Update on mucosal immunoglobulin A in... : Current Opinion in Gastroenterology (original) (raw)

Introduction

The pathogenesis of gastrointestinal diseases should be viewed in the light of current knowledge on the immunophysiology of gut mucosa and gut-associated lymphoid tissue (GALT). The prevailing adaptive mucosal immune effector mechanism is an immunoglobulin A (IgA)-producing B-cell system, which basically provides noninflammatory first-line defense by giving rise to secretory IgA (SIgA) antibodies, which perform ‘immune exclusion’ . This term is coined for antibody functions at the mucosal surface, aiming to control both microbial colonization and penetration of noxious antigens through the epithelial barrier .

The generation of SIgA depends on IgA-producing plasma cells and their immediate precursors (plasmablasts), which accumulate in the mucosa by selective homing mechanisms after being primed in GALT, including Peyer's patches, isolated lymphoid follicles (ILFs) and the appendix . At least 80% of the body's immunoglobulin-producing cells are located in the gut, which, therefore, constitutes the largest effector organ of humoral immunity . This article will review recent and previously established information on how the effector functions of the mucosal IgA system could be involved in the pathogenesis of gastrointestinal diseases.

Immunoglobulin A-mediated mucosal homeostasis

Most mucosal plasma cells produce dimers and larger polymers of IgA (collectively called pIgA), which contain a disulfide-linked 15-kDa polypeptide called the ‘joining’ or J chain.

Secretory immunity and immune exclusion

The J chain is a prerequisite for active export of pIgA through secretory epithelia such as intestinal crypts and antral glands . This transport is mediated by the polymeric immunoglobulin receptor (pIgR), originally called membrane secretory component. J chain-containing pentameric immunoglobulin M (IgM) is externally transported by the same mechanism .

Apical cleavage of the extracellular portion of pIgR enables release of SIgA and secretory SIgM to the lumen. In this manner, the ectodomain of pIgR is ‘sacrificed’ to become bound secretory component, which stabilizes the quaternary structure of the secretory antibodies, particularly by covalent bonding in SIgA . Immune exclusion performed by SIgA and IgM antibodies, thus, as explained in the Introduction, depends on an intimate cooperation between the mucosal B-cell system and the pIgR-expressing epithelium (Fig. 1), although serum-derived and locally produced immunoglobulin G (IgG) antibodies reaching the lumen by paracellular diffusion contribute . IgG is rapidly degraded in the gut lumen, but the hepatic superantigen (protein Fv) may form large complexes with degraded antibodies of different specificities, thereby reinforcing their immune exclusion function .

Other immunoglobulin A antibody functions

The numerous pIgA+ plasma cells are also important for homeostasis within the mucosa by several anti-inflammatory mechanisms. IgA lacks ordinary complement-activating properties and may, therefore, block nonspecific biological amplification triggered by locally produced or serum-derived IgG antibodies . This is important in view of the fact that immune complexes are probably formed even within the normal lamina propria due to some influx of soluble antigens, particularly following food intake . In-vitro and in-vivo experiments have suggested that soluble antigens – after pIgA-mediated noninflammatory trapping in immune complexes – may be cleared by the secretory epithelium via pIgR-mediated translocation to the lumen (Fig. 1) . Similar experiments have suggested that pIgA antibodies can neutralize lipopolysaccharide (LPS) and viruses within secretory epithelial cells during pIgR-mediated export . In-vivo data have confirmed that the latter mechanism may participate in the intestinal defense against rotavirus infection .

Locally produced pIgA may further influence homeostasis by interacting with the Fcα receptor (CD89) on leukocytes in the lamina propria. First, pIgA-containing immune complexes are able to suppress attraction of neutrophils, eosinophils and monocytes, thereby reducing their proinflammatory activities . Second, IgA can apparently downregulate the secretion of proinflammatory cytokines such as tumor necrosis factor-alpha (TNFα) from activated monocytes . However, it is uncertain whether this mechanism operates in the normal gut (Fig. 1) because mucosal macrophages do not express detectable surface CD89, at least not in the small intestine . Third, neutrophil and monocyte activation that results in generation of reactive oxygen metabolites (‘respiratory burst’) is reportedly inhibited by IgA . Conversely, pIgA may temporarily trigger monocytes to enhanced activity – including TNFα secretion – and IgA (particularly SIgA) appears to be a potent activator of eosinophils . These in-vitro results suggest that the participation of pIgA in mucosal homeostasis is quite fine-tuned, perhaps being skewed toward a proinflammatory potential in gastrointestinal disease in which there are numerous granulocytes and recently recruited monocyte-like macrophages with expression of the LPS receptor CD14 and Toll-like receptors (TLRs) such as TLR2 and TLR4 .

Secretory antibodies in epithelial barrier function

Although human gut closure normally occurs mainly before birth, the mucosal barrier may be inadequate up to 2 years of age. The mechanisms involved remain poorly defined , but the development of secretory immunity is probably a decisive variable. Importantly, knockout mice deficient in pIgR that lack both SIgA and SIgM exhibit aberrant mucosal leakiness and excessive uptake of commensal bacteria and food proteins . These mice show significantly increased production of systemic antimicrobial IgG antibodies but not food antibodies. The undue influx of microbial products causes a generalized hyperreactive state with overactivation of the innate cellular nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription pathway, resulting in 50% liability to anaphylactic death after systemic sensitization to ovalbumin (OVA) and low-dose intradermal OVA challenge . However, the mice show enhanced capacity for induction of regulatory T (Treg) cells mediating oral tolerance. This homeostatic mechanism is fully able to control IgG1-dependent and T-cell-dependent hypersensitivity against OVA after feeding with the same antigen .

This observation implies that, although an inadequate gut barrier in the newborn represents a risk for hypersensitivity reactions, it will promote tolerance against the offending antigen when continuously present in the gut. The balance between the epithelial barrier function and oral tolerance thus appears to be critical for homeostasis. Also, although the incidence of food allergy [apparently non-immunoglobulin E (IgE)-mediated] is increased in children with IgA deficiency, it is not strikingly elevated , perhaps because the induction of Treg cells is enhanced in addition to compensatory SIgM, which in such individuals partially replaces the lacking SIgA in the gut . IgA-deficient knockout mice also have compensatory SIgM in their gut and show no increased susceptibility to dextran sodium sulfate (DSS)-induced colitis, whereas pIgR knockout mice that lack both SIgA and SIgM do .

Interactions between secretory immunoglobulin A and commensals

In mice with SIgA deficiency due to lack of immunoglobulin class switching combined with incompetent SIgM antibody, a striking hypertrophy of ILFs develops over time in response to overgrowth of anaerobic commensal bacteria . This development has some resemblance to the irregular lymphoid aggregates seen in long-standing inflammatory bowel disease (IBD) . Indeed, the take-home lesson from most disease models in gene-manipulated animals is that a predilection exists for immunopathology to occur in the distal gut – where most commensals reside – when adaptive immunity is dysregulated and innate immunity or the intestinal barrier function compromised .

It has recently been shown that an intestinal immune response to a single commensal microbial epitope (capsular polysaccharide A, PSA) can be immunomodulatory and protect against pathogen-induced colitis . Experiments with germfree mice monocontaminated with the gut commensal Bacteriodes thetaiotaomicron demonstrated that specific SIgA antibodies directed against PSA inhibit activation of innate response markers such as oxidative burst and NF-κB, thus inducing a crucial modulation of immune homeostasis as well as antigenic drift .

Experimental studies have, moreover, revealed how intestinal homeostasis is mediated by host–microbial interactions in mice monocolonized with the _Clostridia_-related segmented filamentous bacterium (SFB), which particularly grows in the distal ileum . SFB adheres to the Peyer's patches and stimulates T-cell as well as IgA responses. Here, a distinction is important between B1 and B2 (classical T-cell-dependent) responses when comparing Peyer's patches and the lamina propria of mice. This distinction is as yet not clear. It is also possible that M cells of GALT may take up immune complexes containing commensals and SIgA via receptors for IgA . Recently, this mechanism was suggested to direct the opportunistic bacterium Alcaligenes into GALT tissue and thereby make it more resistant to pathogen invasion .

Alterations of the mucosal immunoglobulin A system in inflammatory bowel disease

IBD lesions exhibit excessive numbers of IgA+ and IgG+ plasma cells with a remarkable skewing toward IgG production, depending on the severity of inflammation . Initially, this shift from the normal pIgA predominance may be beneficial as a powerful second line of defense because IgG antibodies can efficiently mediate immune elimination of bacteria via phagocytosis and antibody-dependent cell-mediated cytotoxicity. Neutrophils and Kupffer cells expressing CD89 may likewise eliminate invading bacteria opsonized with monomeric serum-type IgA.

Humoral immunity and immune exclusion

The chronicity of IBD signifies that a defective epithelial barrier over time results in severely altered mucosal homeostasis (Fig. 2). Thus, whereas fluorescent in-situ hybridization on tissue sections from normal colon reveals no microorganisms, 83% of ulcerative colitis and 25% of colonic Crohn's disease specimens show mucosal invasion of commensal bacteria . In ulcerative colitis, a proinflammatory antimicrobial response is additionally promoted by a significant shift toward the highly complement-activating IgG1 subclass , apparently reflecting a genetic impact, as revealed by comparing identical twins, healthy or afflicted with ulcerative colitis .

In parallel with the disproportionately increased IgG+ plasma cell subset, the J-chain expression is decreased in IBD lesions and there is a shift from the IgA2 to the less-stable IgA1 subclass . Thus, more than 50% of the IgA1+ plasma cells are J chain-deficient, and therefore producing monomers that cannot be exported by the pIgR . The same is true for a fraction (25–35%) of the expanded IgA2+ subset. These adverse local plasma cell alterations supposedly reflect a less restricted leukocyte extravasation due to a changed profile of adhesion molecules and chemokines on the mucosal microvascular endothelium, allowing B cells expressing characteristics of systemic immunity to enter the lesion (Fig. 2).

A deficient epithelial barrier in IBD not only promotes bacterial invasion but also increases food-antigen uptake and sensitization after rectal challenge, as shown in Crohn's disease patients . This finding harmonizes with the increased mucosal leakiness of pIgR knockout mice . Of further note, the frequency of IgA deficiency among Crohn's disease patients is significantly increased compared with the healthy population in Sweden, that is, one in 100 compared with one in 600 (Lennart Hammarström, personal communication).

Antibodies to commensals and break of tolerance

Locally produced IgG in IBD lesions has been reported to react with cytoplasmic antigens from a range of Gram-positive and Gram-negative fecal bacteria, with higher activity in Crohn's disease than in ulcerative colitis, and higher in ulcerative colitis than in other types of intestinal inflammation . Thus, nonspecific mucosal damage and bacterial invasion alone do not seem to explain the intensified local IgG response to commensals. Studies in rodents have shown that indigenous gut bacteria normally are poorly stimulatory for the B-cell system. One explanation might be that the enteric microbiota induces waves of self-limiting SIgA responses in GALT while permanently colonizing the gut . Such intermittent immune exclusion could contribute to the hyporesponsiveness that exists toward gut commensals. This mechanism is clearly abrogated in IBD , which agrees with several experimental models of intestinal inflammation in rodents . Also, it has been shown that dysfunction in either the adaptive or innate mucosal immune system leads to systemic antibody hyperreactivity to the gut microbiota .

Such a break of microbial tolerance is signified by increased in-vivo antibody coating of gut bacteria. In healthy controls, approximately 40% of fecal anaerobic bacteria are coated with IgA, 12% with IgG and 12% with IgM . In IBD, these figures are raised to 65, 45 and 50%, respectively, with no difference between ulcerative colitis and Crohn's disease . In addition to some leakage of antibodies from serum (Fig. 2), this result reflects the markedly elevated mucosal immunoglobulin production in IBD , with the relative average increase being more prominent for IgG (×30) and IgM (×2.5) than for IgA (×1.7–2.0). In fact, adjacent to Crohn's disease ulcers, the number of plasma cells is increased 100–200-fold for the IgG class and 8–12-fold for the IgM class compared with 1.2–6.7-fold for the IgA class. On the basis of analysis of serum antibodies, however, there seems to be considerable heterogeneity in microbial specificities among IBD patients; rather than a global loss of tolerance against intestinal bacteria, individual subsets of patients with varying immune responses to selected microbial antigens have been identified . Whether this is the cause or the effect of a more restricted gut microbiota – with 25% fewer bacterial genes than normal – is currently unknown .

Putative role of the appendix

No clear answers with regard to predisposition to IBD have emerged from international case–control studies, except for a decreased incidence of prior appendectomy in ulcerative colitis patients . Appendectomy at an early age (before 20 years) may also protect against Crohn's disease, at least by delaying its onset . It seems that the beneficial effect is explained by inflammation in the appendix or mesenteric lymph nodes , implying overstimulation at these immune-inductive sites. Both the appendix and mesenteric lymph nodes contain B-cell follicles that generate a substantial contingent of IgG+ plasma cells, often with downregulated J chain as a sign of clonal maturity . Thus, in the appendix, there are approximately equal proportions of IgG+ and IgA+ plasma cells in the follicle-associated lamina propria, and the same is true for ILFs in the colon and ileum . Perhaps cells derived from a similar B-cell subset – after homing to the large bowel mucosa – could develop a proinflammatory IgG response against indigenous bacteria (and autoantigens?) that predisposes to IBD .

This possibility is corroborated by the strikingly reduced gut inflammation observed in T-cell receptor-α knockout mice after early (<5 weeks of age) ‘appendectomy’ (removal of the cecal patch) . Interestingly, the proliferative response of B cells from the appendix of such mice is quite strong after stimulation with Escherichia coli antigens, and increased levels of autoantibodies to tropomyosin are also produced . Appendectomy (but not splenectomy) has likewise been shown to reduce disease severity in a DSS-induced murine model of colitis . Together, these findings strongly support the suggested importance of the appendix as a site for activation of B cells involved in production of pathogenic proinflammatory antimicrobial IgG antibodies.

Mucosal antibody response in celiac disease

The immunoglobulin pattern of plasma cells in gluten-sensitive enteropathy shows only minor proinflammatory skewing. Thus, IgA+ plasma cells remain remarkably dominating in the lamina propria in both treated and untreated adult celiac disease, although the numbers of IgA+, IgM+ and IgG+ plasma cells per tissue unit are on average increased 2.4, 4.6 and 6.5 times, respectively . The results in celiac children and adult patients with dermatitis herpetiformis are comparable .

Predominantly homeostatic expansion of plasma cells

This relatively homeostatic response reflects a well preserved microvascular profile of adhesion molecules in the celiac lesion, with leukointegrin α4β7 and mucosal addressin intercellular adhesion molecule-1 being the two most important interacting molecules . The plasma cell data cited above agree with the result obtained by enzyme-linked immunosorbent spot assay performed with dispersed mononuclear cells from untreated celiac lesions, showing on average 68% of the antigliadin cells to be of IgA+, whereas up to 30% was occasionally accounted for by IgG+ and IgM+ cells .

Immunohistochemistry has shown that the IgA+ plasma cells consist of 47% IgA2 in untreated patients compared with 29% in healthy controls, and both subclasses of IgA+ plasma cells maintain a mucosal phenotype with abundant J-chain expression . The estimated potential for local SIgA2 export is increased to approximately 50% of total SIgA in untreated celiac lesions compared with a basal level of about 30% in the normal jejunum . A marked increase of local IgM production and elevated pIgR expression also contribute to enhanced secretory immunity in celiac disease.

Immunoglobulin A antibodies to gluten and tissue transglutaminase

By means of ELISA, relatively high concentrations of IgA and IgM antibodies to gluten/gliadin (only IgM in IgA deficiency) have been detected in jejunal fluid from untreated celiac patients , in agreement with the mucosal plasma cell data. The IgA antibodies were, as expected, found to be mainly SIgA and to contain a relatively high proportion of IgA2 . Moreover, the IgA antibodies were shown to disappear more slowly from intestinal fluid than from serum during gluten restriction , and the jejunal IgM antibodies persisted for quite prolonged periods in treated adults .

Excessive IgA production in the celiac lesion seems to explain most of the increased serum IgA levels, characteristic of untreated or gluten-challenged celiac patients; a strong positive correlation exists between the serum level of IgA antibodies to gluten/gliadin and the number of jejunal IgA+ plasma cells . The fact that 57–61% of the circulating antibodies are pIgA, in addition to an enrichment of the IgA2 fraction, also implies a mucosal origin. Alternatively, gluten/gliadin antibodies may be secreted in peripheral blood by circulating IgA+ plasmablasts on their way from inductive GALT to seed the lamina propria .

The relationship between the severity of celiac disease or dermatitis herpetiformis and the serum level of endomysial antibodies (IgA-EMAs) suggests that these antibodies, as well as gluten/gliadin antibodies, are produced in the mucosal lesions . However, whereas 31% of the gluten/gliadin antibodies belong to the IgA2 subclass, only 6% of the IgA-EMAs do, perhaps reflecting an extraintestinal contribution . Notably, however, even in celiac disease, most jejunal IgA+ plasma cells (53%) actually produce IgA1 , and IgA-EMAs are exported to the gut lumen of patients with gluten-sensitive enteropathy . Also importantly, culture fluid of mucosal biopsies from untreated patients contains IgA-EMAs, and production of such antibodies can be induced in jejunal specimens from treated patients restimulated ex vivo with gliadin peptides . Low levels of circulating IgG1-EMAs likewise seem to be produced in the lesion . Importantly, the actual (or major) autoantigen detected by IgA-EMAs has been identified as tissue transglutaminase (tTG) type 2, which belongs to a ubiquitous enzyme family abundantly released from cells during stress and tissue damage .

Putative pathogenic role of polymeric and secretory immunoglobulin A antibodies

Whether antibodies to tTG represent an epiphenomenon or are of pathogenic importance remains an issue of controversy. It should be kept in mind that celiac disease occasionally occurs against a background of severe hypogammaglobulinemia , which implies that antibodies to tTG cannot generally be pathogenic. It is nevertheless intriguing to speculate that such antibodies might contribute to the pathogenesis of villous atrophy . IgA (probably pIgA) is deposited in the subepithelial site where the enhanced tTG expression is seen in the lesion , and this feature may predict villous atrophy . The development of absorptive enterocytes may partly depend on transforming growth factor-beta (TGF-β), which is secreted by a variety of cell types as an inactive or ‘latent’ form in a protein complex. Degradation of the prosegments associated with the mature cytokine homodimer by proteases (e.g., plasmin) is necessary to release the active form. Because tTG apparently has a significant role in preparing latent TGF-β for such proteolytic activation, antibodies to tTG might inhibit enterocyte differentiation.

An additional disease-promoting effect of SIgA has recently been proposed . This work demonstrated that gluten peptides can enter enterocytes by receptor-mediated retrotranscytosis rather than by a paracellular pathway, and thereby be delivered intact into the lamina propria. The intracellular transport involves particularly the immunostimulatory 33-mer (peptide 56–89) and is not observed in patients on a gluten-free diet or healthy controls, in whom the peptides are almost entirely degraded after entering the enterocytes. By contrast, in active celiac disease, a large proportion of the peptides are rapidly translocated in a protected manner into the lamina propria. It was shown that intact peptides in the intestinal lumen bind to SIgA; retrotranscytosis of such immune complexes is mediated by the transferrin receptor (CD71), which shows affinity for IgA1. This receptor is upregulated and abnormally expressed at the apical surface of enterocytes in active celiac disease.

The retrotranscytosis of gluten peptides may maintain intestinal inflammation in active celiac disease, although the role of this process in the onset of the disease is uncertain. Enterocyte expression of CD71 is markedly upregulated in response to decreased iron stocks, a condition observed in young women following pregnancies . This period is typically associated with the onset of celiac disease. However, that SIgA-dependent retrotranscytosis is of major importance for uptake of the 33-mer could not be verified in a gluten-sensitive macaque model .

Marked and altered mucosal immunoglobulin A response in gastritis

In health, the stomach shows immunological activity mainly in the antrum, where IgA+ plasma cells are abundant and pIgA is exported by pIgR-expressing epithelium . In chronic gastritis, there is a marked plasma cell expansion, which partly extends to the gastric body . However, this is not a homeostatic response because a skewing toward local IgG production is seen, although not to the same extent as in IBD. Also, there is reduced J-chain expression and a plasma cell shift toward IgA1 . Notably, however, Helicobacter pylori does not produce IgA1 proteases and bacteria deep in gastric pits are coated with IgA, apparently being protected against complement attack .

It has recently been reported that the expression of the generalized mucosal chemokine (C–C motif) ligand 28 (CCL28) is elevated in gastritis and shows chemotactic activity toward gastric mucosal IgA+ plasmablasts . Therefore, CCL28 most likely plays an important role in the massive expansion of IgA+ plasma cells seen in the gastric lesion. Nevertheless, the inductive site for B cells homing to the stomach remains elusive, although a mouse model of _H. pylori_-induced gastritis suggested that Peyer's patches are the origin of gastric plasma cells . A contribution from locally induced ILFs in gastritis seems likely as well.

Food allergy

A decreased IgA response, together with multiple defects of innate immunity, has been implied in the pathogenesis of food allergy . Such dysregulation of immune mechanisms, including the SIgA system, could contribute to a leaky gut barrier, which, together with inadequate development of Treg cells, seems to contribute to the lack of oral tolerance leading to food allergy. This topic has recently been extensively reviewed .

Conclusion

Mucosal IgA is generally considered to be beneficial by performing immune exclusion of potentially harmful antigens and pathogens, containing the gut microbiota and reinforcing the epithelial barrier function. However, putative adverse functions of SIgA have also been identified.

Acknowledgements

Studies at LIIPAT were supported by the Research Council of Norway, the Norwegian Cancer Society, the University of Oslo and Oslo University Hospital. The author is grateful to Hege Eliassen for excellent secretarial assistance.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 656–657).

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95 Berstad AE, Kilian M, Valnes KN, Brandtzaeg P. Increased mucosal production of monomeric IgA1 but no IgA1 protease activity in Helicobacter pylori gastritis. Am J Pathol 1999; 155:1097–1104.
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99 Latcham F, Merino F, Lang A, et al. A consistent pattern of minor immunodeficiency and subtle enteropathy in children with multiple food allergy. J Pediatr 2003; 143:39–47.
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Keywords:

celiac disease; epithelial barrier; food allergy; gastritis; inflammatory bowel disease