Two Distinct Pathways of B-Cell Development in Peyer’s Patches

The developmental biology of sheep ileal and jejunal Peyer’s patches (PP) was investigated using corticosteroids to deplete immature B lymphocytes. During a 7-day treatment with dexamethasone, ileal PP follicular (iPf)B-cell proliferation was arrested and most iPfB-cells died. This resulted in follicular involution with the survival of mesenchymal cells. No iPfB-cell proliferation was detected in follicular remnants for 4 weeks postdexamethasone treatment, and during a subsequent 3-month period, there was limited iPfB-cell proliferation that resulted in a partial regeneration of follicles. Ileal PP involution was also associated with a severe B lymphopenia that persisted for over 14 weeks and was characterized by the survival of primarily isotype-switched and CD5+sIgM+B-cells in blood. In contrast, the size of jejunal PP follicles was reduced following dexamethasone treatment, but intrafollicular B-cell proliferation was not arrested. Furthermore, within 4 weeks, the jejunal PP follicles had recovered in size and cellularity and there was no disruption in IgA plasma-cell production. Thus, dexamethasone selectively depleted iPfB-cells and revealed that the ileal and jejunal PPs contain functionally distinct B-cell populations. The partial regeneration of the iPfB-cell population indicated that either an intrafollicular, corticosteroid-resistant B-stem cell existed or that ileal PP follicles can be repopulated by circulating B-cells. Finally, the association between ileal PP involution and the absence of circulating, CD5-B-cells confirmed that this lymphoid tissue provides an essential environment for conventional sIgM+B-cell development.

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The Effect of Dosage, Gestational Age and Splenectomy on Anti-IgM Interception of Prenatal B-cell Development in Sheep

Clinical and Developmental Immunology ◽

10.1080/10446670310001598500 ◽

2003 ◽

Vol 10 (1) ◽

pp. 19-26 ◽

Cited By ~ 2

Author(s):

P. McCullagh ◽

C. McL. Press ◽

S. J. McClure ◽

H. J. Larsen ◽

T. Landsverk

Keyword(s):

Stem Cells ◽

B Cells ◽

B Cell ◽

Cell Development ◽

B Cell Development ◽

Peyer's Patches ◽

Peyer’S Patches ◽

B Cell Depletion ◽

Limited Period ◽

In Pregnancy

The administration of a single bolus of anti-IgM antibody to foetal lambs early in pregnancy produces prolonged B-cell depletion. The present study investigated this depletion by examining the effect, on B-cell development in the ileal Peyer's patches, of varying the timing and dosage of antibody administration and by supplementing anti-IgM with surgical splenectomy. The capacity of a 1 mg bolus of anti-IgM to deplete Peyer's patches of B cells was lost if its administration was deferred until two thirds of the way through pregnancy, but persisted beyond this time if weight-adjusted doses were used. Splenectomy of the foetus performed at an earlier age failed to extend the age at which a 1 mg dose of antibody remained effective. As the concentration of murine immunoglobulin in foetal serum was greatly reduced after 21 days, it is inferred that ongoing suppression of B-cell development is not dependent on the continued presence of murine immunoglobulin. The enduring nature of suppression could be attributable to a limited period during which differentiation of B cells from stem cells normally occurs, although further studies will be needed to investigate this and other possible explanations for the effect of anti-IgM treatment on prenatal B-cell development in sheep.

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CtIP is essential for early B cell proliferation and development in mice

Journal of Experimental Medicine ◽

10.1084/jem.20181139 ◽

2019 ◽

Vol 216 (7) ◽

pp. 1648-1663 ◽

Cited By ~ 7

Author(s):

Xiangyu Liu ◽

Xiaobin S. Wang ◽

Brian J. Lee ◽

Foon K. Wu-Baer ◽

Xiaohui Lin ◽

...

Keyword(s):

Cell Proliferation ◽

B Cells ◽

B Cell ◽

Essential Gene ◽

Nuclease Activity ◽

Cell Development ◽

Nuclear Body ◽

B Cell Development ◽

Immunoglobulin Gene ◽

End Resection

B cell development requires efficient proliferation and successful assembly and modifications of the immunoglobulin gene products. CtIP is an essential gene implicated in end resection and DNA repair. Here, we show that CtIP is essential for early B cell development but dispensable in naive B cells. CtIP loss is well tolerated in G1-arrested B cells and during V(D)J recombination, but in proliferating B cells, CtIP loss leads to a progressive cell death characterized by ATM hyperactivation, G2/M arrest, genomic instability, and 53BP1 nuclear body formation, indicating that the essential role of CtIP during proliferation underscores its stage-specific requirement in B cells. B cell proliferation requires phosphorylation of CtIP at T847 presumably by CDK, but not its interaction with CtBP or Rb or its nuclease activity. CtIP phosphorylation by ATM/ATR at T859 (T855 in mice) promotes end resection in G1-arrested cells but is dispensable for B cell development and class switch recombination, suggesting distinct roles for T859 and T847 phosphorylation in B cell development.

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Constitutively Activated STAT3 Promotes Cell Proliferation and Survival in the Activated B Cell Subtype of Diffuse Large B Cell Lymphomas.

Blood ◽

10.1182/blood.v110.11.1621.1621 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1621-1621

Author(s):

Bihui Hilda Ye ◽

Beibei Belinda Ding ◽

Jian Jessica Yu ◽

Raymond Y.-L. Yu ◽

Lourdes M. Mendez ◽

...

Keyword(s):

Cell Proliferation ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

B Cell Lymphoma ◽

Cell Development ◽

B Cell Development ◽

Reciprocal Relationship ◽

B Cell Lymphomas ◽

Large B Cell

Abstract During B cell development, cell proliferation and survival are regulated by stage-specific transcription factors. Accordingly, distinct oncogenic pathways are employed by B cell lymphomas representing different stages of B cell development. Diffuse large B cell lymphoma (DLBCL) contains at least two main phenotypic subtypes, i.e. the germinal center B cell-like (GCB-DLBCL) and the activated B cell-like (ABC-DLBCL) groups. It has been shown that GCB-DLBCL responds favorably to chemotherapy and expresses high levels of BCL6, a transcription repressor known to play a causative role in lymphomagenesis. In comparison, ABC-DLBCL has lower levels of BCL6, constitutively activated NF-kappaB and tends to be refractory to chemotherapy. In this study, we investigated the relationship between BCL6 and STAT3 expression/activation in DLBCL and normal GC B cells. Our results demonstrate that BCL6 directly inhibits transcription of the STAT3 gene by binding to two BCL6 sites in its 5′ regulatory region. As a result, high level STAT3 expression and activation are preferentially detected in ABC-DLBCL and BCL6-negative normal germinal center B cells. Specifically, in tonsillar GCs, STAT3 expression and activation is restricted to a previously uncharacterized subset of BCL6−Blimp-1− B cells in the apical light zone. The location and phenotype of these cells suggest that they are in the process of exiting the BCL6-directed GC program and transitioning to a plasma cell differentiation process governed by Blimp-1. The reciprocal relationship between BCL6 and STAT3 is also conserved in DLBCL such that STAT3 expression and activation is preferentially associated with the BCL6-low, ABC subtype. Most importantly, inactivating STAT3 by either AG490 or small interference RNA in ABC-DLBCL cells inhibits cell proliferation and triggers apoptosis. These phenotypes are accompanied by decreased expression of several known STAT3 target genes, including c-Myc, JunB and Mcl-1, and increased expression of the cell cycle inhibitor p27. In addition to identifying STAT3 as a novel BCL6 target gene, our results define STAT3 activation as a second oncogenic pathway operating in ABC-DLBCL and suggest that blocking STAT3 may be potentially therapeutic in treatment of these aggressive lymphomas.

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Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription

Journal of Experimental Medicine ◽

10.1084/jem.20160514 ◽

2017 ◽

Vol 214 (7) ◽

pp. 2059-2071 ◽

Cited By ~ 11

Author(s):

Kenia Ubieta ◽

Mireia Garcia ◽

Bettina Grötsch ◽

Steffen Uebe ◽

Georg F. Weber ◽

...

Keyword(s):

Cell Proliferation ◽

Transcription Factors ◽

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Cell Development ◽

B Cell Development ◽

Gene Profiling ◽

B Cell Differentiation

The role of AP-1 transcription factors in early B cell development and function is still incompletely characterized. Here we address the role of Fra-2 in B cell differentiation. Deletion of Fra-2 leads to impaired B cell proliferation in the bone marrow. In addition, IL-7–stimulated pro–B cell cultures revealed a reduced differentiation from large pre–B cells to small B cells and immature B cells. Gene profiling and chromatin immunoprecipitation sequencing analyses unraveled a transcriptional reduction of the transcription factors Foxo1, Irf4, Ikaros, and Aiolos in Fra-2–deficient B cells. Moreover, expression of IL7Rα and Rag 1/2, downstream targets of Irf4 and Foxo1, were also reduced in the absence of Fra-2. Pro–B cell proliferation and small pre–B cell differentiation were fully rescued by expression of Foxo1 and Irf4 in Fra-2–deficient pro–B cells. Hence, Fra-2 is a key upstream regulator of Foxo1 and Irf4 expression and influences proliferation and differentiation of B cells at multiple stages.

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Ileal Peyer’s Patches Are Not Necessary for Systemic B Cell Development and Maintenance and Do Not Contribute Significantly to the Overall B Cell Pool in Swine

The Journal of Immunology ◽

10.4049/jimmunol.1101879 ◽

2011 ◽

Vol 187 (10) ◽

pp. 5150-5161 ◽

Cited By ~ 32

Author(s):

Marek Sinkora ◽

Katerina Stepanova ◽

John E. Butler ◽

David Francis ◽

Kristina Santiago-Mateo ◽

...

Keyword(s):

B Cell ◽

Cell Development ◽

B Cell Development ◽

Peyer's Patches ◽

Peyer’S Patches ◽

Cell Pool

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Increased O-GlcNAcylation of c-Myc Promotes Pre-B Cell Proliferation

Cells ◽

10.3390/cells9010158 ◽

2020 ◽

Vol 9 (1) ◽

pp. 158 ◽

Cited By ~ 2

Author(s):

Da Hee Lee ◽

Na Eun Kwon ◽

Won-Ji Lee ◽

Moo-Seung Lee ◽

Doo-Jin Kim ◽

...

Keyword(s):

Cell Proliferation ◽

B Cells ◽

B Cell ◽

Cell Development ◽

B Cell Development ◽

Mouse Bone Marrow ◽

Cell Stage ◽

Heavy Chains ◽

Nucleocytoplasmic Proteins ◽

And Function

O-linked β-N-acetylglucosamine (O-GlcNAc) modification regulates the activity of hundreds of nucleocytoplasmic proteins involved in a wide variety of cellular processes, such as gene expression, signaling, and cell growth; however, the mechanism underlying the regulation of B cell development and function by O-GlcNAcylation remains largely unknown. Here, we demonstrate that changes in cellular O-GlcNAc levels significantly affected the growth of pre-B cells, which rapidly proliferate to allow expansion of functional clones that express successfully rearranged heavy chains at the pro-B stage during early B cell development. In our study, the overall O-GlcNAc levels in these proliferative pre-B cells, which are linked to the glucose uptake rate, were highly induced when compared with those in pro-B cells. Thus, pharmacologically, genetically, or nutritionally, inhibition of O-GlcNAcylation in pre-B cells markedly downregulated c-Myc expression, resulting in cell cycle arrest via blockade of cyclin expression. Importantly, the population of B cells after the pro-B cell stage in mouse bone marrow was severely impaired by the administration of an O-GlcNAc inhibitor. These results strongly suggest that O-GlcNAcylation-dependent expression of c-Myc represents a new regulatory component of pre-B cell proliferation, as well as a potential therapeutic target for the treatment of pre-B cell-derived leukemia.

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Natural history of MZ B cells

Journal of Experimental Medicine ◽

10.1084/jem.20202700 ◽

2021 ◽

Vol 218 (4) ◽

Author(s):

David Nemazee

Keyword(s):

B Cells ◽

Natural History ◽

B Cell ◽

Lymphoid Tissue ◽

Marginal Zone ◽

Cell Development ◽

B Cell Development ◽

Memory Cells ◽

History Of

In this issue, Tull et al. (https://doi.org/10.1084/jem.20202001) and Kibler et al. (https://doi.org/10.1084/jem.20201952) track human marginal zone B cell development from early progenitors to the memory compartment, addressing changes in age and autoimmunity, the sequence of development in the gut-associated lymphoid tissue, and clonal sharing among memory cells.

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Differentiated B lymphocytes. Potential to express particular antibody variable and constant regions depends on site of lymphoid tissue and antigen load.

Journal of Experimental Medicine ◽

10.1084/jem.149.1.216 ◽

1979 ◽

Vol 149 (1) ◽

pp. 216-227 ◽

Cited By ~ 73

Author(s):

P J Gearhart ◽

J J Cebra

Keyword(s):

B Cells ◽

B Cell ◽

Lymphoid Tissue ◽

Variable Region ◽

Peyer's Patches ◽

Peyer’S Patches ◽

Peyer’S Patch ◽

Peyer's Patch ◽

Cell Potential ◽

Variable Regions

B cells have the potential to respond to an antigen by producing antibodies with a variety of variable and constant regions. We have quantitatively analyzed B-cell potential at the single cell level to determine the effect of lymphoid tissue site and antigen load on the expression of variable and constant regions. Concerning variable region expression, although the total frequency of B-cell precursors for phosphorylcholine is similar between nonimmune spleen and gut-associated Peyer's patch tissues, the proportion of cells producing non-TEPC 15 idiotypes is greater from Peyer's patch than from spleen. Oral immunization with phosphorylcholine-containing Ascaris suum increased the frequency of non-TEPC 15 B cells. Thus variation in the proportion of cells bearing different variable regions may be related to the distinct antigenic environment of cells in Peyer's patches compared to that of cells in spleen. Regarding constant region expression, although B cells from both spleen and Peyer's patches generate clones producing IgM, IgGl, and IgA singly and in all combinations, cells from Peyer's patches generate more clones secreting only IgA than cells from spleen. B cells specific for phosphorylcholine and inulin, which are found on intestinal bacteria, produce more IgA-only clones than B cells specific for the dinitrophenyl determinant. This striking correlation between IgA expression and variable region specificity for antigen implies that environmental antigens have expanded certain B cells in Peyer's patches which then have the ability to generate progeny that express only IgA. Evidence supporting the secondary nature of precursors for IgA-only clones is obtained by their ability to produce this isotype after stimulation with histoincompatible T cells. The role of gut antigens may be to clonally expand IgA precursors and perhaps to stimulate the proliferation of less differentiated cells within the unique microenvironment of the Peyer's patches, allowing them to differentiate to IgA precursors.

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