All tested bacteria apparently elicited a waxing followed by a long-term waning IgA response, which was accompanied by a GC reaction that notably showed a much more rapid development as well as decline.
Such homeostatic immune modulation has been particularly well documented with segmented filamentous bacteria SFB, related to Clostridia , which become a major gut colonizer of the distal ileum of mice after weaning.
Several uncertainties need to be solved before full understanding of the biology of the mucosal IgA system is achieved, and one of the open questions concerns the specificity of the intestinal immune response Monoassociation of germ-free mice with SFB, followed by super-colonization with Morganella morganii after days, induced little change in production of total intestinal IgA although the specific response to M.
The chronic GC reaction observed in GALT of conventional mice is therefore most likely caused by continuous exposure of the gut to novel microbial antigens.
Thus, germ-free mice monoassociated with the comensal B. Furthermore, when germ-free mice were colonized with an E. Thus, the sustained colonization of gut bacteria exhibiting novel epitopes may provide the necessary chronic bystander stimulation of previously induced cross-reactive and specific IgA production.
SIgA antibodies can hence control the intestinal microbiota in a non-inflammatory, symbiotic, or mutualistic relationship with the host , Other studies have shown that IgA autoantibodies produced in duodenal mucosa of patients with celiac disease are of high affinity but with little adaptation by SHMs, exhibiting mainly a germline repertoire In this context it is of considerable interest that mouse experiments recently indicated the presence of two disparate differentiation pathways for memory B cells — one dedicated to generation of high-affinity somatic antibody mutants, and the other with preserved germline specificities to arm the host for rapid responses to encountered variants of potentially dangerous antigens — perhaps including commensals with the potential of causing disease, so-called pathobionts , The near-germline feature is characteristic for the IgA repertoire of human neonates , as also reflected in neonatal secretions Both the duodenal and the parotid PC frequency of IgA V H mutations of adults is much higher than that in adult human spleen, apparently because of the constant antigenic pressure on MALT In clean laboratory rats, however, a more restricted IgA repertoire near germline was revealed in salivary glands than in the distal small intestine, probably reflecting the regional difference in bacterial load This process of SHM may be enhanced when antigen recall drives B cell to re-enter the dark zone for a new GC cycle Figure 6 , or to enter a preformed follicle after exit from the GC Attempts have been made to characterize murine memory B cells by their transcriptional program in relation to Ig isotype as both SHM and class-switch recombination CSR depends on activation-induced cytidine deaminase AID which targets specific DNA motifs in the B cell , However, characterization of human memory B cells has mainly been based on phenotyping and the molecular history of SHM and proliferation As alluded to previously, this view has been refuted by our recent molecular study of IgA-subclass switching in intestinal effector sites compared with inductive sites Lin et al.
Interestingly, it was found that the response was highly synchronized throughout the entire intestine by involving multiple PPs. Thus, by reutelizing already existing CGs, antigen-specific B cells would be subjected to clonal expansion and SHM, probably in the manner discussed previously. The difficult issue of affinity maturation of mucosal B cells and how the mucosal immune system can distinguish between the indigenous microbiota and overt exogenous pathogens has been discussed in several recent articles — The mucosal barrier and its reinforcement by SIgA, as well as the mucosal immunoregulatory network, require both adaptive and innate induction by antigens and conserved microbe-associated molecular patterns MAMPs — the latter activating germline-encoded cellular PRRs such as TLRs , It is elusive how such receptors would be able to discriminate between signals provided by MAMPs from commensals and MAMPs from pathogens previously called pathogen-associated molecular patterns, PAMPs ; but this distinction is clearly required to elicit tolerogenic versus proinflammatory immune responses needed for protection against invasive infections Figure 8.
Various scenarios may be visualized — the most likely being that overt pathogens, in addition to signaling through PRRs and BCRs, exhibit special danger signals, or immune evasion mechanisms related to the pathogenicity — that is, factors determining virulence and invasiveness — , or so-called effector-triggered immunity , , while competition for metabolically shared nutrients may also be involved , , Figure 8.
Hypothetical depiction of how the intestinal immune system handles symbionts and potentially pathogenic residents pathobionts of the commensal microbiota versus overt exogenous pathogens. Secretory IgA SIgA antibody levels against commensal bacteria may go in waves because of epitope drift and shielding of gut-associated lymphoid tissue from antigen uptake. The overall affinity of SIgA antibodies probably increases with age and may be enhanced or reduced against pathobionts during dysbiosis, and particularly raised by persistent stimulation with overt pathogens.
One goal of mutualism with commensals is mucosal barrier reinforcement by mechanisms listed such as SIgA export and induction of regulatory T cells, whereas pathogens exhibit various virulence mechanisms to break the barrier. In vivo coating of bacteria with IgA present in external secretions can be directly demonstrated by immunostaining Figure 9 A ; and although this apparently does not inhibit bacterial growth 57 , it is considered to provide containment of the microbiota, counteract invasiveness, and contribute to immune homeostasis 24 , Figure 9.
IgA coating of commensal bacteria may modulate mucosal immunity and metabolism. A Direct immunofluorescence staining of bacterial sediment from whole saliva to demonstrate in vivo IgA coating. Contaminating epithelial cell is faintly visualized because of autofluorescence. Numerous cocci mainly diplococci — partly adhering to epithelial cell — have bound IgA, which also decorates older cell-wall segments of streptococci forming long chains, whereas new crosswalls formed by growth in vitro after sampling are negative as indicated.
Adapted from Brandtzaeg et al. Secretory IgA binds to commensal bacteria, and the IgA-coated bacteria modulate mucosal immunity and homeostasis by delivering signals through innate microbial sensors red such as pattern recognition receptors on the epithelial cells.
In addition to enhancing innate defense through immune pathways controlled by interferon IFN cytokines, these signals also regulate the intake of food lipids through metabolic pathways controlled by the transcription factor Gata4.
When IgA is lacking not shown , the gut epithelium upregulates its expression of IFN-dependent innate defense genes to compensate for the lack of adaptive IgA immunity. This upregulation leads to a downregulation of the genes controlled by Gata4 The resulting gene imbalance impairs the epithelial absorption of lipids, such as cholesterol, resulting in metabolic disorders with reduced leptin levels and fat storage.
Modified from Chorny and Cerutti Such IgA containment of commensals, without eliminating them, is probably important for the mutual host—microbe interaction, contributing to sustainable homeostasis by dampening proinflammatory signaling in the host and providing an immune pressure on commensal bacteria , This results in antigenic drift without altered composition of the microbiota, or so-called dysbiosis , In mice, the IgA coating of gut bacteria has been shown to be unrelated to the total amount of SIgA exported to the intestinal lumen, suggesting that a specific reaction is involved Also, other recent mouse experiments demonstrated that the commensal coating with IgA in feces depended on appropriate clonal B-cell selection and affinity maturation in GCs of GALT, and perhaps to some extent also in the lamina propria Thus, this finding showed that the coating to a substantial degree reflects a specific IgA response.
It has therefore been speculated that pathobionts might show increased IgA coating in the gut lumen. Thus, increased antibody coating could reflect dysbiosis Figure 8. However, in celiac disease, where there is also dysbiosis, the IgA coating of fecal bacteria is significantly reduced So the biological significance of this phenomenon remains uncertain, and the degree of IgA coating might reflect a combination of innate and specific bacterial binding properties of SIgA.
Altogether, SIgA does not seem to cause clearance of commensal bacteria, but controls in various ways their colonization and inhibits the penetration of agents that could potentially cause hypersensitivity reactions or infection As a consequence, the epithelial gene signature might correlate with the development of lipid malabsorption The intestinal epithelial barrier is a cross-road between surface defense and nutrition, and SIgA is apparently essential to keep the balance between these two functions and thus maintain mucosal homeostasis Figure 9 B.
Secretory immunoglobulin A constitutes the largest humoral immune system of the body and performs antigen exclusion at mucosal surfaces and neutralizes virus and endotoxin within epithelial cells without causing tissue damage 24 , The enormous innate drive of the mucosal immune system does not only enhance anybody diversity but also immunological memory.
Mainly by its extensive polyreactivity, innate-like SIgA is persistently containing commensal bacteria outside the epithelial barrier; but by increased antibody affinity SIgA can also target invasion of pathogens and penetration of harmful antigens after mucosal infection or vaccination.
Host resistance to toxin-producing bacteria such as V. Like natural infections, live attenuated vaccines or adequate combinations of non-replicating vaccines and mucosal adjuvants administered by the oral route to target GALT, give rise not only to SIgA antibodies but also to longstanding serum IgG and IgA responses Also, although immunological memory is generated after mucosal priming, this may be masked by a self-limiting response shielding the inductive lymphoid tissue in the gut.
The intranasal route of vaccine application targeting NALT may be more advantageous for certain infections, but only if successful stimulation is achieved without the use of toxic adjuvants that might reach the central nervous system The degree of protection obtained after mucosal vaccination ranges from reduction of symptoms to complete inhibition of re-infection.
In this scenario, it is often difficult to determine the relative importance of SIgA versus serum antibodies, but infection models in knockout mice strongly support the notion that SIgA exerts a decisive role in protection and cross-protection against a variety of infectious agents.
Nevertheless, relatively few mucosal vaccines have been approved for human use, and more basic work is needed in vaccine and adjuvant design, including particulate or live-vectored combinations It is a fundamental problem in this field that clinical trials are risky and expensive, so much of the basic work has to be performed in experimental animals such as mice.
There are always difficulties in knowing to what extent immunological information obtained in animals can be directly transferred to human application. For instance, human hepatocytes do not express pIgR whereas rodent hepatocytes do It is therefore difficult to know to what extent SIgA antibodies in rodent gut fluid reflect a local mucosal immune response.
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IgA can be oligomeric, comprised of 2—4 IgA monomers. SIgA is always oligomeric in structure, primarily dimeric, and the polymers are linked by additional polypeptide chains, including a 15KD joining chain J chain and a 70KD secretory component chain produced in epithelial cells and involved in the transcellular transport of SIgA See Figure 1.
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