The antibody/microbiota interface in health and disease

Sterlin, Delphine; Fadlallah, Jehane; Slack, Emma; Gorochov, Guy

doi:10.1038/s41385-019-0192-y

Cited by 49 publications

(37 citation statements)

References 110 publications

(177 reference statements)

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“…5,[7][8][9][10][11][12][13][14][15][16] Considering the enormous numbers and highly variable species diversity along with the large number of potential antigenic determinants on bacterial structures, it is probable that all three mechanisms participate in the protective activity of secretory IgA (SIgA). [2][3][4][5]8,17,18 We reported that the binding of gram-negative bacteria to the glycan receptors on epithelial cells is inhibited by IgA-associated glycans as confirmed and extended to other species of both gram-positive and gramnegative bacteria. 10,17,[19][20][21][22] In addition to the heavy (H) α chains of IgA, secretory component (SC), the extracellular part of the polymeric Ig receptor (pIgR), is heavily glycosylated and acts as a highly effective inhibitor of bacteria adherence to epithelial cells 7,10,13,14,19,20,23,24 thus enforcing the protective functions of SIgA.…”

Section: Introductionmentioning

confidence: 69%

Secretory IgA N-glycans contribute to the protection against E. coli O55 infection of germ-free piglets

et al. 2021

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Mucosal surfaces are colonized by highly diverse commensal microbiota. Coating with secretory IgA (SIgA) promotes the survival of commensal bacteria while it inhibits the invasion by pathogens. Bacterial coating could be mediated by antigen-specific SIgA recognition, polyreactivity, and/or by the SIgA-associated glycans. In contrast to many in vitro studies, only a few reported the effect of SIgA glycans in vivo. Here, we used a germ-free antibody-free newborn piglets model to compare the protective effect of SIgA, SIgA with enzymatically removed N-glycans, Fab, and Fc containing the secretory component (Fc-SC) during oral necrotoxigenic E. coli O55 challenge. SIgA, Fab, and Fc-SC were protective, whereas removal of N-glycans from SIgA reduced SIgA-mediated protection as demonstrated by piglets’ intestinal histology, clinical status, and survival. In vitro analyses indicated that deglycosylation of SIgA did not reduce agglutination of E. coli O55. These findings highlight the role of SIgA-associated N-glycans in protection. Further structural studies of SIgA-associated glycans would lead to the identification of those involved in the species-specific inhibition of attachment to corresponding epithelial cells.

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Section: Introductionmentioning

confidence: 69%

Secretory IgA N-glycans contribute to the protection against E. coli O55 infection of germ-free piglets

et al. 2021

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“…Interestingly, ILFs from aged mice produce lower amounts of chemokines yet produce more IgA than their younger counter parts. ILFs and their precursors are present in GF mice 50 , but microbial colonization promotes the maturation of these TLTs 40 , and intestinal microbiota are frequently the antigenic target of IgA produced therein 51 . These studies establish that TLTs do not absolutely require a live microbiota, implying that they could target non-microbial antigens as well.…”

Section: Discussionmentioning

confidence: 99%

Single cell and tissue-transcriptomic analysis of murine bladders reveals age- and TNFα-dependent but microbiota-independent tertiary lymphoid tissue formation

et al. 2020

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Aging has multifaceted effects on the immune system, but how aging affects tissue-specific immunity is not well-defined. Bladder diseases characterized by chronic inflammation are highly prevalent in older women, but mechanisms by which aging promotes these pathologies remain unknown. Tissue transcriptomics of unperturbed, young and aged bladders identified a highly altered immune landscape as a fundamental feature of the aging female bladder. Detailed mapping of immune cells using single cell RNA-sequencing revealed novel subsets of macrophages and dendritic cells and unique changes to the immune repertoire in the aged bladder. B and T cells are highly enriched in aged bladders and spontaneously form organized bladder tertiary lymphoid tissues (bTLTs). Naïve, activated, and germinal center B cells and IgA + plasma cells are found within bTLT and associated with increased urinary IgA concentrations. bTLTs form with increasing age and their formation is dependent on TNFα. Microbiota are not required to form bTLT form, as aged germfree mice harbor them. Thus, bTLTs require age-dependent TNFα but are independent of the microbiota. Our results indicate that chronic, age-associated inflammation underlies a fundamental alteration to the bladder and establishes a resource for further investigation of the bladder immune system in homeostasis, aging, and disease.

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“…As we showed here, E2 can also modulate the effect of SCFAs, the major metabolites of gut commensal bacteria. The gastrointestinal microbiome profoundly impacts on various immune responses, including B cell maturation, activation and IgA antibody responses (115,116). In the gut, which contains high concentration of butyrate and propionate, IgA is produced extensively.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Reverses HDAC Inhibitor-Mediated Repression of Aicda and Class-Switching in Antibody and Autoantibody Responses by Downregulation of miR-26a

Casali

Shen

et al. 2020

Front. Immunol.

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Estrogen contributes to females' strong antibody response to microbial vaccines and proneness to autoimmunity, particularly antibody-mediated systemic autoimmunity, in females. We have hypothesized that this is due to estrogen-mediated potentiation of class switch DNA recombination (CSR) and somatic hypermutation (SHM). As we have shown, estrogen boosts AID expression, which is critical for both CSR and SHM, through upregulation of HoxC4, which together with NF-κB critically mediates Aicda (AID gene) promoter activation. We contend here that additional regulation of Aicda expression by estrogen occurs through epigenetic mechanisms. As we have shown, histone deacetylase inhibitors (HDIs) short-chain fatty acid (SCFA) butyrate and propionate as well as the pharmacologic HDI valproic acid upregulate miRNAs that silence AID expression, thereby modulating specific antibody responses in C57BL/6 mice and autoantibody responses in lupus-prone MRL/Fas lpr/lpr mice. Here, using constitutive knockout Esr1 −/− mice and B cells as well as conditional knockout Aicda cre/cre Esr1 flox/flox mice and B cells, we showed that the HDI-mediated downregulation of Aicda expression as well as the maturation of antibody and autoantibody responses is reversed by estrogen and enhanced by deletion of ERα or E2 inhibition. Estrogen's reversion of HDI-mediated inhibition of Aicda and CSR in antibody and autoantibody responses occurred through downregulation of B cell miR-26a, which, as we showed, targets Aicda mRNA 3 ′ UTR. miR-26a was significantly upregulated by HDIs. Accordingly, enforced expression of miR-26a reduced Aicda expression and CSR, while miR-26a-sponges (competitive inhibitors of miR-26a) increased Aicda expression and CSR. Thus, our findings show that estrogen reverses the HDI-mediated downregulation of AID expression and CSR through selective modulation of miR-26a. They also provide mechanistic insights into the immunomodulatory activity of this hormone and a proof-of-principle for using combined ER inhibitor-HDI as a potential therapeutic approach.

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The antibody/microbiota interface in health and disease

Cited by 49 publications

References 110 publications

Secretory IgA N-glycans contribute to the protection against E. coli O55 infection of germ-free piglets

Secretory IgA N-glycans contribute to the protection against E. coli O55 infection of germ-free piglets

Single cell and tissue-transcriptomic analysis of murine bladders reveals age- and TNFα-dependent but microbiota-independent tertiary lymphoid tissue formation

Estrogen Reverses HDAC Inhibitor-Mediated Repression of Aicda and Class-Switching in Antibody and Autoantibody Responses by Downregulation of miR-26a

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