Interleukins and IgA synthesis. Human and murine interleukin 6 induce high rate IgA secretion in IgA-committed B cells.

Freshly isolated murine PP B cells were cultured with 10 different cytokines, including IL-1 alpha, IL-2, IL-4, IL-5, IL-6, IL-7, IFN-gamma, TNF-alpha, and TGF-beta, to investigate a possible role for these cytokines in induction of Ig synthesis. Of interest was the finding that only IL-5 and both mouse recombinant (mr) and human recombinant (hr) IL-6 enhanced IgA synthesis. The effect was greater with either mrIL-6 or hrIL-6 than with mrIL-5. IL-6 induced cycling mIgA+ PP B cells to secrete high levels of IgA (approximately 7-fold increase over control). Of importance was the finding that mrIL-6 had little effect on secretion of IgM or IgG by PP B cell cultures. hrIL-6 also increased IgA secretion by PP B cells and this enhancement was abolished by a goat anti-hrIL-6 antiserum. mrIL-6 did not cause B cell proliferation but induced a sharp increase in numbers of B cells secreting IgA. Isotype-switching was not a mechanism for this marked increase in IgA synthesis since mIgA- PP B cells were not induced to secrete IgA by mrIL-6. From these studies we conclude that IL-6 plays an important role in promoting the terminal differentiation of PP B cells to IgA-secreting plasma cells.

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The RNase III enzyme Dicer is essential for germinal center B-cell formation

Blood ◽

10.1182/blood-2011-05-355412 ◽

2012 ◽

Vol 119 (3) ◽

pp. 767-776 ◽

Cited By ~ 64

Author(s):

Shengli Xu ◽

Ke Guo ◽

Qi Zeng ◽

Jianxin Huo ◽

Kong-Peng Lam

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Plasma Cells ◽

Cytidine Deaminase ◽

Cell Formation ◽

Terminal Differentiation ◽

Mature Mirnas ◽

Rnase Iii ◽

Proapoptotic Protein

Abstract MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression and are important for pre-B and follicular B lymphopoiesis as demonstrated, respectively, by mb-1-Cre– and cd19-Cre–mediated deletion of Dicer, the RNase III enzyme critical for generating mature miRNAs. To explore the role of miRNAs in B-cell terminal differentiation, we use Aicda-Cre to specifically delete Dicer in activated B cells where activation-induced cytidine deaminase is highly expressed. We demonstrate that mutant mice fail to produce high-affinity class-switched antibodies and generate memory B and long-lived plasma cells on immunization with a T cell–dependent antigen. More importantly, germinal center (GC) B-cell formation is drastically compromised in the absence of Dicer, as a result of defects in cell proliferation and survival. Dicer-deficient GC B cells express higher levels of cell cycle inhibitor genes and proapoptotic protein Bim. Ablation of Bim could partially rescue the defect in GC B-cell formation in Dicer-deficient mice. Taken together, our data suggest that Dicer and probably miRNAs are critical for GC B-cell formation during B-cell terminal differentiation.

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The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation

Journal of Experimental Medicine ◽

10.1084/jem.20140425 ◽

2014 ◽

Vol 211 (11) ◽

pp. 2169-2181 ◽

Cited By ~ 77

Author(s):

Sebastian Carotta ◽

Simon N. Willis ◽

Jhagvaral Hasbold ◽

Michael Inouye ◽

Swee Heng Milon Pang ◽

...

Keyword(s):

Transcription Factors ◽

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Plasma Cell ◽

Plasma Cells ◽

Terminal Differentiation ◽

Plasma Cell Differentiation ◽

Class Switch ◽

Complex Functions

Activated B cells undergo immunoglobulin class-switch recombination (CSR) and differentiate into antibody-secreting plasma cells. The distinct transcriptomes of B cells and plasma cells are maintained by the antagonistic influences of two groups of transcription factors: those that maintain the B cell program, including BCL6 and PAX5, and plasma cell–promoting factors, such as IRF4 and BLIMP-1. We show that the complex of IRF8 and PU.1 controls the propensity of B cells to undergo CSR and plasma cell differentiation by concurrently promoting the expression of BCL6 and PAX5 and repressing AID and BLIMP-1. As the PU.1–IRF8 complex functions in a reciprocal manner to IRF4, we propose that concentration-dependent competition between these factors controls B cell terminal differentiation.

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Suppression of Signal Transducer and Activator of Transcription 3–Dependent B Lymphocyte Terminal Differentiation by Bcl-6

Journal of Experimental Medicine ◽

10.1084/jem.192.12.1841 ◽

2000 ◽

Vol 192 (12) ◽

pp. 1841-1848 ◽

Cited By ~ 173

Author(s):

Rajko Reljic ◽

Simon D. Wagner ◽

Luke J. Peakman ◽

Douglas T. Fearon

Keyword(s):

B Cells ◽

B Cell ◽

B Lymphocyte ◽

Plasma Cells ◽

Somatic Hypermutation ◽

Terminal Differentiation ◽

Cell Development ◽

Signal Transducer ◽

Effector Cells ◽

Transcription 3

Lymphocytes usually differentiate into effector cells within days after antigen exposure, except in germinal centers where terminal differentiation is delayed while somatic hypermutation creates high-affinity antibody mutants. Here we investigate whether arrest of terminal differentiation can be mediated by BCL-6, a transcriptional repressor that is expressed by germinal center B cells and is required for this phase of B cell development. We find that BCL-6 suppresses the differentiation of transformed and primary B cells to plasma cells by inhibiting the signal transducer and activator of transcription 3–dependent expression of the major regulator of plasma cell development, the B lymphocyte–induced maturation protein (Blimp-1). This function of BCL-6 as a repressor of B lymphocyte differentiation may also underlie the association between chromosomal translocations of its gene and B cell lymphomas.

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Human pre-B cells differentiate into Ig-secreting plasma cells in the presence of interleukin-4 and activated CD4+ T cells or their membranes

Blood ◽

10.1182/blood.v82.9.2781.2781 ◽

1993 ◽

Vol 82 (9) ◽

pp. 2781-2789 ◽

Cited By ~ 29

Author(s):

J Punnonen ◽

G Aversa ◽

JE de Vries

Keyword(s):

T Cells ◽

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Cell Cultures ◽

Cd4 T Cells ◽

Plasma Cells ◽

Interleukin 4 ◽

B Cell Differentiation ◽

Ig Synthesis

Abstract Studies on human B-cell development have been hampered by the lack of reproducible culture techniques to induce pre-B cells to differentiate into Ig-secreting plasma cells. Here, we describe that highly purified surface (s) mu-, cytoplasmic (c) mu+, CD10+, CD19+ human pre-B cells derived from fetal bone marrow (BM) differentiate with high frequencies into Ig-secreting plasma cells, when cocultured with activated, cloned CD4+ T cells and with interleukin-4 (IL-4). Production of IgM, total IgG, IgG4, and IgE in pre-B-cell cultures was detected, indicating that the cells also underwent Ig isotype switching. Pre-B-cell differentiation occurred in the absence of BM stromal cells, IL-7, and stem cell factor (SCF). However, IL-7 significantly enhanced the levels of Ig produced, whereas SCF was ineffective. Neutralizing anti-IL-4 monoclonal antibodies (MoAbs) completely inhibited pre-B-cell differentiation showing the specificity of the reaction. Intact CD4+ T- cell clones could be replaced by membrane preparations of these cells, indicating that the costimulatory signals provided by the activated CD4+ T cells are contact-mediated. In contrast, anti-CD40 MoAbs failed to provide the costimulatory signal required for pre-B-cell differentiation, which may be related to the very low expression of CD40 on fetal BM B cells. Activated CD4+ T cells and IL-4 also induced s mu expression and Ig synthesis in cultures initiated with pre-B cells that had been preincubated in medium for 2 days, and from which spontaneously emerging s mu+ B cells were removed by using a fluorescence-activated cell sorter. These results support the notion that the Ig synthesis observed in pre-B-cell cultures was not caused by outgrowth and differentiation of cells that spontaneously matured into s mu+ B cells. In addition, IL-4 and CD4+ T cells strongly enhanced CD40 and HLA-DR expression on the majority of cultured pre-B cells, further indicating that CD4+ T cells and IL-4 activate bona fide pre-B cells. Taken together, these data indicate that activated CD4+ T cells and IL-4 can provide all the necessary signals required for human pre-B cells to differentiate into Ig-secreting plasma cells.

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Memory B Cells Are Biased Towards Terminal Differentiation: A Strategy That May Prevent Repertoire Freezing

Journal of Experimental Medicine ◽

10.1084/jem.186.6.931 ◽

1997 ◽

Vol 186 (6) ◽

pp. 931-940 ◽

Cited By ~ 117

Author(s):

Christophe Arpin ◽

Jacques Banchereau ◽

Yong-Jun Liu

Keyword(s):

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Plasma Cell ◽

Plasma Cells ◽

Cell Clone ◽

Terminal Differentiation ◽

Memory B Cells ◽

B Cell Differentiation

Isolation of large numbers of surface IgD+CD38− naive and surface IgD−CD38− memory B cells allowed us to study the intrinsic differences between these two populations. Upon in vitro culture with IL-2 and IL-10, human CD40–activated memory B cells undergo terminal differentiation into plasma cells more readily than do naive B cells, as they give rise to five- to eightfold more plasma cells and three- to fourfold more secreted immunoglobulins. By contrast, naive B cells give rise to a larger number of nondifferentiated B blasts. Saturating concentrations of CD40 ligand, which fully inhibit naive B cell differentiation, only partially affect that of memory B cells. The propensity of memory B cells to undergo terminal plasma cell differentiation may explain the extensive extra follicular plasma cell reaction and the limited germinal center reaction observed in vivo after secondary immunizations, which contrast with primary responses in carrier-primed animals. This unique feature of memory B cells may confer two important capacities to the immune system: (a) the rapid generation of a large number of effector cells to efficiently eliminate the pathogens; and (b) the prevention of the overexpansion and chronic accumulation of one particular memory B cell clone that would freeze the available peripheral repertoire.

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Neutral maltase: the first human B-cell enzymatic marker reflecting terminal differentiation of mature B cells into plasma cells

Blood ◽

10.1182/blood.v62.2.505.bloodjournal622505 ◽

1983 ◽

Vol 62 (2) ◽

pp. 505-508

Author(s):

PJ Philip ◽

J Giudicelli ◽

P Delque ◽

JP Cassuto ◽

P Sudaka ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Plasma Cells ◽

Cell Lineage ◽

Terminal Differentiation ◽

Normal Subjects ◽

Lymphoid Leukemia ◽

Maltase Activity ◽

Enzymatic Marker ◽

B Lymphoid

Neutral maltase activity (alpha-D-glucoside glucohydrolase; EC: 3.2.1.20) was measured in B and T lymphocytes from peripheral blood of normal subjects and patients suffering from chronic or acute lymphoid leukemias. Neutral maltase activity is undetectable in T cells from normal subjects as well as in patients with chronic or acute T-lymphoid leukemias. Conversely, whereas this enzyme activity is always undetectable in chronic or acute B-lymphoid leukemia, neutral maltase activity is expressed in mature B cells from normal subjects. The detection of higher neutral maltase activity in plasma cells from myelomas than in normal B cells supports the concept that the expression of neutral maltase activity is related to the stages of differentiation and maturation reached by lymphocytes of the B-cell lineage. Neutral maltase therefore appears as the first B-cell enzymatic marker described that is expressed in the course of terminal differentiation of mature B cells into plasma cells.

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Human pre-B cells differentiate into Ig-secreting plasma cells in the presence of interleukin-4 and activated CD4+ T cells or their membranes

Blood ◽

10.1182/blood.v82.9.2781.bloodjournal8292781 ◽

1993 ◽

Vol 82 (9) ◽

pp. 2781-2789

Author(s):

J Punnonen ◽

G Aversa ◽

JE de Vries

Keyword(s):

T Cells ◽

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Cell Cultures ◽

Cd4 T Cells ◽

Plasma Cells ◽

Interleukin 4 ◽

B Cell Differentiation ◽

Ig Synthesis

Studies on human B-cell development have been hampered by the lack of reproducible culture techniques to induce pre-B cells to differentiate into Ig-secreting plasma cells. Here, we describe that highly purified surface (s) mu-, cytoplasmic (c) mu+, CD10+, CD19+ human pre-B cells derived from fetal bone marrow (BM) differentiate with high frequencies into Ig-secreting plasma cells, when cocultured with activated, cloned CD4+ T cells and with interleukin-4 (IL-4). Production of IgM, total IgG, IgG4, and IgE in pre-B-cell cultures was detected, indicating that the cells also underwent Ig isotype switching. Pre-B-cell differentiation occurred in the absence of BM stromal cells, IL-7, and stem cell factor (SCF). However, IL-7 significantly enhanced the levels of Ig produced, whereas SCF was ineffective. Neutralizing anti-IL-4 monoclonal antibodies (MoAbs) completely inhibited pre-B-cell differentiation showing the specificity of the reaction. Intact CD4+ T- cell clones could be replaced by membrane preparations of these cells, indicating that the costimulatory signals provided by the activated CD4+ T cells are contact-mediated. In contrast, anti-CD40 MoAbs failed to provide the costimulatory signal required for pre-B-cell differentiation, which may be related to the very low expression of CD40 on fetal BM B cells. Activated CD4+ T cells and IL-4 also induced s mu expression and Ig synthesis in cultures initiated with pre-B cells that had been preincubated in medium for 2 days, and from which spontaneously emerging s mu+ B cells were removed by using a fluorescence-activated cell sorter. These results support the notion that the Ig synthesis observed in pre-B-cell cultures was not caused by outgrowth and differentiation of cells that spontaneously matured into s mu+ B cells. In addition, IL-4 and CD4+ T cells strongly enhanced CD40 and HLA-DR expression on the majority of cultured pre-B cells, further indicating that CD4+ T cells and IL-4 activate bona fide pre-B cells. Taken together, these data indicate that activated CD4+ T cells and IL-4 can provide all the necessary signals required for human pre-B cells to differentiate into Ig-secreting plasma cells.

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Spi-B inhibits human plasma cell differentiation by repressing BLIMP1 and XBP-1 expression

Blood ◽

10.1182/blood-2008-01-136440 ◽

2008 ◽

Vol 112 (5) ◽

pp. 1804-1812 ◽

Cited By ~ 42

Author(s):

Heike Schmidlin ◽

Sean A. Diehl ◽

Maho Nagasawa ◽

Ferenc A. Scheeren ◽

Remko Schotte ◽

...

Keyword(s):

Transcription Factors ◽

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Plasma Cell ◽

Target Genes ◽

Plasma Cells ◽

Terminal Differentiation ◽

Transactivation Domain ◽

Plasma Cell Differentiation

Abstract The terminal differentiation of B cells into antibody-secreting plasma cells is tightly regulated by a complex network of transcription factors. Here we evaluated the role of the Ets factor Spi-B during terminal differentiation of human B cells. All mature tonsil and peripheral blood B-cell subsets expressed Spi-B, with the exception of plasma cells. Overexpression of Spi-B in CD19+ B cells inhibited, similar to the known inhibitor BCL-6, the expression of plasma cell–associated surface markers and transcription factors as well as immunoglobulin production, ie, in vitro plasma cell differentiation. The arrest in B-cell differentiation enforced by Spi-B was independent of the transactivation domain, but dependent on the Ets-domain. By chromatin immunoprecipitation and assays using an inducible Spi-B construct BLIMP1 and XBP-1 were identified as direct target genes of Spi-B mediated repression. We propose a novel role for Spi-B in maintenance of germinal center and memory B cells by direct repression of major plasma cell factors and thereby plasma cell differentiation.

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Neutral maltase: the first human B-cell enzymatic marker reflecting terminal differentiation of mature B cells into plasma cells

Blood ◽

10.1182/blood.v62.2.505.505 ◽

1983 ◽

Vol 62 (2) ◽

pp. 505-508 ◽

Cited By ~ 1

Author(s):

PJ Philip ◽

J Giudicelli ◽

P Delque ◽

JP Cassuto ◽

P Sudaka ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Plasma Cells ◽

Cell Lineage ◽

Terminal Differentiation ◽

Normal Subjects ◽

Lymphoid Leukemia ◽

Maltase Activity ◽

Enzymatic Marker ◽

B Lymphoid

Abstract Neutral maltase activity (alpha-D-glucoside glucohydrolase; EC: 3.2.1.20) was measured in B and T lymphocytes from peripheral blood of normal subjects and patients suffering from chronic or acute lymphoid leukemias. Neutral maltase activity is undetectable in T cells from normal subjects as well as in patients with chronic or acute T-lymphoid leukemias. Conversely, whereas this enzyme activity is always undetectable in chronic or acute B-lymphoid leukemia, neutral maltase activity is expressed in mature B cells from normal subjects. The detection of higher neutral maltase activity in plasma cells from myelomas than in normal B cells supports the concept that the expression of neutral maltase activity is related to the stages of differentiation and maturation reached by lymphocytes of the B-cell lineage. Neutral maltase therefore appears as the first B-cell enzymatic marker described that is expressed in the course of terminal differentiation of mature B cells into plasma cells.

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Interleukin 4 induces selective production of interleukin 6 from normal human B lymphocytes.

Journal of Experimental Medicine ◽

10.1084/jem.170.4.1463 ◽

1989 ◽

Vol 170 (4) ◽

pp. 1463-1468 ◽

Cited By ~ 67

Author(s):

E B Smeland ◽

H K Blomhoff ◽

S Funderud ◽

M R Shalaby ◽

T Espevik

Keyword(s):

B Cells ◽

B Lymphocytes ◽

Interleukin 6 ◽

Specific Effect ◽

Interleukin 4 ◽

Tnf Alpha ◽

Ifn Gamma ◽

Normal Human ◽

Tnf Secretion

In this paper we have shown that extensively purified human B lymphocytes respond to IL-4 treatment with a marked production of IL-6. Addition of anti-mu potentiated the effect of IL-4 on IL-6 production. Other cytokines tested like TNF-alpha and-beta, IFN-gamma, IL-1, IL-2, and IL-5 did not induce IL-6 secretion when given to resting B cells. Although B cells generally also produced TNF-alpha and TNF-beta upon stimulation, IL-4 did not induce TNF secretion and seemingly had a specific effect on IL-6 production.

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