B cell receptor and Toll-like receptor signaling coordinate to control distinct B-1 responses to both self and the microbiota

Kreuk, Lieselotte; Koch, Meghan A.; Slayden, Leianna C; Lind, Nicholas A.; Chu, Sophia; Savage, Hannah P; Kantor, Aaron B.; Baumgarth, Nicole; Barton, Gregory M.

doi:10.7554/elife.47015

Cited by 50 publications

(59 citation statements)

References 70 publications

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“…B1a cells of Nfkbiedeficient mice show a significant downregulation of IgM expression in peritoneal B1a cells, with respect to WT and presented two B220lowCD19+CD5+B1a populations with different levels of IgM expression (B1a IgMhi and B1a IgMlow). Nfkbie −/− B1a IgMlow population showed impaired proliferation response to TLRs stimuli and reduced ex vivo survival compared to B1a IgMhi cells, in agreement with the key role of BCR in B1 cells expansion and activation 28,30,[45][46][47][48][49] . Downregulation of IgM on B cells contributes to a physiological B-cell immune tolerance mechanism called anergy, and serves to restrain their response to endogenous/self-antigens and to chronic BCR stimulation 50 .…”

Section: Discussionsupporting

confidence: 76%

“…BCR signaling plays an instructive role in B1a cell lineage determination and maintenance 28,30,44,45 . In addition, recent studies showed that BCR signaling cooperates with TLR signaling in controlling expansion and activation of B1a B cells [46][47][48][49] . NF-κB is one of the key transcription factors activated by BCR and TLR signaling.…”

Section: Discussionmentioning

confidence: 99%

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Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

et al. 2020

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Aberrant NF-κB activation is a hallmark of most B-cell malignancies. Recurrent inactivating somatic mutations in the NFKBIE gene, which encodes IκBε, an inhibitor of NF-κB-inducible activity, are reported in several B-cell malignancies with highest frequencies in chronic lymphocytic leukemia and primary mediastinal B-cell lymphoma, and account for a fraction of NF-κB pathway activation. The impact of NFKBIE deficiency on B-cell development and function remains, however, largely unknown. Here, we show that Nfkbie-deficient mice exhibit an amplification of marginal zone B cells and an expansion of B1 B-cell subsets. In germinal center (GC)-dependent immune response, Nfkbie deficiency triggers expansion of GC B-cells through increasing cell proliferation in a B-cell autonomous manner. We also show that Nfkbie deficiency results in hyperproliferation of a B1 B-cell subset and leads to increased NF-κB activation in these cells upon Toll-like receptor stimulation. Nfkbie deficiency cooperates with mutant MYD88 signaling and enhances B-cell proliferation in vitro. In aged mice, Nfkbie absence drives the development of an oligoclonal indolent B-cell lymphoproliferative disorders, resembling monoclonal B-cell lymphocytosis. Collectively, these findings shed light on an essential role of IκBε in finely tuning B-cell development and function.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

et al. 2020

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“…B1 cells are selected for autoreactivity and form a pool of long-lived, self-renewing B cells that produce the majority of circulating, naturally occurring, low-affinity IgM and IgG, that cross-react with both autoantigens and conservative microbial antigens. According to recent data, Toll-like receptors (TLR)-mediated activation of B1 cells through CpG oligonucleotides, or lipopolysaccharides, leads to a rapid increase in the production of protective natural Abs (IgM, IgG) [ 42 , 43 ]. Interestingly, B2 lymphocytes can differentiate directly into B1 lymphocytes, and this process is controlled by a self-reactive B cell receptor [ 44 ].…”

Section: Diversity Of Abs Types: Antigen-specific Natural Polyrementioning

confidence: 99%

Immunoglobulins with Non-Canonical Functions in Inflammatory and Autoimmune Disease States

Ermakov

Nevinsky

Buneva

2020

IJMS

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Immunoglobulins are known to combine various effector mechanisms of the adaptive and the innate immune system. Classical immunoglobulin functions are associated with antigen recognition and the initiation of innate immune responses. However, in addition to classical functions, antibodies exhibit a variety of non-canonical functions related to the destruction of various pathogens due to catalytic activity and cofactor effects, the action of antibodies as agonists/antagonists of various receptors, the control of bacterial diversity of the intestine, etc. Canonical and non-canonical functions reflect the extreme human antibody repertoire and the variety of antibody types generated in the organism: antigen-specific, natural, polyreactive, broadly neutralizing, homophilic, bispecific and catalytic. The therapeutic effects of intravenous immunoglobulins (IVIg) are associated with both the canonical and non-canonical functions of antibodies. In this review, catalytic antibodies will be considered in more detail, since their formation is associated with inflammatory and autoimmune diseases. We will systematically summarize the diversity of catalytic antibodies in normal and pathological conditions. Translational perspectives of knowledge about natural antibodies for IVIg therapy will be also discussed.

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“…28,31 Indeed, work from the Barton laboratory shows that expansion of PtC-specific BCRs in the B1a compartment is regulated by endosomal TLRs that recognize nucleic acids. 44 Conversely, endosomal…”

Section: T H Y 1 -/ -H O S T / a T Amentioning

confidence: 99%

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

Tan

Noviski

Huizar

et al. 2019

Immunological Reviews

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Efficient mechanisms of central tolerance, including receptor editing and deletion, prevent highly self-reactive B cell receptors (BCRs) from populating the periphery.Despite this, modest self-reactivity persists in (and may even be actively selected into) the mature B cell repertoire. In this review, we discuss new insights into mechanisms of peripheral B cell tolerance that restrain mature B cells from mounting inappropriate responses to endogenous antigens, and place recent work into historical context. In particular, we discuss new findings that have arisen from application of a novel in vivo reporter of BCR signaling, Nur77-eGFP, expression of which scales with the degree of self-reactivity in both monoclonal and polyclonal B cell repertoires. We discuss new and historical evidence that self-reactivity is not just tolerated, but actively selected into the peripheral repertoire. We review recent progress in understanding how dual expression of the IgM and IgD BCR isotypes on mature naive follicular B cells tunes responsiveness to endogenous antigen recognition, and discuss how this may be integrated with other features of clonal anergy. Finally, we discuss how expression of Nur77 itself couples chronic antigen stimulation with B cell tolerance. K E Y W O R D Sanergy, B cell, IgD, IgM, Nur77/Nr4a1, tolerance Previous work from our laboratory exploiting an in vivo reporter of antigen recognition, Nur77-eGFP BAC Tg, addresses this important point ( Figure 1A). 15 GFP expression in this reporter line is under the control of the regulatory region of Nr4a1/ Nur77. Nr4a1-3 encode a small family of orphan nuclear hormone receptors which were originally cloned as signal-dependent primary response genes (also known as immediate-early genes), and are highly upregulated by a range of mitogens, including antigen receptor stimulation. [16][17][18] Consequently, antigen stimulation rapidly triggers reporter expression in B and T cells in vitro ( Figure 1B), and GFP is also induced by infection or immunization in antigen-specific lymphocytes in

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B cell receptor and Toll-like receptor signaling coordinate to control distinct B-1 responses to both self and the microbiota

Cited by 50 publications

References 70 publications

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

Immunoglobulins with Non-Canonical Functions in Inflammatory and Autoimmune Disease States

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

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