.

The FcR γ-chain, but not the FcαR, contains in its cytoplasmic domain, immunoreceptor tyrosine-based activation motifs (ITAMs) that are phosphorylated on tyrosine residues subsequently to FcαR cross-linking 88, 94. Phosphorylation of ITAMs correlates with the activation of several sets of cytoplasmic protein tyrosine kinases (PTKs) 60. Src family phosphotyrosine kinases are the first set of these PTKs, and in contrast to FcγR, only p56Lyn kinase seems implicated in FcαR/γ-chain signal transduction 95. Phosphorylation of Src kinases results in the recruitment of p72Syk family member and Bruton tyrosine kinase (Btk) to the FcαR/FcR γ-chain complex 95, 96. This process leads to the phosphorylation and, therefore, the activation of further downstream proteins such as PKC, PLCγ 97, and mitogen-activated protein kinases (MAPK) (MAPK). Tyrosine kinases could phosphorylate other intracellular proteins, such as phospholipids and phospholipases 71. Signals triggered following the phosphorylation of ITAMs could join the biochemical pathways generated by other antigen receptors 60. These include the increased concentration of intracellular Ca2+, activation of PKC, and ras pathways that, in the end, phosphorylate MAPKs, which activate transcription factors regulating gene expression (fig. 4⇓).

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Fig. 4.— \sSchematic representation of the leukocyte immunoglobulin-A (IgA) crystallizable fragment (Fc) receptor (FcαR) associated with crystallizable fragment receptor FcR γ-chain, and the outside-in and inside-out signaling pathways that regulate functional aspects of FcαR and its expression, respectively (>: increase, <: decrease, ⊕: activation). NH2: amino group; IL: interleukin; TNF-α: tumor necrosis factor-α; ERK: extracellular signal-regulated kinase; TGF-β: transforming growth factor-β; Ca++: calcium ions; PKC: protein kinase-C; ADCC: antibody-dependent cell-mediated cytotoxicity; COOH: carboxylic acid; Fcγ: crystallizable fragment-γ. Immunoglobulin-A leukocyte receptor expression and regulation Different mechanisms regulate FcαR expression according to the type of myeloid cell. For example, PMA enhances the expression of FcαR on monocytic cell lines but not on eosinophils, while a Ca2+-ionophore upregulates FcαR on eosinophils without modulating that on monocytes 70. Several studies have reported that the expression of FcαR on leukocytes can be either up- or down-regulated by either Th1 or Th2 cytokines and endotoxins, but also by different agents such as phorbol esters, calcitriol, and ionomycin. Chemotactic peptides such as formyl-methionyl leucyl phenylalanine also increase the expression of FcαR on neutrophils, suggesting that this receptor is stored in intracellular pools on the membrane of secretory vesicles 98. Cross-linking of FcαR with IgA upregulates FcαR expression itself 69, 99. Table 2⇓ summarizes the modulation of FcαR expression in leukocytes 100–107. Inline viewing View the popup Table 2— \sDistribution and modulation of the CD89 surface expression on leukocytes Several molecules involved in the signal transduction pathways after FcαR activation are now well recognized. Interestingly, the regulation of FcαR expression can also be modulated by an "inside-out" signaling which results in either an increased number of FcαR on the cell surface or a higher affinity for their ligands. PI-3K and p38 MAPK, but not MAPKinase/ERKinase–Kinase (MEK) kinases, play for example a critical role in the binding of IgA to IL-4- and IL-5-primed eosinophils 108. The mechanisms by which PI-3K and p38 MAPK activate FcαR are unknown. However, it is important to outline that these two kinases regulate the cytoskeletal reorganization 109, 110 suggestings; therefore, the cytoskeletal organization may be a determinant for FcαR activation. Indeed, cytochalasin D-treated eosinophils fail to bind IgA complexes 93. In addition to its membrane-bound form, FcαR exists in soluble forms 111. These soluble molecules are produced by alternative splicing of the FcαR primary transcript or proteolysis of the membrane-associated full-length receptor. Recent data suggest that monocytes could be the major source of soluble FcαR as PMN does not release it in vitro 111. Soluble FcαR can downregulate FcαR signaling by competing for IgA. This suggests that soluble FcαR is biologically active and potentially beneficial in cases where FcαR/IgA complexes induce cytotoxicity. Soluble FcαR may, therefore, have potential therapeutic effects in IgA-mediated disorders. Functions of the mucosal immunoglobulin-A system The 400 m2 surface area (300 m2 and 100 m2 for the digestive and lung surfaces, respectively) of mucosa continuously in contact with innocuous and potentially harmful microorganisms and antigens represents a major challenge for the defense system. IgA-dependent immunity is suggested by several lines of evidence to fit these particular conditions by providing, in cooperation with nonspecific innate factors such as mucociliary clearance, an efficient "first-line" of defense against external agents without inducing a potentially harmful inflammatory response. The following observations indirectly support the fact that SIgs (mainly SIgA) make a large contribution to this "first-line" mucosal defense by performing a so-called "immune exclusion" of infectious agents from mucosal tissues. The structure itself of SIgA is a compromise between the high cross-linking capacity of pentameric IgM and the great tissue diffusion ability of monomeric IgG. In addition, and especially when the first line of defense is encompassed, IgA may recruit the inflammatory system by activating FcαR-expressing mucosal leukocytes. On the other hand, immune tolerance is developed towards innocuous antigens encountering mucosal surfaces. Protective effects of immunoglobulin-A against infectious agents Several groups have reported inhibition of the adherence of bacteria such as Escherichia coli to the epithelium by SIgA-specific antibodies 112, as well as by free SC. In this respect, it has been shown that SIgA antibodies have a broader specificity than comparable serum antibodies, as supported by deletions and insertions in the complementary determining regions of Ig variable region genes from mucosal immunocytes 113. The relatively high level of polyreactive "natural" SIgA antibodies is probably designed to assume immediate protection before eliciting an adaptive response and thus participates in innate immunity 114. SIgA (as well as free SC) has also been shown to bind to S. pneumoniae through a bacterial surface protein called S. pneumoniae surface protein A: SpsA 115. Interestingly, Zhang et al. 116 recently illustrated that the interaction of SpsA with the pIgR on nasopharyngeal epithelial cells mimics the infectious process since it initiates adherence and internalization of S. pneumoniae and its transcytosis towards the basolateral pole where the bacteria are released. This might represent an example of deviation by a pathogen of a mucosal defense mechanism. However, IgA, which was not present in this in vitro system, might interfere with this invasion process by binding to the pIgR. In addition to the putative luminal exclusion of bacteria performed by SIgA, a specific intraepithelial neutralization of viruses (such as influenza or rotavirus) through interferences with their assembling processes has been demonstrated in pIgR-expressing MDCK cells 117. Furthermore, it has also been shown that pIgA present in immune complexes (i.e., dimeric (d)IgA against dinitrophenyl/bovine serum albumin complex) can be excreted from the basal into the apical compartment by confluent monolayers of pIgR-expressing MDCK cells. Thus, IgA appears to be able to neutralize infectious agents or antigens at the 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 a loss of bacterial plasmids encoding molecules related to adherence or antibiotic resistance, as well as interference with growth factors (such as iron) or enzymes required for pathogen growth and invasion. It is probably through these different beneficial mechanisms identified in vitro that SIgA antibodies have been shown in vivo to confer protection to naive mice against oral challenge with Taenia taeniaeformis 118 or that many states of resistance to infection are correlated with titers of specific SIgA antibodies 119. Immunoglobulin-A leukocyte receptor-mediated leukocyte response. In addition to the neutralization performed in the mucosa by IgA through its Fab fragment, IgA-containing immune complexes also initiate immune responses that could play a crucial role in host defense and inflammatory diseases. Like the other FcRs associated with ITAMs, cross-linking of FcαR via Fc fragments of IgA triggers several biological responses which seem to be dependent on the cell type in the myeloid lineage. These responses, which are generally mediated by Ca2+ mobilization and PKC activation 97, include phagocytosis of IgA immune complexes 120, 121, antibody-dependent cell-mediated cytotoxicity 120, killing of IgA-opsonized bacteria and parasites 122–124, and production of reactive oxygen intermediates 64, 125, 126, inflammatory mediators and cytokines 127, as well as leukotrienes and prostaglandins 128. Cross-linking of FcαR by IgA complexes on monocytes induces increased TNF-α, IL-1β, and IL-6 99, 128–130. Activation of FcαR may, thus, result in enhanced production of cytokines, which could modulate inflammatory immune responses and tissue infiltration by PMN. The interaction of IgA, particularly SIgA, with FcαR is critical in protecting the epithelial immune barrier. Human IgA can mediate both phagocytosis and post phagocytic intracellular events. This is a relevant effect, especially at mucosal surfaces where the inflammatory response and released cytokines following bacterial adherence and invasion can stimulate FcαR expression and phagocytosis of IgA-opsonized particles by PMN 131. FcαR also plays an important role in eosinophil degranulation 132 and killing parasites such as schistosomes 124. In addition, eosinophils may bind SIgA via a specific receptor for SC and therefore constitute potential candidates in host mucosal defense against parasite invasion. Moreover, it was also shown that SIgA induces the degranulation of human basophils after priming with IL-3 133, although no receptor for IgA has been characterized so far on basophils or mast cells. The triggering of FcαR by IgA is not exclusively associated with activating proinflammatory processes such as cytokine release and oxidative metabolism. Several studies have shown that IgA downregulates the oxidative burst and the release of inflammatory cytokines such as TNF-α and IL-6 by activated monocytes 134. Moreover, in contrast with IgM or IgG, IgA immune complexes exhibit limited complement (C) activation capacity. This occurs through the alternate pathway (via C3b binding) since IgA complexes fail to activate the C classical pathway 135. Furthermore, specific IgA can competitively block the IgG-mediated C activation 136. These FcαR-mediated anti-inflammatory effects are critical in controlling mucosal and systemic inflammation, protecting host tissues from injury 137, 138. Indeed, excessive production of cytotoxic oxygen metabolites and inflammatory mediators are often associated with chronic inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), or fibrosing alveolitis. However, it is important to outline that this FcαR-mediated down-regulation is dependent on the type of co-stimulatory signals and the type of effector cell triggered. In this context, the demonstration of spliced variants of FcαR on the surface of the alveolar macrophages is interesting. Although the role of these receptors remains to be defined, they are likely to provide additional regulatory mechanisms of phagocytic and inflammatory responses 80. Mucosal tolerance In contrast to the immune response elicited by noxious antigens, which efficient M-cells most likely take up, an inflammatory response against innocuous agents is avoided, particularly in the gut, where food and microflora bacterial antigens are constantly in contact. This is known as "oral tolerance" (reviewed in 139), a type of peripheral tolerance in which mature tissue lymphocytes are rendered nonfunctional or hyporesponsive by prior antigen administration. This immune tolerance is also present in the nasal and bronchial mucosa. Nonetheless, the mechanisms underlying this tolerance to innocuous and self-antigens, likely impaired in coeliac disease and chronic inflammatory disorders of the bowel or airways, are unknown. They are most likely the result of multiple pathways, including the rapid removal of luminal soluble antigens from the mucosa by poorly activated or "tolerogenic" APCs (dendritic cells, naive B-cells, or alveolar macrophages lacking co-stimulatory molecules CD80/CD86 or ICAM-1) 140. While several studies have shown that CD4+ rather than CD8+ T-cells are required for tolerance induction, CD8+ T-cells primed by HLA class I (or CD1)-restricted presentation by epithelial cells were initially thought to be the effectors of oral tolerance. Furthermore, TCR-expressing CD8+ T-cells have been shown to play an important role. IgE responses to inhaled antigens in rodent models of nasal or bronchial-induced tolerance could be suppressed by antigen-specific + T-cell transfer 141. In vivo treatment with specific anti-TCR antibodies, on the other hand, inhibited the induction of oral tolerance in ovalbumin-fed mice 142. In contrast, Fujihashi et al. 143 reported that T-cells from the gut epithelium inhibited oral tolerance. The Th-cell balance may also be involved, as oral or nasal tolerance induction is associated with increased Th2 cell activation and decreased Th1 cell activation. However, IL-4 144 is not required for subsequent tolerance. Active cellular regulation by specific Th subsets, such as Th3 cells producing primarily TGF- or IL-10 dependent TGF-secreting regulatory T-cells (Tr1 cells), has been implicated, particularly after antigen administration at low doses. In contrast to CD28-expressing cells, activated CD4+ T-cells expressing cytotoxic T-lymphocyte-associated molecule (CTLA-4) may provide negative signals leading to T-cell apoptosis, anergy, and down-regulation of Th-cell responses in response to higher antigen doses 145. Although the mechanisms underlying both active and anergic immune tolerance have yet to be fully understood, the mucosal route to access a major part of the immune system appears extremely appealing from a clinical standpoint and should hasten the development of mucosally administered antigens for the treatment of diseases such as respiratory tract infections. In respiratory diseases, mucosal immunity is important. A lack of immunoglobulin A A selective IgA deficiency, defined as a serum IgA concentration of 0.05 mgmL1 with normal levels of the other immunoglobulin classes, is common in serum from healthy blood donors, with a prevalence of 0.125-0.2%. This heritable humoral deficiency is caused by defects in genes that regulate isotype switching rather than those that encode -chains. The mucosa of these subjects appears devoid of IgA-producing cells. In contrast, normal J-chain-expressing B-cells' normal migration and maturation increase IgG and IgM-producing cells 146. Although most of these IgA-deficient people are healthy, this immunodeficiency is linked to an increased prevalence of atopy 147, food antigen sensitization 148, recurrent infections (particularly in childhood), and neoplastic and autoimmune disorders. It's interesting to note that allergic and infectious diseases associated with IgA deficiency primarily affect the respiratory tract. This could be due to IgM's less efficient compensation in the respiratory mucosa compared to the gut and to IgD's putative proinflammatory activity, which is more prevalent in the upper airways. pIgR-deficient mice, like IgA-deficient subjects, appear relatively healthy despite the absence of SIgs. However, these mice have higher concentrations of mIgA and albumin in secretions, indicating plasma leakage, and higher concentrations of IgG in serum, including IgG antibodies against their own E. coli, indicating a deficient epithelial barrier 149. Furthermore, their susceptibility to pathogens and allergens is currently unknown. Immunoglobulin A response in chronic inflammatory diseases of the airways In addition to the permanent genetic IgA deficiency, acquired and transient secretory immunity defects can occur. Thus, there was a decrease of IgA+ plasma cells in the bronchial mucosa from COPD patients compared to COPD patients who died from other causes, as well as a decrease of IgA in bronchial secretions from heavy smokers 150. However, variable levels of IgA and SC have been reported in smokers' and COPD patients' airway secretions, which may be related to the different titration methods used or the potential role of infection. Thus, increased sputum IgA concentrations in chronic bronchitis were associated with a clinical respiratory infection 151. According to a recent study, patients with severe COPD have lower pIgR bronchial expression, which correlates with airflow limitation and PMN infiltration 36. Although the implications of these findings are still hypothetical, it is possible that in this acquired deficiency, compensatory mechanisms are absent or inappropriate when the inflammatory response is elicited. Thus, in some susceptible smokers, persistent impairment of secretory Ig production and transport due to decreased pIgR expression may promote bacterial colonization and, thus, PMN infiltration of the airways. The continuation of this process may contribute to the progressive remodeling of bronchial structures seen in COPD. Furthermore, bacteria and PMN can degrade IgA via proteolytic cleavage 119, resulting in a vicious circle of impaired secretory immunity combined with an amplified inflammatory response. Similarly, a decrease in SIgA in saliva and bronchial secretions has been observed in cystic fibrosis patients 152. This finding is consistent with a study that found SC expression in the bronchial epithelium of cystic fibrosis patients was significantly lower than in control patients transplanted for primary pulmonary hypertension 153. In these patients, however, no significant correlation was found between SC expression and functional parameters. As a result, secretory immunity appears severely compromised in COPD and cystic fibrosis, characterized by chronic obstruction, PMN infiltration, and bacterial colonization of the airways. With decreased mucociliary clearance and IgA secretion, the epithelial damage associated with these disorders contributes to an ineffective first line of defense. The role of secretory immunity in the pathogenesis of asthma is more debatable. While the level of SC appeared to be lower in the bronchoalveolar fluid of asthmatics 154, many studies found an increase in IgA production in these patients' airway secretions, possibly due to the release of cytokines such as IL-4 and IL-5, which are known to upregulate IgA production and transport. Furthermore, D. farinae-sensitized asthmatics had higher levels of specific IgA antibodies to both D. farinae and S. pneumoniae in their sputum compared to controls 155. In this regard, it has been demonstrated that IgA antibodies to pollen allergens in asthmatic tears are directed against epitope determinants other than those eliciting IgE synthesis 156. Granulocyte activation is thought to be a driving force in asthma and a wide range of inflammatory diseases. IgA could influence the fate of inflammatory diseases such as macrophage-dependent lung injury 157, dermatitis herpetiformis 158, IgA-nephropathy 159, viral infection via FcR-mediated uptake of IgA-coated viruses 160, and asthma where eosinophils, particularly in the activated stage 161, could be controlled by IgA-dependent mechanisms. IgA, which is abundant on mucosal surfaces in asthma, can thus induce eosinophil degranulation 132, resulting in the destruction and damage of the respiratory epithelium. Furthermore, FcR expression is increased on allergic eosinophils 70, and unlike healthy donors, eosinophils from asthmatic patients do not require additional cytokine priming to bind IgA in vitro 162. TNF-which has been linked to eosinophil-mediated cytotoxicity 163, is abundantly produced in allergic inflammatory diseases 164, and high TNF levels are detected in asthmatic patients' bronchoalveolar fluid 165. TNF—primed eosinophils from asthmatic patients bind more IgA than primed eosinophils from healthy donors 162. Furthermore, sputum IgA levels in asthmatic patients correlated significantly with eosinophil cationic protein levels 155, indicating that IgA plays a role in eosinophil activation in asthma. Several other groups were interested in IgA nephropathy, characterized by IgA (mostly pIgA1) deposition in the renal glomerular mesangial area, where IgA receptors have been reported to be expressed on human mesangial cells 71. IgA-nephropathy is characterized by delayed plasma clearance of IgA immune complexes and impaired FcR endocytosis 166. It has been demonstrated that IgA from these patients is undergalactosylated 167, which could explain the impaired IgA catabolism. IgA deposition in the kidney glomerular mesangium is frequently associated with IgG, IgM, and complement, resulting in renal tissue damage. It is unknown whether the production of proinflammatory cytokines, primarily TNF- and IL-6, following IgA binding to mesangial cells contributes to the amplification of human renal injury. In contrast to the rat model, local inflammation is not associated with increased proliferation of human mesangial cells induced by IL-6 168. Medicinal applications Immunization with secretory immunoglobulin-A antibodies is done passively. Several experimental models have demonstrated that passive immunization with specific pIgA or SIgA can protect animals against a variety of infections, and clinical trials have now begun 169. In addition to SIgA, IgA purified from human serum and hyperimmune bovine colostrum, which contains mostly IgG antibodies, provided some protection against infections in immunocompromised patients. A promising approach is to take advantage of the fact that in recombinant secretory antibodies, both J-chain-containing pIgA and SC can be produced in the same cell if the appropriate gene transfections are performed and that specificity can be selected by cloning Ig variable region genes from murine monoclonal antibodies. When applied to the tooth surfaces of volunteers 170, recombinant anti-Streptococcus mutants chimeric SIgA/IgG antibodies produced in plant cells provided long-lasting protection against recolonization. Mucosal vaccination that is active In contrast to particulate or replicating antigens, which frequently induce active mucosal immunity, all thymus-dependent soluble antigens have the potential to induce oral tolerance. This feature has hampered the successful development of oral vaccines, particularly for autoimmune diseases. Some adjuvants, such as conjugation to the B subunit of cholera toxin, have been shown to promote tolerance. Furthermore, in vivo 171, the ability to tolerate even a sensitized host has been demonstrated. However, inconsistent results have been obtained in clinical trials for disorders such as rheumatoid arthritis, systemic sclerosis, and food allergies, primarily due to dose-dependent effects. Gene or protein delivery via polymeric immunoglobulin receptors Expression plasmids encoding, for example, the cystic fibrosis transmembrane regulator (CFTR), are specifically and efficiently incorporated into pIgR-expressing epithelial cells when complexed to polylysine-linked Fab fragments of antibodies directed against SC. This discovery has evolved into a potential method for introducing normal copies of the CFTR gene into the respiratory cells of cystic fibrosis patients 172. However, issues with the variable level of gene expression or the route of administration exist for this pIgR-targeted gene therapy, because the plasmids must be injected into the blood to reach the basolateral pole of the respiratory epithelium and thus cross the endothelial barrier. A fusion protein composed of an anti-SC single chain variable fragment (Fv) linked to human 1antitrypsin has recently been shown to transport efficiently in vitro across respiratory epithelial cells 173. In addition to its potential use in 1antitrypsin-deficient patients, this fusion protein could provide a strategy for delivering 1antitrypsin into the bronchial epithelial lining fluid of cystic fibrosis patients to neutralize neutrophil elastase activity, which likely contributes to disease progression. Conclusion A complex network of cells and mediators is required to protect the respiratory tract from various insults, including infection. Over 40 years ago, immunoglobulin-A was discovered and quickly identified as the major immunoglobulin in mucosal secretions, at least quantitatively. Despite this, and in contrast to immunoglobulin-G, little was known about immunoglobulin-specific A's role in the mucosa. Extensive research has revealed unique features of the immunoglobulin-A system, particularly those related to mucosal surface protection and the mechanisms regulating immunoglobulin-A active transport at the epithelial cell level. With the recent discovery of the immunoglobulin-A leukocyte receptor on phagocytes, including alveolar macrophages, an increased understanding of immunoglobulin-A biology has opened up new avenues for basic and clinical research, potentially leading to the development of novel therapeutic modalities for respiratory disorders. QUESTION
Introduction: The ANS is the part of the nervous system that supplies the internal organs and structures, including the blood vessels, stomach, intestine, liver, kidneys, bladder, genitals, lungs, pupils, heart, and sweat, salivary, and digestive glands. Two divisions of ANS (the sympathetic and parasympathetic) have opposite functions. As we learned, the sympathetic nervous system prepares the body for intense physical activity and is often referred to as the fight-or-flight response. The parasympathetic nervous system has almost the exact opposite effect, relaxes the body, and is often referred to as the rest-and-digest response.

For this post, you have to write at least 400 words addressing the following 5 points. Please identify each point in your answer.

Choose an organ in the body that has autonomic innervation. (LUNGS)
Next, describe how the organ you have chosen is affected by one of the two divisions of the ANS. Is it stimulated? Inhibited? Which part of the organ is affected? Do not do both divisions of the ANS.
Identify the location and neurotransmitters of the preganglionic and postganglionic neurons that innervate the organ you chose from the division (sympathetic or parasympathetic) you chose.
Would your organ be controlled through a gray ramus communicans, splanchnic nerve, cranial nerve, or sacral spinal nerve?
Describe a situation, like a car crash, that increases or decreases the activity of your organ, and explain the effect that situation would have on your organ. Compare that effect to normal basal levels of your organ’s activity. Explain how the change(s) in the activity of the organ of your choice might be perceived, if at all. Other situations could include a job interview, relaxing on a beach, encountering a growling dog while walking outside, jumping out of the way of an oncoming vehicle, getting a massage, feeling unsafe while walking down a dark street at night.
This is a first come first serve choice, so please review the previous postings to choose your organ. If one student chooses an organ like the eye, then only the regulation by either the sympathetic or parasympathetic nervous system should be discussed. One organ per student. Duplications are not allowed, and such postings will be deleted by the instructor. If you cite a specific source, please include the reference (APA format).