scholarly journals The Functions and Mechanism of a New Oligopeptide BP9 from Avian Bursa on Antibody Responses, Immature B Cell, and Autophagy

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Xiu Li Feng ◽  
Man Man Zong ◽  
Guang Fang Zhou ◽  
Yang Zheng ◽  
Yuan Nan Yu ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bursa Of Fabricius ◽  
B Cell Differentiation ◽  
Active Peptide ◽  
Humoral Immune ◽  
Wehi 231 ◽  
Immature B Cells

The bursa of Fabricius is an acknowledged central humoral immune organ unique to birds, which is vital to B cell differentiation and antibody production. However, the function and mechanism of the biological active peptide isolated from bursa on B cell development and autophagy were less reported. In this study, we isolated a new oligopeptide with nine amino acids Leu-Met-Thr-Phe-Arg-Asn-Glu-Gly-Thr from avian bursa following RP-HPLC, MODIL-TOP-MS, and MS/MS, which was named after BP9. The results of immunization experiments showed that mice injected with 0.01 and 0.05 mg/mL BP9 plus JEV vaccine generated the significant increased antibody levels, compared to those injected with JEV vaccine only. The microarray analysis on the molecular basis of BP9-treated immature B cell showed that vast genes were involved in various immune-related biological processes in BP9-treated WEHI-231 cells, among which the regulation of cytokine production and T cell activation were both major immune-related processes in WEHI-231 cells with BP9 treatment following network analysis. Also, the differentially regulated genes were found to be involved in four significantly enriched pathways in BP9-treated WEHI-231 cells. Finally, we proved that BP9 induced the autophagy formation, regulated the gene and protein expressions related to autophagy in immature B cell, and stimulated AMPK-ULK1 phosphorylation expression. These results suggested that BP9 might be a strong bursal-derived active peptide on antibody response, B cell differentiation, and autophagy in immature B cells, which provided the linking among humoral immunity, B cell differentiation, and autophagy and offered the important reference for the effective immunotherapeutic strategies and immune improvement.

scholarly journals The immunomodulatory functions and molecular mechanism of a new bursal heptapeptide (BP7) in immune responses and immature B cells

2019 ◽  
Vol 50 (1) ◽  
Author(s):  
Xiu Li Feng ◽  
Yang Zheng ◽  
Man Man Zong ◽  
Shan Shan Hao ◽  
Guang Fang Zhou ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Bursa Of Fabricius ◽  
Biological Factor ◽  
Mrna Levels ◽  
B Cell Differentiation ◽  
Immune Functions ◽  
Wehi 231

Abstract The bursa of Fabricius (BF) is the acknowledged central humoural immune organ unique to birds and plays a vital role in B lymphocyte development. In addition, the unique molecular immune features of bursal-derived biological peptides involved in B cell development are rarely reported. In this paper, a novel bursal heptapeptide (BP7) with the sequence GGCDGAA was isolated from the BF and was shown to enhance the monoclonal antibody production of a hybridoma. A mouse immunization experiment showed that mice immunized with an AIV antigen and BP7 produced strong antibody responses and cell-mediated immune responses. Additionally, BP7 stimulated increased mRNA levels of sIgM in immature mouse WEHI-231 B cells. Gene microarray results confirmed that BP7 regulated 2465 differentially expressed genes in BP7-treated WEHI-231 cells and induced 13 signalling pathways and various immune-related functional processes. Furthermore, we found that BP7 stimulated WEHI-231 cell autophagy and AMPK-ULK1 phosphorylation and regulated Bcl-2 protein expression. Finally, chicken immunization showed that BP7 enhanced the potential antibody and cytokine responses to the AIV antigen. These results suggested that BP7 might be an active biological factor that functions as a potential immunopotentiator, which provided some novel insights into the molecular mechanisms of the effects of bursal peptides on immune functions and B cell differentiation.

scholarly journals An IRF4-MYC-mTORC1 integrated pathway controls cell growth and the proliferative capacity of activated B cells during B cell differentiation in vivo

2021 ◽  
Author(s):  
Dillon G Patterson ◽  
Anna K Kania ◽  
Madeline J Price ◽  
James R Rose ◽  
Christopher D Scharer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
B Cells ◽  
Cell Growth ◽  
B Cell ◽  
Proliferative Response ◽  
Cell Activation ◽  
B Cell Differentiation ◽  
B Cell Activation

Cell division is an essential component of B cell differentiation to antibody-secreting plasma cells, with critical reprogramming occurring during the initial stages of B cell activation. However, a complete understanding of the factors that coordinate early reprogramming events in vivo remain to be determined. In this study, we examined the initial reprogramming by IRF4 in activated B cells using an adoptive transfer system and mice with a B cell-specific deletion of IRF4. IRF4-deficient B cells responding to influenza, NP-Ficoll and LPS divided, but stalled during the proliferative response. Gene expression profiling of IRF4-deficient B cells at discrete divisions revealed IRF4 was critical for inducing MYC target genes, oxidative phosphorylation, and glycolysis. Moreover, IRF4-deficient B cells maintained an inflammatory gene expression signature. Complementary chromatin accessibility analyses established a hierarchy of IRF4 activity and identified networks of dysregulated transcription factor families in IRF4-deficient B cells, including E-box binding bHLH family members. Indeed, B cells lacking IRF4 failed to fully induce Myc after stimulation and displayed aberrant cell cycle distribution. Furthermore, IRF4-deficient B cells showed reduced mTORC1 activity and failed to initiate the B cell-activation unfolded protein response and grow in cell size. Myc overexpression in IRF4-deficient was sufficient to overcome the cell growth defect. Together, these data reveal an IRF4-MYC-mTORC1 relationship critical for controlling cell growth and the proliferative response during B cell differentiation.

scholarly journals Mad3 Negatively Regulates B Cell Differentiation in the Spleen by Inducing Id2 Expression

2010 ◽  
Vol 21 (11) ◽  
pp. 1864-1871 ◽  
Author(s):  
Yael Gore ◽  
Frida Lantner ◽  
Gili Hart ◽  
Idit Shachar
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Negative Regulator ◽  
Maturation Process ◽  
B Cell Differentiation ◽  
Final Maturation ◽  
Immature B Cells

Immature B cells migrate to the spleen where they differentiate into mature cells. This final maturation step is crucial to enable B cells to become responsive to antigens and to participate in the immune response. Previously, we showed that Id2 acts as a negative regulator of the differentiation of immature B cells occurring in the spleen. Id2 expression has been found to depend on Myc–Max–Mad transcriptional complexes in mammary epithelial cells. Nearly all studies to date have shown that Mad proteins inhibit proliferation, presumably by antagonizing the function of Myc proteins. In the current study, we followed the Mad family members during peripheral B cell differentiation. We show that Mad3 actively regulates B cell differentiation. Our results demonstrate that high expression levels of Mad3 in immature B cells induce Id2 expression, which inhibits transcription of genes essential for B cell differentiation. During their differentiation to mature cells, B cells reduce their Mad3 expression, enabling the maturation process to occur.

Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation

Gut ◽  
2017 ◽  
Vol 67 (9) ◽  
pp. 1663-1673 ◽  
Author(s):  
Gitta M Seleznik ◽  
Theresia Reding ◽  
Lukas Peter ◽  
Anurag Gupta ◽  
Sabrina G Steiner ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Autoimmune Pancreatitis ◽  
Cell Activation ◽  
Kinase Inhibitors ◽  
Acinar Cells ◽  
Pancreatic Injury ◽  
Humoral Immune ◽  
Inflammatory Processes

ObjectiveChronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21—a member of cyclin-dependent kinase inhibitors—can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development. We therefore examined the role of p21-mediated inflammation in AIP.DesignWe intercrossed lymphotoxin (LT) overexpressing mice (Tg(Ela1-LTa,b))—a model to study AIP development—with p21-deficient mice. Furthermore, we characterised p21 expression in human AIP and non-AIP specimens.Resultsp21 deficiency in LT mice (LTp21−/−) prevented early pancreatic injury and reduced inflammation. In acinar cells, diminished proliferation and abrogated activation of non-canonical nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway was observed. In contrast, 12-month-old LT mice with and without p21 had similar inflammatory signatures and T–B cell infiltration. Interestingly, LT and LTp21−/− mice had comparable tertiary lymphoid organs (TLOs), autoantibodies and elevated IgG levels. However, acinar cell proliferation, acinar-to-ductal metaplasia and acinar non-canonical NF-κB pathway activation remained impaired in LTp21−/− pancreata.ConclusionsOur findings indicate that p21 is crucial for pancreatic inflammation in LT-driven pancreatic injury. p21 is involved in early acinar secretion of inflammatory mediators that attract innate immune cells. However, p21 is not essential for humoral immune response, accountable for autoimmunity. Remarkably, p21 renders acinar cells less susceptible to proliferation and transdifferentiation. We therefore suggest that AIP can also develop independent of chronic inflammatory processes.

scholarly journals Differentiation, functions, and roles of T follicular regulatory cells in autoimmune diseases

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
He Hao ◽  
Shingo Nakayamada ◽  
Yoshiya Tanaka
Keyword(s):  
Cell Differentiation ◽  
Autoimmune Diseases ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Regulatory Cells ◽  
Autoantibody Production ◽  
Follicular Helper ◽  
Autoantibody Response

AbstractT follicular helper cells participate in stimulating germinal center (GC) formation and supporting B cell differentiation and autoantibody production. However, T follicular regulatory (Tfr) cells suppress B cell activation. Since changes in the number and functions of Tfr cells lead to dysregulated GC reaction and autoantibody response, targeting Tfr cells may benefit the treatment of autoimmune diseases. Differentiation of Tfr cells is a multistage and multifactorial process with various positive and negative regulators. Therefore, understanding the signals regulating Tfr cell generation is crucial for the development of targeted therapies. In this review, we discuss recent studies that have elucidated the roles of Tfr cells in autoimmune diseases and investigated the modulators of Tfr cell differentiation. Additionally, potential immunotherapies targeting Tfr cells are highlighted.

The Balance between Myc and Bcl6 Determines Self-Renewal or Differentiation of Pre-B Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 797-797 ◽  
Author(s):  
Cihangir Duy ◽  
Ignacio Moreno de Alboran ◽  
Hassan Jumaa ◽  
Markus Muschen
Keyword(s):  
Cell Differentiation ◽  
Acute Lymphoblastic Leukemia ◽  
B Cells ◽  
B Cell ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
B Cell Development ◽  
B Cell Differentiation ◽  
Self Renewal ◽  
Immature B Cells

Abstract Myc and Bcl6 represent classical proto-oncogenes in B-cell malignancies, mainly through translocation into the immunoglobulin (Ig) heavy chain locus in Burkitt’s (MYC) and diffuse large B cell lymphoma (BCL6). While BCL6 was previously established as a factor regulating differentiation of germinal center B cells, the function of MYC and BCL6 in early B-cell development was not previously studied. Investigating requirements for the differentiation of pre-B cells into immature B-cells, we found that both withdrawal of IL7 from murine pre-B-cell cultures and inhibition of BCR-ABL1 in BCR-ABL1-transformed pre-B-cells terminates self-renewal and initiates differentiation into Ig light chain-expressing immature B-cells. Interestingly, IL7 and BCR-ABL1 are exchangeable at this checkpoint: Both IL7 and BCR-ABL1 promote self-renewal and prevent differentiation of pre-B-cells. While inhibition of BCR-ABL1 usually induces apoptosis and partial differentiation, both effects were entirely suppressed by IL7. These findings indicate that IL7 may confer resistance to BCR-ABL1 inhibitors in patients with BCR-ABL1-transformed acute lymphoblastic leukemia. Likewise, inhibition of either IL7 or BCR-ABL1 signaling resulted in complete silencing of Myc expression and strong de novo expression of Bcl6. Because expression of Myc and Bcl6 are mutually exclusive at the pre-B to immature B-cell checkpoint, we tested whether the two proto-oncogenes have distinct functions at this transition. Interestingly, forced expression of Myc rendered BCR-ABL1-transformed pre-B-cells resistant to induction of differentiation upon inhibition of BCR-ABL1. Besides downregulation of Myc, also de novo expression of Bcl6 is critical for the pre-B to immature B-cell differentiation: shmiR-mediated silencing of Bcl6 suppressed B-cell differentiation even if Myc was downregulated. However, forced expression of Bcl6 alone only modestly induced differentiation of pre-B cells if Myc was not downregulated. To test the interplay between Myc and Bcl6 at the pre-B to immature B cell transition more systematically, we analyzed bone marrow pre-B cells from Mycfl/fl mice. Mycfl/fl pre-B cells that also carry MxCre deleted the Myc locus on both alleles upon stimulation with IFNß. As controls, Mycfl/fl pre-B cells without MxCre were used. Pre-B cells were also transduced with a retroviral vector encoding Bcl6/GFP or GFP alone. Upon Myc deletion, more than 80 precent of the Bcl6/GFP transduced pre-B cells underwent differention as compared to 25 percent GFP-transduced pre-B cells. In the absence of Myc deletion, about 15 percent of Bcl6/GFP-transduced pre-B cells initiated differentiation as compared to 5 percent of GFP-transduced pre-B cells. These findings establish that Myc and Bcl6 have critical and antagonistic functions in early B cell development and that both downregulation of Myc together with upregulation Bcl6 are required to initiate differentiation of pre-B cells. The MYC/BCL6 balance may also be a target of leukemic transformation of human pre-B cells: The ratio of MYC/BCL6 mRNA levels in normal human pro- and pre-B cells at 0.52 is dramatically increased in various subtypes of acute lymphoblastic leukemia (6.4 for BCR-ABL1-, 2.6 for E2A-PBX1-, 14.4 for MLL-AF4- and 3.3 for TEL-AML1-transformed acute lymphoblastic leukemia).

STAT3 phosphorylation mediates the stimulatory effects of interferon alpha on B cell differentiation and activation in SLE

Rheumatology ◽  
2019 ◽  
Author(s):  
Aurélie De Groof ◽  
Julie Ducreux ◽  
Floor Aleva ◽  
Andrew J Long ◽  
Alina Ferster ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Type I ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Loss Of Function ◽  
Stat3 Phosphorylation

Abstract Objective Type I IFNs play a well-known role in the pathogenesis of SLE, through activation of CD4 T and antigen-presenting cells. Here, we investigated the effects of IFN alpha (IFNα) on SLE B cell activation and differentiation. Methods Peripheral blood mononuclear cells (PBMCs) and purified total or naïve B cells were obtained from healthy controls and SLE patients. The effects of IFNα on B cell differentiation were studied by flow cytometry. The role of STAT3 in B cell responses to IFNα was studied using pharmacological inhibitors and PBMCs from STAT3-deficient individuals. Results Incubation of normal PBMCs with IFNα induces a B cell differentiation pattern as observed spontaneously in SLE PBMCs. IFNα displays direct stimulatory effects on purified naïve B cells from healthy individuals, as evidenced by a significant induction of cell surface CD38 and CD95 in the presence of the cytokine. In purified naïve B cells, IFNα also induces STAT3 phosphorylation. IFNα-induced naïve B cell differentiation in total PBMCs is significantly inhibited in the presence of STAT3 inhibitors, or in PBMCs from individuals with STAT3 loss of function mutations. Spontaneous levels of STAT3, but not STAT1, phosphorylation are significantly higher in total B cells from SLE patients compared with controls. Pharmacological STAT3 inhibition in SLE PBMCs inhibits naïve B cell activation and differentiation. Conclusion IFNα displays direct stimulatory effects on B cell differentiation and activation in SLE. STAT3 phosphorylation mediates the effects of IFNα stimulation in naïve B cells, an observation that opens new therapeutic perspectives in SLE.

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