Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals

Magri, Giuliana; Comerma, Laura; Pybus, Marc; Sintes, Jordi; Lligé, David; Segura-Garzón, Daniel; Bascones, Sabrina; Yeste, Ada; Grasset, E.; Gutzeit, Cindy; Uzzan, Mathieu; Ramanujam, Meera; Zelm, Menno C. van; Albero-González, Raquel; Vázquez, Ivonne; Iglesias, Mar; Serrano, Sergi; Márquez, Lucía; Mercadé, Montse; Mehandru, Saurabh; Cerutti, Andrea

doi:10.1016/j.immuni.2017.06.013

Cited by 156 publications

(173 citation statements)

References 50 publications

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“…As we delve into these subsets, it is now clear that a lack of terminal differentiation endows cells with enhanced plasticity. For example, our work and the work of others have demonstrated that IgM + MBCs can rapidly class switch to IgG‐expressing plasmablasts, whereas work from Cerutti and colleagues has demonstrated that IgM + MBCs can also switch to IgA‐expressing plasmablasts . Whether these IgM precursors are related or not is an open question.…”

Section: Discussionmentioning

confidence: 80%

Memory B cell heterogeneity: Remembrance of things past

Pritchard

Pepper

2018

Journal of Leukocyte Biology

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B cells that persist for long periods of time after antigen encounter exist as either antibody-producing plasma cells (long-lived plasma cells, LLPCs) that reside primarily in the bone marrow or rapidly responsive memory B cells (MBCs) that reside in the spleen and circulation. Although LLPCs are thought to be non-responsive to a secondary infection, MBCs respond to subsequent infection through the production of antibody-secreting cells, formation of new germinal centers (GCs), and repopulation of the memory pool. Dogma suggests that MBCs express class-switched, somatically hypermutated BCRs after undergoing a GC reaction. Yet this narrow view of MBCs has been challenged over the years and it is now well recognized that diverse MBC subsets exist in both rodents and humans. Here, we review current thoughts on the phenotypic and functional characteristics of MBCs, focusing on a population of somatically hypermutated, high affinity IgM MBCs that are rapidly responsive to a secondary malaria infection.

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Section: Discussionmentioning

confidence: 80%

Memory B cell heterogeneity: Remembrance of things past

Pritchard

Pepper

2018

Journal of Leukocyte Biology

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“…This observation, together with the recent characterization of dually coated (IgA + IgM + ) mucus-embedded bacteria with increased richness compared to IgA-only-coated bacteria (52), suggests that IgM may compensate IgA deficiency. We show that microbial IgM binding is highly variable between patients.…”

Section: Of 15mentioning

confidence: 81%

Microbial ecology perturbation in human IgA deficiency

et al. 2018

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Paradoxically, loss of immunoglobulin A (IgA), one of the most abundant antibodies, does not irrevocably lead to severe infections in humans but rather is associated with relatively mild respiratory infections, atopy, and auto immunity. IgA might therefore also play covert roles, not uniquely associated with control of pathogens. We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. Metagenomic analysis highlights an expected pathobiont expansion but a less expected depletion in some typi cally beneficial symbionts. Gut colonization by species usually present in the oropharynx is also reminiscent of spatial microbiota disorganization. IgM only partially rescues IgA deficiency because not all typical IgA targets are efficiently bound by IgM in the intestinal lumen. Together, IgA appears to play a nonredundant role at the fore front of the immune/microbial interface, away from the intestinal barrier, ranging from pathobiont control and regulation of systemic inflammation to preservation of commensal diversity and community networks.

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“…In mouse, B1 cells serve as the major source for polyclonal low‐affinity anti‐commensal IgM responses as a primitive natural antibody response . However, in contrast to mice, humans have more abundant IgM + plasma cells in the gut, which secrete IgM antibodies that help retain a diverse community of commensals in the mucus layer in synergy with IgA . Surprisingly, a considerable amount of IgG2b and IgG3 has been identified in the secretory compartment in the gut as well.…”

Section: B‐cell–gut Microbiota Interactionsmentioning

confidence: 99%

Adaptive immune education by gut microbiota antigens

2018

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SummaryHost-microbiota mutualism has been established during long-term coevolution. A diverse and rich gut microbiota plays an essential role in the development and maturation of the host immune system. Education of the adaptive immune compartment by gut microbiota antigens is important in establishing immune balance. In particular, a critical time frame immediately after birth provides a 'window of opportunity' for the development of lymphoid structures, differentiation and maturation of T and B cells and, most importantly, establishment of immune tolerance to gut commensals. Depending on the colonization niche, antigen type and metabolic property of different gut microbes, CD4 T-cell responses vary greatly, which results in differentiation into distinct subsets. As a consequence, certain bacteria elicit effector-like immune responses by promoting the production of pro-inflammatory cytokines such as interferon-c and interleukin-17A, whereas other bacteria favour the generation of regulatory CD4 T cells and provide help with gut homeostasis. The microbiota have profound effects on B cells also. Gut microbial exposure leads to a continuous diversification of B-cell repertoire and the production of Tdependent and -independent antibodies, especially IgA. These combined effects of the gut microbes provide an elegant educational process to the adaptive immune network. Contrariwise, failure of this process results in a reduced homeostasis with the gut microbiota, and an increased susceptibility to various immune disorders, both inside and outside the gut. With more definitive microbial-immune relations waiting to be discovered, modulation of the host gut microbiota has a promising future for disease intervention.

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Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals

Cited by 156 publications

References 50 publications

Memory B cell heterogeneity: Remembrance of things past

Memory B cell heterogeneity: Remembrance of things past

Microbial ecology perturbation in human IgA deficiency

Adaptive immune education by gut microbiota antigens

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