BOB.1/OBF.1 is required during B cell ontogeny for B cell differentiation and germinal center function

Abstract The circulating lymphocytes of 88 consecutive patients following autologous, conventional, or T-cell depleted bone marrow transplantation were serially analyzed for B-cell surface antigen expression and function. In the majority of patients, except for those who developed chronic graft-versus-host disease, the number of circulating CD20+ B cell normalized by the fourth posttransplant month. The earliest detectable B cells normally expressed HLA-DR, CD19, surface immunoglobulin (slg), CD21, Leu-8, and lacked expression of CD10 (CALLA). In addition, the circulating B cells expressed CD1c, CD38, CD5, and CD23 for the first year following transplant, antigens that are normally expressed on a small percentage of circulating B cells in normal adults, but highly expressed on cord blood B cells. Similar to cord blood B cells, patient B cells isolated during the first year following transplant, proliferated normally to Staphylococcus aureus Cowan strain I (SAC), and produced IgM, but minimal or no IgG when stimulated with pokeweed mitogen and SAC, unlike normal adult B cells that produce both. The similar phenotype and function of posttransplant and cord blood B cells, and their similar rate of decline in patients and normal children adds further evidence to support the hypothesis that B-cell differentiation posttransplant is recapitulating normal B-cell ontogeny.

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Cooperative transcriptional repression by BCL6 and BACH2 in germinal center B-cell differentiation

Blood ◽

10.1182/blood-2013-07-518605 ◽

2014 ◽

Vol 123 (7) ◽

pp. 1012-1020 ◽

Cited By ~ 50

Author(s):

Chuanxin Huang ◽

Huimin Geng ◽

Isaac Boss ◽

Ling Wang ◽

Ari Melnick

Keyword(s):

Cell Differentiation ◽

B Cell ◽

Germinal Center ◽

Transcriptional Repression ◽

B Cell Development ◽

B Cell Differentiation ◽

Cooperative Action ◽

Germinal Center B Cell ◽

Key Points ◽

Biochemical Mechanisms

Key Points BCL6 and BACH2 cooperatively regulate GC B-cell development. The cooperative action of BCL6 and BACH2 is through both transcriptional and biochemical mechanisms.

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Tissue inhibitor of metalloproteinases 1 regulation of interleukin-10 in B-cell differentiation and lymphomagenesis

Blood ◽

10.1182/blood.v97.6.1796 ◽

2001 ◽

Vol 97 (6) ◽

pp. 1796-1802 ◽

Cited By ~ 33

Author(s):

Liliana Guedez ◽

Adnan Mansoor ◽

Bente Birkedal-Hansen ◽

Megan S. Lim ◽

Paula Fukushima ◽

...

Keyword(s):

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

Interleukin 10 ◽

Tissue Inhibitors Of Metalloproteinases ◽

B Cell Differentiation ◽

Non Hodgkin Lymphoma ◽

Negative Prognostic Factor ◽

Germinal Center B Cells

Tissue inhibitors of metalloproteinases (TIMPs), first described as specific inhibitors of matrix metalloproteinases, have recently been shown to exert growth factor activities. It was previously demonstrated that TIMP-1 inhibits apoptosis in germinal center B cells and induces further differentiation. Interleukin-10 (IL-10) is reported as a vital factor for the differentiation and survival of germinal center B cells and is also a negative prognostic factor in non-Hodgkin lymphoma (NHL). However, the mechanism of IL-10 activity in B cells and the regulation of its expression are not well understood. IL-10 has been shown to up-regulate TIMP-1 in tissue macrophages, monocytes, and prostate cancer cell lines, but IL-10 modulation of TIMP-1 in B cells and the effect of TIMP-1 on IL-10 expression has not been previously studied. It was found that TIMP-1 expression regulates IL-10 levels in B cells and that TIMP-1 mediates specific B-cell differentiation steps. TIMP-1 inhibition of apoptosis is not IL-10 dependent. TIMP-1 expression in B-cell NHL correlates closely with IL-10 expression and with high histologic grade. Thus, TIMP-1 regulates IL-10 expression in B-cell NHL and, through the inhibition of apoptosis, appears responsible for the negative prognosis associated with IL-10 expression in these tumors.

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Microenvironment-Mediated Regulation of Micrornas In B-Lymphocytes as a Novel Mechanism for Terminal B-Cell Differentiation and Lymphomagenesis.

Blood ◽

10.1182/blood.v116.21.3853.3853 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3853-3853

Author(s):

Jianhong Lin ◽

Tint Lwin ◽

Wayne Tam ◽

Jian-Jun Zhao ◽

Luis Crespo ◽

...

Keyword(s):

Cell Differentiation ◽

B Cell ◽

B Lymphocytes ◽

Germinal Center ◽

Binding Sites ◽

Culture System ◽

B Cell Lymphoma ◽

Cell Contact ◽

B Cell Differentiation ◽

Stroma Cell

Abstract Abstract 3853 B-cell differentiation is tightly regulated by synchronized suppression and/or induction of specific transcription factors. Among them, B-cell lymphoma 6 (BCL6) and PRDM1 are considered to be master regulators for germinal center formation and terminal B-cell differentiation. Dysregulation of BCL6 and PRDM1 also have been associated with lymphomagenesis. Their regulation still need further study especially at the posttranscriptional level. Here, by using co-culture system and whole genomic microRNA microarray profiling, we show for the first time that direct B lymphoma cell-stroma cell contact between follicular dendritic cells and B-lymphocytes could induce upregulation of miR-30 family and downregulation of miR-9 and let-7 family. In silico analysis showed that miR-30s can target genes BCL6 and miR-9/let7 can target PRDM1 with direct binding sites in 3`UTR region of their mRNAs. The microarray data can be proved by microRNA specific Q-RT-PCR. Specifically, by both gain of function and loss of function studies, we functionally verified that FDCs Regulate Expression of BCL6 and PRDM1 via Cell-Cell Direct Contact induced correlated microRNA dysregulation. To further validate the direct interaction between BCL6 and miR-30, we constructed luciferase reporters containing the BCL6 3`-UTR that included miR-30 binding sites and a mutant 3`-UTR harboring mutations in the “seed pairing” sequences of the miR-30 binding site. Co-transfection of miR-30 and reporter construct into cells significantly decreased luciferase activity in wild-type but not in mutant BCL6-3`-UTR transfected cells, supporting the role of miR-30 family in the regulation of BCL6 expression. BCL6 and PRDM1 and their regulation miRNAs, let-7 and miR-30, also can be validated in primary normal B-lymphocytes and lymphoma cells by using our co-culture system. Dysregulation of BCL6 and PRDM1 is often associated with lymphomagenesis. We firstly identified that BCL6 is the direct target of miR-30 family and also verified PRDM1 is the target of miR-9, and let-7 in our system. Our studies provide a novel mechanism of post-transcriptional regulation of BCL6 and PRDM1 by several microRNAs. In the context of micro-environment, it provides a clue for germinal center B-cell differentiation as well as B-cell lymphomas progression regulated by lymphocyte cell-stroma cell contact through microRNAs. Disclosures: No relevant conflicts of interest to declare.

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Regulation of germinal center B-cell differentiation

Immunological Reviews ◽

10.1111/imr.12396 ◽

2016 ◽

Vol 270 (1) ◽

pp. 8-19 ◽

Cited By ~ 73

Author(s):

Yang Zhang ◽

Laura Garcia-Ibanez ◽

Kai-Michael Toellner

Keyword(s):

Cell Differentiation ◽

B Cell ◽

Germinal Center ◽

B Cell Differentiation ◽

Germinal Center B Cell

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Extracellular matrix protein 1 promotes follicular helper T cell differentiation and antibody production

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1801196115 ◽

2018 ◽

Vol 115 (34) ◽

pp. 8621-8626 ◽

Cited By ~ 13

Author(s):

Lan He ◽

Wangpeng Gu ◽

Meng Wang ◽

Xiaoyan Chang ◽

Xiaoyu Sun ◽

...

Keyword(s):

Extracellular Matrix ◽

Cell Differentiation ◽

B Cell ◽

Antibody Production ◽

Germinal Center ◽

Matrix Protein ◽

Extracellular Matrix Protein ◽

B Cell Differentiation ◽

Follicular Helper ◽

Extracellular Matrix Protein 1

T-follicular helper (TFH) cells are a subset of CD4+ helper T cells that help germinal center (GC) B-cell differentiation and high-affinity antibody production during germinal center reactions. Whether important extracellular molecules control TFH differentiation is not fully understood. Here, we demonstrate that a secreted protein extracellular matrix protein 1 (ECM1) is critical for TFH differentiation and antibody response. A lack of ECM1 inhibited TFH cell development and impaired GC B-cell reactions and antigen-specific antibody production in an antigen-immunized mouse model. ECM1 was induced by IL-6 and IL-21 in TFH cells, promoting TFH differentiation by down-regulating the level of STAT5 phosphorylation and up-regulating Bcl6 expression. Furthermore, injection of recombinant ECM1 protein into mice infected with PR8 influenza virus promoted protective immune responses effectively, by enhancing TFH differentiation and neutralizing antibody production. Collectively, our data identify ECM1 as a soluble protein to promote TFH cell differentiation and antibody production.

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