Gut T cell–independent IgA responses to commensal bacteria require engagement of the TACI receptor on B cells

Grasset, E.; Chorny, Alejo; Casas-Recasens, Sandra; Gutzeit, Cindy; Bongers, Gerold; Thomsen, Irene; Chen, Lili; He, Zhengxiang; Matthews, Dean B.; Oropallo, Michael A.; Veeramreddy, P.; Uzzan, Mathieu; Mortha, Arthur; Carrillo, Jorge; Reis, Bernardo Sgarbi; Ramanujam, Meera; Sintes, Jordi; Magri, Giuliana; Maglione, Paul J.; Cunningham‐Rundles, Charlotte; Bram, Richard J.; Faith, Jeremiah J.; Mehandru, Saurabh; Pabst, Oliver; Cerutti, Andrea

doi:10.1126/sciimmunol.aat7117

Cited by 47 publications

(55 citation statements)

References 82 publications

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“…Interactions between CD40L expressed in T FH cells and CD40 expressed in B cells are necessary for the TD pathways. A similar process is accomplished in the TI pathways through interactions between BAFF/APRIL and three possible receptors, the transmembrane activator and calcium‐modulating cyclophilin ligand interactor (TACI), the BAFF receptor, and B cell maturation antigen expressed in B cells 47,48 . Of these possible receptors of BAFF and APRIL, TACI has been recently identified as indispensable in the intestinal TI pathways 48 .…”

Section: Generation Of Intestinal Secretory Igamentioning

confidence: 99%

“…A similar process is accomplished in the TI pathways through interactions between BAFF/APRIL and three possible receptors, the transmembrane activator and calcium‐modulating cyclophilin ligand interactor (TACI), the BAFF receptor, and B cell maturation antigen expressed in B cells 47,48 . Of these possible receptors of BAFF and APRIL, TACI has been recently identified as indispensable in the intestinal TI pathways 48 . This TACI‐mediated intestinal TI pathways induces intestinal IgA + ASCs independent of the GCs and can elicit specific IgA responses to gut microbes 48 .…”

Section: Generation Of Intestinal Secretory Igamentioning

confidence: 99%

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Interaction between IgA and gut microbiota and its role in controlling metabolic syndrome

et al. 2020

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Summary Immunoglobulin A (IgA) is the most abundant immunoglobulin isotype secreted into the mucosal tissues, mainly intestinal mucus. Humans can produce several grams of IgA every day, accounting for three quarters of the body's total immunoglobulin content. IgA, together with mucus and antimicrobial peptides, forms the first line of defence for intestinal epithelial cells, protecting them from a significant number of intestinal antigens. IgA also plays a principal role in controlling the gut microbiota (GM), and disruption in IgA can result in dysbiosis, such as the enrichment of Proteobacteria, which are generally bound by IgA. Proteobacteria overexpansion is also usually seen in obesity and colitis. Consistent with this, IgA dysfunction frequently results in metabolic syndrome (MetS), including conditions such as obesity, adiposity, insulin resistance, and inflammation. In contrast, enhanced IgA function can improve, and even prevent, MetS. Interactions among IgA, GM, and metabolism provide a promising avenue to combat MetS.

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Section: Generation Of Intestinal Secretory Igamentioning

confidence: 99%

Section: Generation Of Intestinal Secretory Igamentioning

confidence: 99%

Interaction between IgA and gut microbiota and its role in controlling metabolic syndrome

et al. 2020

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“…Bacteroides fragilis produces a surface polysaccharide that promotes IgA binding and facilitates mucus layer colonization [6] and the mucin-degrader Akkermansia muciniphila induces host IgA and IgG responses [7]. Other studies have suggested that low-affinity IgA contributes to microbiota maintenance, while high-affinity IgA acts on pathogens to promote clearance and inhibit virulence [8][9][10][11][12][13][14][15]. Pathobionts are members of the microbiota that are typically harmless under homeostatic conditions but can drive disease given certain environmental stimuli [16].…”

Section: Introductionmentioning

confidence: 99%

“…We refer to the sorted IgA bound bacteria as the IgA+ fraction, the sorted unbound bacteria as the IgA-fraction, and the sample before sorting as the pre-sort sample. IgA-Seq has been used to uncover antibody targeting of taxa by both T-cell dependent and T-cell independent pathways [7,10,12,21,22], as well as differential binding of taxa during disease. IgA-Seq was first described by Palm et al to identify taxa differentially bound by IgA in inflammatory bowel disease (IBD) patients [17] and was adapted by Kau et al to identify increased binding of Enterobacteriaceae by IgA in malnourished infants [18].…”

Section: Introductionmentioning

confidence: 99%

“…IgA-Seq is additionally limited to scoring relative, overall, IgA binding between taxa. Understanding what drives the observed differences, such as alterations in the spatial distribution of bacteria or changes in the affinities of host IgA, requires additional targeted experiments, such as fluorescence in situ hybridisation and enzyme-linked immunosorbent assays[10,20].We have developed an optimised experimental protocol and novel scoring methodologies for IgA-Seq. These enable robust and accurate identification of commensal bacteria targeted by the host immune response.…”

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confidence: 99%

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Accurate identification and quantification of commensal microbiota bound by host immunoglobulins

Jackson

Pearson

Ilott

et al. 2020

Preprint

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Background: Identifying which taxa are targeted by immunoglobulins can uncover important host-microbe interactions. Immunoglobulin binding of commensal taxa can be assayed by sorting bound bacteria from samples and using amplicon sequencing to determine their taxonomy, a technique most widely applied to study Immunoglobulin A (IgA-Seq). Previous experiments have scored taxon binding in IgA-Seq datasets by comparing abundances in the IgA bound and unbound sorted fractions. However, as these are relative abundances, such scores are influenced by the levels of the other taxa present and represent an abstract combination of these effects. Diversity in the practical approaches of prior studies also warrants benchmarking of the individual stages involved. Here, we provide a detailed description of the design strategy for an optimised IgA-Seq protocol. Combined with a novel scoring method for IgA-Seq datasets that accounts for the aforementioned effects, this platform enables accurate identification and quantification of commensal gut microbiota targeted by host immunoglobulins. Results: Using germ-free and Rag1-/- mice as negative controls, and a strain-specific IgA antibody as a positive control, we determine optimal reagents and fluorescence activated cell sorting (FACS) parameters for IgA-Seq. Using simulated IgA-Seq data, we show that existing IgA-Seq scoring methods are influenced by pre-sort relative abundances. This has consequences for the interpretation of case-control studies where there are inherent differences in microbiota composition between groups. We show that these effects can be addressed using a novel scoring approach based on posterior probabilities. Finally, we demonstrate the utility of both the IgA-Seq protocol and probability-based scores by examining both novel and published data from in vivo disease models. Conclusions: We provide a detailed IgA-Seq protocol to accurately isolate IgA-bound taxa from intestinal samples. Using simulated and experimental data, we demonstrate novel probability-based scores that adjust for the compositional nature of relative abundance data to accurately quantify taxon-level IgA binding. All scoring approaches are made available in the IgAScores R package. These methods should improve the generation and interpretation of IgA-Seq datasets and could be applied to study other immunoglobulins and sample types.

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MOG-IgA as a Potential Marker of Germinal Center Activity—Reply

Kulsvehagen,

Ayroza Galvão Ribeiro Gomes,

Pröbstel

2024

JAMA Neurol

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COMMENT & RESPONSEIn Reply We thank Handel and colleagues for their interest and thoughtful comments on our article. The authors addressed the role of autoantigen-reactive immunoglobulin A (IgA) antibodies as markers of germinal center (GC)-based immunoglobulin class-switching and the importance of longitudinal testing for myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) and M (IgM) in patients seropositive for MOG-IgA.Upon the identification of isolated and coexisting MOG-IgA in patients with demyelinating central nervous system disease, we suggested that differences in the inflammatory milieu in the context of the type and site of preceding infections or vaccinations may account for the diverse immunoglobulin responses. 1 Indeed, most patients belonging to the isolated MOG-IgA group presented clinical attacks after recent infection or vaccination. This supports the hypothesis of infectious triggers being directly involved in MOG-specific IgA generation, a process that can be GC dependent or independent (the latter particularly in mucosal tissues). 2,3 In that regard, MOG-IgA as a potential marker for ongoing GC-based immunoglobulin class-switching is an interesting hypothesis raised by Handel and colleagues, especially in patients with coexisting MOG-IgG or MOG-IgM antibodies. Although ongoing GCbased immunoglobulin class-switching has previously been suggested for coexisting N-methyl-D-aspartate receptor (NMDAR) IgA in patients with NMDAR-IgG or NMDAR-IgM in the context of intratumoral tertiary lymphoid structures in teratomas and in cervical lymph nodes, 4,5 the reported frequency of teratomas in patients positive for MOG immunoglobulin, including our cohort, is low. 1,6 Further, the relevance of GC activity in patients with isolated IgA autoantibodies remains unclear. Yet, although we did not detect seroconversion in patients longitudinally followed up who were seropositive for MOG-IgG, MOG-IgA, and/or MOG-IgM, we cannot exclude class-switching before the first sample time point for patients with an earlier disease onset.Regarding future studies, the longitudinal assessment of MOG immunoglobulin serostatus as proposed by Handel and colleagues, especially in the MOG-IgG and MOG-IgA doubleseropositive group, will shed light on sites and mechanisms of the divergent immunoglobulin responses. In our study, the sample size was not sufficient to look at treatment response to anti-CD20. 1 Hence, clinical studies assessing responsiveness to B-cell targeting therapies and immunophenotypic studies of cervical lymph nodes in patients positive for MOG immunoglobulins are needed to guide treatment strategies.

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Gut T cell–independent IgA responses to commensal bacteria require engagement of the TACI receptor on B cells

Cited by 47 publications

References 82 publications

Interaction between IgA and gut microbiota and its role in controlling metabolic syndrome

Interaction between IgA and gut microbiota and its role in controlling metabolic syndrome

Accurate identification and quantification of commensal microbiota bound by host immunoglobulins

MOG-IgA as a Potential Marker of Germinal Center Activity—Reply

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