The gut mucosa is exposed to a large community of commensal bacteria that are required for the processing of nutrients and the education of the local immune system. Conversely, the gut immune system ...generates innate and adaptive responses that shape the composition of the local microbiota. One striking feature of intestinal adaptive immunity is its ability to generate massive amounts of noninflammatory immunoglobulin A (IgA) antibodies through multiple follicular and extrafollicular pathways that operate in the presence or absence of cognate T-B cell interactions. Here we discuss the role of intestinal IgA in host-commensal mutualism, immune protection, and tolerance and summarize recent advances on the role of innate immune cells in intestinal IgA production.
Summary
Complex and diverse communities of bacteria establish mutualistic and symbiotic relationships with the gut after birth. The intestinal immune system responds to bacterial colonization by ...acquiring a state of hypo‐responsiveness against commensals and active readiness against pathogens. The resulting homeostatic balance involves a continuous dialog between the microbiota and lymphocytes with the intermediation of epithelial and dendritic cells. This dialog causes massive production of immunoglobulin A (IgA), a non‐inflammatory antibody specialized in mucosal protection. Here, we discuss recent advances on the regulation of intestinal IgA responses and their role in host‐microbe interaction.
IgD emerged soon after IgM at the time of inception of the adaptive immune system. Despite its evolutionary conservation from fish to humans, the specific functions of IgD have only recently begun to ...be elucidated. Mature B cells undergo alternative mRNA splicing to express IgD and IgM receptors with identical antigenic specificity. The enigma of dual IgD and IgM expression has been tackled by several recent studies showing that IgD helps peripheral accumulation of physiologically autoreactive B cells through its functional unresponsiveness to self‐antigens but prompt readiness against foreign antigens. IgD achieves this balance by attenuating IgM‐mediated anergy while promoting specific responses to multimeric non‐self‐antigens. Additional research has clarified how and why certain mucosal B cells become plasmablasts or plasma cells specializing in IgD secretion. In particular, the microbiota has been shown to play an important role in driving class switch‐mediated replacement of IgM with IgD. Secreted IgD appears to enhance mucosal homeostasis and immune surveillance by “arming” myeloid effector cells such as basophils and mast cells with IgD antibodies reactive against mucosal antigens, including commensal and pathogenic microbes. Here we will review these advances and discuss their implications in humoral immunity in human and mice.
IgD and IgM engagement by microbial antigens induces B cell entry into a germinal center pathway that generates plasma cells secreting IgG,IgA, IgE or IgD. In self‐reactive B cells, engagement of IgM by self‐antigen induces an IgD‐modulated anergy‐inducing program that is shut off by microbial antigens cross‐reactive with self‐epitopes.
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.
Mucosal surfaces are colonized by large communities of commensal bacteria and represent the primary site of entry for pathogenic agents. To prevent microbial intrusion, mucosal B cells release large ...amounts of immunoglobulin (Ig) molecules through multiple follicular and extrafollicular pathways. IgA is the most abundant antibody isotype in mucosal secretions and owes its success in frontline immunity to its ability to undergo transcytosis across epithelial cells. In addition to translocating IgA onto the mucosal surface, epithelial cells educate the mucosal immune system as to the composition of the local microbiota and instruct B cells to initiate IgA responses that generate immune protection while preserving immune homeostasis. Here we review recent advances in our understanding of the cellular interactions and signaling pathways governing IgA production at mucosal surfaces and discuss new findings on the regulation and function of mucosal IgD, the most enigmatic isotype of our mucosal antibody repertoire.
There are great interest and demand for the development of vaccines to prevent and treat diverse microbial infections. Mucosal vaccines elicit immune protection by stimulating the production of ...antibodies at mucosal surfaces and systemic districts. Being positioned in close proximity to a large community of commensal microbes, the mucosal immune system deploys a heterogeneous population of cells and a complex regulatory network to maintain the balance between surveillance and tolerance. A successful mucosal vaccine relies on leveraging the functions of these immune cells and regulatory components. We review the important cellular interactions and molecular pathways underlying the induction and regulation of mucosal antibody responses and discuss their implications on mucosal vaccination.
A dense mucus layer in the large intestine prevents inflammation by shielding the underlying epithelium from luminal bacteria and food antigens. This mucus barrier is organized around the ...hyperglycosylated mucin MUC2. Here we show that the small intestine has a porous mucus layer, which permitted the uptake of MUC2 by antigen-sampling dendritic cells (DCs). Glycans associated with MUC2 imprinted DCs with anti-inflammatory properties by assembling a galectin-S-Dectin-1-FcyRIIB receptor complex that activated β-catenin. This transcription factor interfered with DC expression of inflammatory but not tolerogenic cytokines by inhibiting gene transcription through nuclear factor κB. MUC2 induced additional conditioning signals in intestinal epithelial cells. Thus, mucus does not merely form a nonspecific physical barrier, but also constrains the immunogenicity of gut antigens by delivering tolerogenic signals.
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.
The B cell helper side of neutrophils Cerutti, Andrea; Puga, Irene; Magri, Giuliana
Journal of leukocyte biology,
10/2013, Volume:
94, Issue:
4
Journal Article
Peer reviewed
Open access
Review on the role of neutrophils in marginal zone B cell activation and antibody production.
Neutrophils use opsonizing antibodies to enhance the clearance of intruding microbes. Recent studies ...indicate that splenic neutrophils also induce antibody production by providing helper signals to B cells lodged in the MZ of the spleen. Here, we discuss the B cell helper function of neutrophils in the context of growing evidence indicating that neutrophils function as sophisticated regulators of innate and adaptive immune responses.
Innate lymphoid cells (ILCs) regulate stromal cells, epithelial cells and cells of the immune system, but their effect on B cells remains unclear. Here we identified RORγt(+) ILCs near the marginal ...zone (MZ), a splenic compartment that contains innate-like B cells highly responsive to circulating T cell-independent (TI) antigens. Splenic ILCs established bidirectional crosstalk with MAdCAM-1(+) marginal reticular cells by providing tumor-necrosis factor (TNF) and lymphotoxin, and they stimulated MZ B cells via B cell-activation factor (BAFF), the ligand of the costimulatory receptor CD40 (CD40L) and the Notch ligand Delta-like 1 (DLL1). Splenic ILCs further helped MZ B cells and their plasma-cell progeny by coopting neutrophils through release of the cytokine GM-CSF. Consequently, depletion of ILCs impaired both pre- and post-immune TI antibody responses. Thus, ILCs integrate stromal and myeloid signals to orchestrate innate-like antibody production at the interface between the immune system and circulatory system.
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