The Eph-related tyrosine kinase ligand Ephrin-B1 marks germinal center and memory precursor B cells

Identification of germinal center (GC) B cells is typically reliant on the use of surface activation markers that exhibit a wide range of expression. Here, we identify Ephrin-B1, a ligand for Eph-related receptor tyrosine kinases, as a specific marker of mature GC B cells. The number of Ephrin-B1+ GC B cells increases during the course of an immune response with Ephrin-B1+ GC B cells displaying elevated levels of Bcl6, S1pr2, and Aicda relative to their Ephrin-B1– counterparts. We further identified a small proportion of recently dividing, somatically mutated Ephrin-B1+ GC B cells that have begun to down-regulate Bcl6 and S1pr2 and express markers associated with memory B cells, such as CD38 and EBI2. Transcriptional analysis indicates that these cells are developmentally related to memory B cells, and likely represent a population of GC memory precursor (PreMem) B cells. GC PreMem cells display enhanced survival relative to bulk GC B cells, localize near the edge of the GC, and are predominantly found within the light zone. These findings offer insight into the significant heterogeneity that exists within the GC B cell population and provide tools to further dissect signals regulating the differentiation of GC B cells.

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Faculty Opinions recommendation of Role of MHC class II on memory B cells in post-germinal center B cell homeostasis and memory response.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1031339.363676 ◽

2006 ◽

Author(s):

David Tarlinton

Keyword(s):

B Cells ◽

B Cell ◽

Mhc Class Ii ◽

Germinal Center ◽

Memory B Cells ◽

Cell Homeostasis ◽

Memory Response ◽

Germinal Center B Cell ◽

B Cell Homeostasis

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Faculty Opinions recommendation of A germinal center-independent pathway generates unswitched memory B cells early in the primary response.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14187959.793458379 ◽

2012 ◽

Author(s):

Kai-Michael Toellner ◽

Laura George

Keyword(s):

B Cells ◽

Germinal Center ◽

Primary Response ◽

Memory B Cells

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Human Germinal Center B Cells Differ from Naïve and Memory B Cells in CD40 Expression and CD40L‐Induced Signaling Response

Cytometry Part A ◽

10.1002/cyto.a.23737 ◽

2019 ◽

Vol 95 (4) ◽

pp. 442-449 ◽

Cited By ~ 3

Author(s):

Kanutte Huse ◽

Cara E. Wogsland ◽

Hannah G. Polikowsky ◽

Kirsten E. Diggins ◽

Erlend B. Smeland ◽

...

Keyword(s):

B Cells ◽

Germinal Center ◽

Memory B Cells ◽

Cd40 Expression ◽

Germinal Center B Cells

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Chronic Exposure to Malaria Is Associated with Inhibitory and Activation Markers on Atypical Memory B Cells and Marginal Zone-Like B Cells

Frontiers in Immunology ◽

10.3389/fimmu.2017.00966 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 17

Author(s):

Itziar Ubillos ◽

Joseph J. Campo ◽

Pilar Requena ◽

Maria Ome-Kaius ◽

Sarah Hanieh ◽

...

Keyword(s):

B Cells ◽

Chronic Exposure ◽

Marginal Zone ◽

Memory B Cells ◽

Activation Markers

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T-independent antigen induces humoral memory through germinal centers

Journal of Experimental Medicine ◽

10.1084/jem.20210527 ◽

2022 ◽

Vol 219 (3) ◽

Author(s):

Xin Liu ◽

Yongshan Zhao ◽

Hai Qi

Keyword(s):

B Cells ◽

Immune Responses ◽

Germinal Center ◽

Plasma Cells ◽

Underlying Mechanism ◽

Memory B Cells ◽

Antigen B ◽

Per Se ◽

Humoral Responses ◽

Human And Mouse

T-dependent humoral responses generate long-lived memory B cells and plasma cells (PCs) predominantly through germinal center (GC) reaction. In human and mouse, memory B cells and long-lived PCs are also generated during immune responses to T-independent antigen, including bacterial polysaccharides, although the underlying mechanism for such T-independent humoral memory is not clear. While T-independent antigen can induce GCs, they are transient and thought to be nonproductive. Unexpectedly, by genetic fate-mapping, we find that these GCs actually output memory B cells and PCs. Using a conditional BCL6 deletion approach, we show memory B cells and PCs fail to last when T-independent GCs are precluded, suggesting that the GC experience per se is important for programming longevity of T-independent memory B cells and PCs. Consistent with the fact that infants cannot mount long-lived humoral memory to T-independent antigen, B cells from young animals intrinsically fail to form T-independent GCs. Our results suggest that T-independent GCs support humoral memory, and GC induction may be key to effective vaccines with T-independent antigen.

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The Normal Counterpart of IgD Myeloma Cells in Germinal Center Displays Extensively Mutated IgVH Gene, Cμ–Cδ Switch, and λ Light Chain Expression

Journal of Experimental Medicine ◽

10.1084/jem.187.8.1169 ◽

1998 ◽

Vol 187 (8) ◽

pp. 1169-1178 ◽

Cited By ~ 97

Author(s):

Christophe Arpin ◽

Odette de Bouteiller ◽

Diane Razanajaona ◽

Isabelle Fugier-Vivier ◽

Francine Brière ◽

...

Keyword(s):

Bone Marrow ◽

B Cells ◽

Light Chain ◽

Germinal Center ◽

Plasma Cells ◽

Precursor Cells ◽

Memory B Cells ◽

Hematopoietic Stem ◽

Myeloma Cells ◽

Λ Light Chain

Human myeloma are incurable hematologic cancers of immunoglobulin-secreting plasma cells in bone marrow. Although malignant plasma cells can be almost eradicated from the patient's bone marrow by chemotherapy, drug-resistant myeloma precursor cells persist in an apparently cryptic compartment. Controversy exists as to whether myeloma precursor cells are hematopoietic stem cells, pre–B cells, germinal center (GC) B cells, circulating memory cells, or plasma blasts. This situation reflects what has been a general problem in cancer research for years: how to compare a tumor with its normal counterpart. Although several studies have demonstrated somatically mutated immunoglobulin variable region genes in multiple myeloma, it is unclear if myeloma cells are derived from GCs or post-GC memory B cells. Immunoglobulin (Ig)D-secreting myeloma have two unique immunoglobulin features, including a biased λ light chain expression and a Cμ–Cδ isotype switch. Using surface markers, we have previously isolated a population of surface IgM−IgD+CD38+ GC B cells that carry the most impressive somatic mutation in their IgV genes. Here we show that this population of GC B cells displays the two molecular features of IgD-secreting myeloma cells: a biased λ light chain expression and a Cμ–Cδ isotype switch. The demonstration of these peculiar GC B cells to differentiate into IgD-secreting plasma cells but not memory B cells both in vivo and in vitro suggests that IgD-secreting plasma and myeloma cells are derived from GCs.

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Germinal centers in human lymph nodes contain reactivated memory B cells

Journal of Experimental Medicine ◽

10.1084/jem.20071006 ◽

2007 ◽

Vol 204 (11) ◽

pp. 2655-2665 ◽

Cited By ~ 41

Author(s):

Richard J. Bende ◽

Febe van Maldegem ◽

Martijn Triesscheijn ◽

Thera A.M. Wormhoudt ◽

Richard Guijt ◽

...

Keyword(s):

B Cells ◽

Lymph Nodes ◽

Germinal Center ◽

Lymphoid Tissue ◽

Somatic Hypermutation ◽

Germinal Centers ◽

Memory B Cells ◽

Cell Clones ◽

Clonal Origin ◽

Successive Recall

To reveal migration trails of antigen-responsive B cells in lymphoid tissue, we analyzed immunoglobulin (Ig)M-VH and IgG-VH transcripts of germinal center (GC) samples microdissected from three reactive human lymph nodes. Single B cell clones were found in multiple GCs, one clone even in as many as 19 GCs. In several GCs, IgM and IgG variants of the same clonal origin were identified. The offspring of individual hypermutated IgG memory clones were traced in multiple GCs, indicating repeated engagement of memory B cells in GC reactions. These findings imply that recurring somatic hypermutation progressively drives the Ig repertoire of memory B cells to higher affinities and infer that transforming genetic hits in non-Ig genes during lymphomagenesis do not have to arise during a single GC passage, but can be collected during successive recall responses.

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Potential anti-EBV effects associated with elevated interleukin-21 levels: a case report

BMC Infectious Diseases ◽

10.1186/s12879-020-05609-z ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Kristian Assing ◽

Christian Nielsen ◽

Marianne Jakobsen ◽

Charlotte B. Andersen ◽

Kristin Skogstrand ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Plasma Cell ◽

Germinal Center ◽

Plasma Cells ◽

Cell Formation ◽

Memory B Cells ◽

Memory B Cell

Abstract Background Germinal center derived memory B cells and plasma cells constitute, in health and during EBV reactivation, the largest functional EBV reservoir. Hence, by reducing germinal center derived formation of memory B cells and plasma cells, EBV loads may be reduced. Animal and in-vitro models have shown that IL-21 can support memory B and plasma cell formation and thereby potentially contribute to EBV persistence. However, IL-21 also displays anti-viral effects, as mice models have shown that CD4+ T cell produced IL-21 is critical for the differentiation, function and survival of anti-viral CD8+ T cells able to contain chronic virus infections. Case presentation We present immunological work-up (flow-cytometry, ELISA and genetics) related to a patient suffering from a condition resembling B cell chronic active EBV infection, albeit with moderately elevated EBV copy numbers. No mutations in genes associated with EBV disease, common variable immunodeficiency or pertaining to the IL-21 signaling pathway (including hypermorphic IL-21 mutations) were found. Increased (> 5-fold increase 7 days post-vaccination) CD4+ T cell produced (p < 0.01) and extracellular IL-21 levels characterized our patient and coexisted with: CD8+ lymphopenia, B lymphopenia, hypogammaglobulinemia, compromised memory B cell differentiation, absent induction of B-cell lymphoma 6 protein (Bcl-6) dependent peripheral follicular helper T cells (pTFH, p = 0.01), reduced frequencies of peripheral CD4+ Bcl-6+ T cells (p = 0.05), compromised plasmablast differentiation (reduced protein vaccine responses (p < 0.001) as well as reduced Treg frequencies. Supporting IL-21 mediated suppression of pTFH formation, pTFH and CD4+ IL-21+ frequencies were strongly inversely correlated, prior to and after vaccination, in the patient and in controls, Spearman’s rho: − 0.86, p < 0.001. Conclusions To the best of our knowledge, this is the first report of elevated CD4+ IL-21+ T cell frequencies in human EBV disease. IL-21 overproduction may, apart from driving T cell mediated anti-EBV responses, disrupt germinal center derived memory B cell and plasma cell formation, and thereby contribute to EBV disease control.

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