Identification of a human splenic marginal zone B cell precursor with NOTCH2-dependent differentiation properties

Descatoire, Marc; Weller, Sandra; Irtan, Sabine; Sarnacki, Sabine; Feuillard, Jean; Storck, Sébastien; Guiochon‐Mantel, Anne; Bouligand, Jérôme; Morali, A.; Cohen, J.; Jacquemin, Emmanuel; Iascone, Maria; Bôle‐Feysot, Christine; Cagnard, Nicolas; Weill, Jean‐Claude; Reynaud, Claude‐Agnès

doi:10.1084/jem.20132203

Cited by 116 publications

(143 citation statements)

References 48 publications

(82 reference statements)

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“…Furthermore, TOX deficient mice (TKO) lacked lymph nodes and had a significant decrease in the frequency and size of Peyer’s patches(40). A recent study provides data that support an important role of TOX expression in B-cell biology(41). TOX was identified as one of the top differentially expressed genes between memory B cells (IgG+ CD27+) and marginal zone B-cells (IgD+ CD27+).…”

Section: Discussionmentioning

confidence: 89%

Genome-Wide Analysis Uncovers Novel Recurrent Alterations in Primary Central Nervous System Lymphomas

Braggio

Wier

Ojha

et al. 2015

Clinical Cancer Research

194

160

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Purpose Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the CNS. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain. Experimental design We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing. Results Biallelic inactivation of TOX and PRKCD were recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. Additionally, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11 and translocations IgH-BCL6. Overall, BCR/TLR/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation. Conclusions In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas.

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Section: Discussionmentioning

confidence: 89%

Genome-Wide Analysis Uncovers Novel Recurrent Alterations in Primary Central Nervous System Lymphomas

Braggio

Wier

Ojha

et al. 2015

Clinical Cancer Research

194

160

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“…However, compared to gut ME-SW B cells, gut ME-M B cells also showed enhanced MZ-like traits (Figure 3I), including increased expression of CD21, CD35, CD1c, and the adhesion molecule CD66a (Descatoire et al., 2014, Seifert et al., 2015). Notwithstanding these similarities, supervised gene expression analysis, flow cytometry, and gene set enrichment analysis (GSEA) indicated that gut ME-M B cells were distinct from splenic MZ B cells (Figures S3B–S3E).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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SummarySecretory 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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“…In mice with a conditionally targeted deletion of Notch-2 mice, their T2 precursor cells and MZ-B cells do not develop. 28 The work of Saito et al 28 has also shown that Notch-2 are preferentially expressed on mature B cells, whereas Descatoire et al 29 have shown that Notch-2 ligand Delta-Like1 expression on precursor MZ-B cells results in the development of MZ-B cells. MINT acts as a negative regulator of Notch-2, and MINT-deficient B cells differentiate more effectively into MZ-B cells.…”

Section: Developmental Origin Of Marginal Zone B Cellsmentioning

confidence: 99%

Heterogeneity of Memory Marginal Zone B Cells

2018

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The marginal zone (MZ) is largely composed of a unique subpopulation of B cells, the so-called MZ-B cells. At a molecular level, memory B cells are characterized by the presence of somatically mutated IGV genes. The earliest studies in the rat have documented the presence of hapten-specific MZ-B cells after immunization in the MZ. This work later received experimental support demonstrating that the IGHV-Cµ transcripts expressed by phenotypically defined splenic MZ-B cells (defined as CD90negIgMhighIgDlow B cells) can carry somatic hypermutation. However, only a minor fraction (< 10%–20%) of these MZ-B cells is mutated and is considered to represent memory B cells. Memory B cells can either be class-switched (IgG, IgA, IgE), or non–class-switched (IgM) B cells. B cells in the MZ are a heterogeneous population of cells and both naïve MZ-B cells; class switched and unswitched memory MZ-B cells are present at this unique site in the spleen. Naïve MZ-B cells carry unmutated Ig genes, produce low-affinity IgM molecules and constitute a first line of defense against invading pathogens. Memory MZ-B cells express high-affinity Ig molecules, directed to (microbial) antigens that have been encountered. In this review, we report on the memory compartment of splenic MZ-B cells in the rat to provide insights into the origin and function of these memory MZ-B cells.

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Identification of a human splenic marginal zone B cell precursor with NOTCH2-dependent differentiation properties

Abstract: Identification in humans of a bona fide marginal zone B cell population, which differentiates from a splenic marginal zone precursor through a NOTCH2 signaling pathway.

Cited by 116 publications

References 48 publications

Genome-Wide Analysis Uncovers Novel Recurrent Alterations in Primary Central Nervous System Lymphomas

Genome-Wide Analysis Uncovers Novel Recurrent Alterations in Primary Central Nervous System Lymphomas

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

Heterogeneity of Memory Marginal Zone B Cells

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