Humoral immune responses at mucosal surfaces have historically focused on IgA. Growing evidence highlights the complexity of IgA-inducing pathways and the functional impact of IgA on mucosal ...commensal bacteria. In the gut, IgA contributes to the establishment of a mutualistic host-microbiota relationship that is required to maintain homeostasis and prevent disease. This Review discusses how mucosal IgA responses occur in an increasingly complex humoral defence network that also encompasses IgM, IgG and IgD. Aside from integrating the protective functions of IgA, these hitherto neglected mucosal antibodies may strengthen the communication between mucosal and systemic immune compartments.
Cellular dynamics that influence mucosal healing are not well understood. In this issue of Immunity, Frede, Czarnewski, Monasterio et al. find that B cells accumulate in the colon following ...intestinal injury. These B cells impair epithelial repair by hindering local stromal-epithelial interactions.
Cellular dynamics that influence mucosal healing are not well understood. In this issue of Immunity, Frede, Czarnewski, Monasterio et al. find that B cells accumulate in the colon following intestinal injury. These B cells impair epithelial repair by hindering local stromal-epithelial interactions.
Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and ...clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus.
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•IgM+ PCs generating SIgM are relatively abundant in human but not mouse gut•IgM+ PCs clonally relate to a large gut repertoire of memory IgM+ B cells•Gut memory IgM+ B cells express a tissue-specific signature and can switch to IgA•Human but not mouse SIgM binds a highly diverse microbiota dually coated by SIgA
Magri et al. found that the human gut includes a large memory IgM+ B cell repertoire clonally related to plasma cells mounting SIgM responses against mucus-embedded commensals co-targeted by SIgA. Dually coated bacteria are detected in humans but not mice and show increased diversity and richness compared to SIgA-only-coated or uncoated bacteria.
Mutations make gut antibodies promiscuous Grasset, Emilie K; Cerutti, Andrea
The Journal of experimental medicine,
11/2020, Letnik:
217, Številka:
11
Journal Article
Recenzirano
Odprti dostop
In this issue, Kabbert et al. (https://doi.org/10.1084/jem.20200275) show that intestinal antibodies from healthy subjects or patients with Crohn's disease cross-target diverse but distinct ...communities of the gut microbiota through a mechanism involving somatic hypermutation but not germline-encoded polyreactivity.
Fecal IgA production depends on colonization by a gut microbiota. However, the bacterial strains that drive gut IgA production remain largely unknown. Here, we assessed the IgA-inducing capacity of a ...diverse set of human gut microbial strains by monocolonizing mice with each strain. We identified Bacteroides ovatus as the species that best induced gut IgA production. However, this induction varied bimodally across different B. ovatus strains. The high IgA-inducing B. ovatus strains preferentially elicited more IgA production in the large intestine through the T cell-dependent B cell-activation pathway. Remarkably, a low-IgA phenotype in mice could be robustly and consistently converted into a high-IgA phenotype by transplanting a multiplex cocktail of high IgA-inducing B. ovatus strains but not individual ones. Our results highlight the critical importance of microbial strains in driving phenotype variation in the mucosal immune system and provide a strategy to robustly modify a gut immune phenotype, including IgA production.
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•Bacteroides ovatus strain variation drives either high or low fecal IgA•CD4+ T cells are critical in B. ovatus-mediated gut IgA production•Cocktails of IgAhighB. ovatus strains convert mice from low- to high-IgA producers
Yang et al. identify that different Bacteroides ovatus strains induce either high or low baseline fecal IgA in mice. Cocktails of IgAhighB. ovatus strains convert mice from low-IgA to high-IgA producers. This demonstrates a role of microbial strains in immune variation and a microbiota-based immune modulation strategy.
B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n = 145; ...validation cohort 1, n = 664; and validation cohort 2, n = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG
plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvβ6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis.
B cells thwart antigenic aggressions by releasing immunoglobulin M (IgM), IgG, IgA, and IgE, which deploy well-understood effector functions. In contrast, the role of secreted IgD remains mysterious. ...We found that some B cells generated IgD-secreting plasma cells following early exposure to external soluble antigens such as food proteins. Secreted IgD targeted basophils by interacting with the CD44-binding protein galectin-9. When engaged by antigen, basophil-bound IgD increased basophil secretion of interleukin-4 (IL-4), IL-5, and IL-13, which facilitated the generation of T follicular helper type 2 cells expressing IL-4. These germinal center T cells enhanced IgG1 and IgE but not IgG2a and IgG2b responses to the antigen initially recognized by basophil-bound IgD. In addition, IgD ligation by antigen attenuated allergic basophil degranulation induced by IgE co-ligation. Thus, IgD may link B cells with basophils to optimize humoral T helper type 2-mediated immunity against common environmental soluble antigens.
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•IgD interacts with basophils through the CD44-binding protein galectin-9•IgD ligation by antigen elicits basophil release of Th2 cell-associated cytokines•IgD-activated basophils enhance B cell production of IgG1 and IgE•IgD interferes with IgE-mediated basophil degranulation
The function of IgD has been mysterious. Shan et al. find that IgD recognized food antigens and targeted basophils through galectin-9. IgD ligation by antigen induced basophil secretion of IL-4, IL-5, and IL-13, which amplified Th2 cell-mediated IgG1 and IgE production by B cells. IgD also constrained IgE-mediated basophil degranulation.
T cell-independent (TI) B cell responses to nonprotein Ags involve multiple cues from the innate immune system. Neutrophils express complement receptors and activated neutrophils can release BAFF, ...but mechanisms effectively linking neutrophil activation to TI B cell responses are incompletely understood. Using germline and conditional knockout mice, we found that TI humoral responses involve alternative pathway complement activation and neutrophil-expressed C3a and C5a receptors (C3aR1/C5aR1) that promote BAFF-dependent B1 cell expansion and TI Ab production. Conditional absence of C3aR1/C5aR1 on neutrophils lowered serum BAFF levels, led to fewer Peyer's patch germinal center B cells, reduced germinal center B cells IgA class-switching, and lowered fecal IgA levels. Together, the results indicate that sequential activation of complement on neutrophils crucially supports humoral TI and mucosal IgA responses through upregulating neutrophil production of BAFF.
Mechanistic target of rapamycin (mTOR) enhances immunity in addition to orchestrating metabolism. Here we show that mTOR coordinates immunometabolic reconfiguration of marginal zone (MZ) B cells, a ...pre-activated lymphocyte subset that mounts antibody responses to T-cell-independent antigens through a Toll-like receptor (TLR)-amplified pathway involving transmembrane activator and CAML interactor (TACI). This receptor interacts with mTOR via the TLR adapter MyD88. The resulting mTOR activation instigates MZ B-cell proliferation, immunoglobulin G (IgG) class switching, and plasmablast differentiation through a rapamycin-sensitive pathway that integrates metabolic and antibody-inducing transcription programs, including NF-κB. Disruption of TACI-mTOR interaction by rapamycin, truncation of the MyD88-binding domain of TACI, or B-cell-conditional mTOR deficiency interrupts TACI signaling via NF-κB and cooperation with TLRs, thereby hampering IgG production to T-cell-independent antigens but not B-cell survival. Thus, mTOR drives innate-like antibody responses by linking proximal TACI signaling events with distal immunometabolic transcription programs.
Retroviral help for B cells Grasset, Emilie K; Cerutti, Andrea
Science (American Association for the Advancement of Science),
12/2014, Letnik:
346, Številka:
6216
Journal Article
Recenzirano
Endogenous retroviruses are footprints left by past retroviral infections that have incorporated viral elements into our genomes (1). They constitute an important component of our virome, the ...collective genomes from viruses peacefully inhabiting our body (2). These viruses are part of a larger community of commensal and symbiotic microorganisms. The most studied members of this microbiota are commensal bacteria colonizing mucosal organs, including the gut (3). Besides breaking down food and generating nutrients, gut commensals impede the growth of pathogens and stimulate immune system development, including the production of antibodies by intestinal and systemic B cells (4, 5). On page 1486 of this issue, Zeng et al. (6) show that endogenous retroviruses can also mobilize B cells to rapidly produce antibodies against pathogenic antigens.Protein antigens usually elicit antibody production by B cells through a T cell-dependent pathway that involves B cell-T cell interaction in lymphoid follicles (7). Engagement of the B cell receptor (BCR) by discrete protein epitopes, as well as the production of B cell-stimulating factors by T cells, trigger the differentiation of follicular B cells into long-lived memory B cells and plasma cells that produce protective immunoglobulin G (IgG) antibodies (8).
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