Intestinal microfold cells are the primary pathway for translocation of secretory IgA (SIgA)-pathogen complexes to gut-associated lymphoid tissue. Uptake of SIgA/commensals complexes is important for ...priming adaptive immunity in the mucosa. This study aims to explore the effect of SIgA retrograde transport of immune complexes in Crohn's disease (CD). Here we report a significant increase of SIgA transport in CD patients with NOD2-mutation compared to CD patients without NOD2 mutation and/or healthy individuals. NOD2 has an effect in the IgA transport through human and mouse M cells by downregulating Dectin-1 and Siglec-5 expression, two receptors involved in retrograde transport. These findings define a mechanism of NOD2-mediated regulation of mucosal responses to intestinal microbiota, which is involved in CD intestinal inflammation and dysbiosis.
Secretory IgMs (SIgMs) were amongst the first identified immunoglobulins. However, their importance was not fully understood and recent advances have shown they play a key role in establishing and ...promoting commensal gut tolerance in mice and humans. The true interactions between SIgMs and the microbiota remain controversial and we aim to consolidate current knowledge in this review. Through comprehensive examination of SIgMs and their corresponding B cell secretors in several different pathological immunological contexts, we review the presumed role of these molecules in gut tolerance, inflammatory bowel diseases, and lung immunity. As SIgMs harbor a mostly tolerogenic function, we posit that their inclusion in further immunological research is paramount.
Human secretory immunoglobulin-M (SIgM) is mostly natural IgM and shapes the colonization of mucosal surfaces.SIgMs can selectively bind commensal bacteria at mucosal surfaces and may have overlapping functions with SIgAs in healthy humans and mice.SIgM can regulate B cell development.SIgMs can promote central and mucosal tolerance, which might influence the development and outcomes of autoimmune conditions in mice and humans.The B-1 cell pool produces the bulk of natural IgM and has regulatory functions in the establishment of tolerance in mice.If robustly elicited, SIgM might be potentially beneficial in helping to treat certain pathologies such as infections or autoimmune diseases, although robust testing is still warranted.
Highlights ► To date, mucosal vaccines are poorly efficient. ► Select antigens, adjuvant and design new mucosal routes of administration. ► Induce protective immunity at mucosal surfaces. ► Mucosal ...vaccine would make immunization procedures easier for mass administration.
Intestinal microfold (M) cells possess a high transcytosis capacity and are able to transport a broad range of materials including particulate antigens, soluble macromolecules, and pathogens from the ...intestinal lumen to inductive sites of the mucosal immune system. M cells are also the primary pathway for delivery of secretory IgA (SIgA) to the gut-associated lymphoid tissue. However, although the consequences of SIgA uptake by M cells are now well known and described, the mechanisms whereby SIgA is selectively bound and taken up remain poorly understood. Here we first demonstrate that both the Cα1 region and glycosylation, more particularly sialic acid residues, are involved in M cell-mediated reverse transcytosis. Second, we found that SIgA is taken up by M cells via the Dectin-1 receptor, with the possible involvement of Siglec-5 acting as a co-receptor. Third, we establish that transcytosed SIgA is taken up by mucosal CX3CR1⁺ dendritic cells (DCs) via the DC-SIGN receptor. Fourth, we show that mucosal and systemic antibody responses against the HIV p24-SIgA complexes administered orally is strictly dependent on the expression of Dectin-1. Having deciphered the mechanisms leading to specific targeting of SIgA-based Ag complexes paves the way to the use of such a vehicle for mucosal vaccination against various infectious diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Transmission of mucosal pathogens relies on their ability to bind to the surfaces of epithelial cells, to cross this thin barrier, and to gain access to target cells and tissues, leading ...to systemic infection. This implies that pathogen-specific immunity at mucosal sites is critical for the control of infectious agents using these routes to enter the body. Although mucosal delivery would ensure the best onset of protective immunity, most of the candidate vaccines are administered through the parenteral route. Objective The present study evaluates the feasibility of delivering the chemically bound p24gag (referred to as p24 in the text) HIV antigen through secretory IgA (SIgA) in nasal mucosae in mice. Results We show that SIgA interacts specifically with mucosal microfold cells present in the nasal-associated lymphoid tissue. p24-SIgA complexes are quickly taken up in the nasal cavity and selectively engulfed by mucosal dendritic cell–specific intercellular adhesion molecule 3–grabbing nonintegrin–positive dendritic cells. Nasal immunization with p24-SIgA elicits both a strong humoral and cellular immune response against p24 at the systemic and mucosal levels. This ensures effective protection against intranasal challenge with recombinant vaccinia virus encoding p24. Conclusion This study represents the first example that underscores the remarkable potential of SIgA to serve as a carrier for a protein antigen in a mucosal vaccine approach targeting the nasal environment.
Abstract Mucosal immunization is designed to induce strong immune responses at portal of pathogen entry. Unfortunately, mechanisms underlying the fate of the vaccine vector co-administered with ...antigens are still partially uncovered and limit further development of mucosal vaccines. Hence, poly(lactic acid) (PLA) nanoparticles being a versatile vaccine vehicle, we have analyzed the fate of these PLA nanoparticles during their uptake at intestinal mucosal sites, both in vivo and ex vivo , to decipher the mechanisms involved during this process. We first designed specific fluorescent PLA nanoparticles exhibiting strong colloidal stability after encapsulation of either 6-coumarin or CellTrace BODIPY® before monitoring their transport through mucosa in the mouse ligated ileal loop model. The journey of the particles appears to follow a three-step process. Most particles are first entrapped in the mucus. Then, crossing of the epithelial barrier takes place exclusively through M-cells, leading to an accumulation in Peyer’s patches (PP). Lastly, we noticed specific interaction of these PLA nanoparticles with underlying B cells and dendritic cells (DCs) of PP. Furthermore, we could document that DCs engulfing some nanoparticles could exhibit a TLR8+ specific expression. Specific targeting of these two cell types strongly supports the use of PLA nanoparticles as a vaccine delivery system for oral use. Indeed, following oral gavage of mice with PLA nanoparticles, we were able to observe the same biodistribution patterns, indicating that these nanoparticles specifically reach immune target required for oral immunization.
Secretory immunoglobulin A (SIgA) can travel to and from the lumen and transport antigen to subepithelial cells. However, IgM can also multimerize into functional secretory component-bound ...immunoglobulin. While it is already known that both SIgA and SIgM undergo transcytosis to be secreted at the mucosal surface, only SIgA has been shown to perform retrotranscytosis through microfold cells (M cells) of the Peyer’s patch. Here, we investigate whether SIgM could also be taken up by M cells via retrotranscytosis. This transport involves FcμR binding at the apical membrane of M cells. We then demonstrate that SIgM can be exploited by SIgM-p24 (HIV-capsid protein) complexes during immunization in the nasal- or gut-associated lymphoid tissue (NALT or GALT), conferring efficient immune responses against p24. Our data demonstrate a mucosal function of SIgM, which could play a role in the regulation of mucosal immunity.
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•SIgM is taken up by TOSO+ M cells of the murine GALT and the NALT•SIgM is retro-transported toward DC-SIGN+ DCs from lymphoid tissues•SIgM-based complexes result in mucosal and systemic antigen-specific antibody responses
Rochereau et al. investigate the transport of SIgM across the murine nasal and gut mucosa. They provide evidence that IgM is taken up by mucosal M cells and then retro-transported toward cells in lymphoid tissues. This function of SIgM could play an important role in the regulation of mucosal immunity.
HIV transmission and spread in the host are based on the survival of the virus or infected cells present in mucosal secretions, and the virus' ability to cross the epithelial barrier and access ...immune target cells, which leads to systemic infection. Therefore, HIV‐specific immunity at mucosal sites is critical for control of infection. Although mucosal delivery would ensure the best onset of protective immunity, most candidate vaccines are administered through the parenteral route. Remarkably, secretory IgA (SIgA) interacts specifically with mucosal microfold (M) cells present in gut‐associated lymphoid tissues. Here we evaluate the feasibility of delivering chemically bound p24HIV antigen via SIgA into the intestinal mucosae in mice. After oral administration, p24–SIgA complexes are quickly delivered into the tissue and selectively captured by CX3CR1+ dendritic cells. Oral immunization with p24gag linked to SIgA (p24–SIgA) adjuvanted with E. coli heat labile enterotoxin (HLT) elicits both humoral and cellular immune responses against p24 at the systemic and mucosal levels and induces efficient protection against rectal challenge with a recombinant vaccinia virus encoding gag. This is the first study which underscores the remarkable potential of SIgA to serve as a vaccine carrier for an HIV antigen in mucosal administration targeting the gastrointestinal environment.
Human secretory immunoglobulins (SIg) A1 and SIgA2 guide mucosal responses toward tolerance or inflammation, notably through reverse‐transcytosis, the apical‐to‐basal transport of IgA2 immune ...complexes via M cells of gut Peyer's patches. As such, the maintenance of a diverse gut microbiota requires broad affinity IgA and glycan–glycan interaction. Here, we asked whether IgA1 and IgA2‐microbiota interactions might be involved in dysbiosis induction during inflammatory bowel diseases. Using stool HPLC‐purified IgA, we show that reverse‐transcytosis is abrogated in ulcerative colitis (UC) while it is extended to IgA1 in Crohn's disease (CD). 16S RNA sequencing of IgA‐bound microbiota in CD and UC showed distinct IgA1‐ and IgA2‐associated microbiota; the IgA1+ fraction of CD microbiota was notably enriched in beneficial commensals. These features were associated with increased IgA anti‐glycan reactivity in CD and an opposite loss of reactivity in UC. Our results highlight previously unknown pathogenic properties of IgA in IBD that could support dysbiosis.
Synopsis
IBD (both CD and UC) is characterized by dysbiosis and altered immune pathways that lead to and sustain prolonged inflammation in the gut. As IgA are the main drivers of commensal selection in the healthy gut, this study aimed at assessing subclass‐related structure and functions of IgA in both CD and UC.
Evidence of a chain of subclass‐dependent functional disparities between CD and UC IgAs affecting antibody glycosylation, transport across epithelia, and affinity, which may interfere in optimal commensal selection to promote dysbiosis
While only IgA2 could undergo RT in non‐IBD, IgA1 in CD had the ability to do so and neither IgA1 nor IgA2 were able to in UC.
Despite predominant dual IgA1 and IgA2 binding on stool microbiota, CD associates with enriched commensal binding in the IgA1+ fraction, and UC with a marked reduction in IgA overall reactivity
IBD (both CD and UC) is characterized by dysbiosis and altered immune pathways that lead to and sustain prolonged inflammation in the gut. As IgA are the main drivers of commensal selection in the healthy gut, this study aimed at assessing subclass‐related structure and functions of IgA in both CD and UC.
Cytomegalovirus (CMV) infects approximately 40% of adults in France and persists lifelong as a latent agent in different organs, including gut. A close relationship is observed between inflammation ...that favors viral expression and viral replication that exacerbates inflammation. In this context, CMV colitis may impact the prognosis of patients suffering from inflammatory bowel diseases (IBDs), and notably those with ulcerative colitis (UC). In UC, the mucosal inflammation and T helper cell (TH) 2 cytokines, together with immunomodulatory drugs used for controlling flare-ups, favor viral reactivation within the gut, which, in turn, increases mucosal inflammation, impairs corticoid and immunosuppressor efficacy (the probability of steroid resistance is multiplied by more than 20 in the case of CMV colitis), and enhances the risk for colectomy. This review emphasizes the virological tools that are recommended for exploring CMV colitis during inflammatory bowel diseases (IBD) and underlines the interest of using ganciclovir for treating flare-ups associated to CMV colitis in UC patients.
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