CD40 Stimulation Induces Pax5/BSAP and EBF Activation through a APE/Ref-1-dependent Redox Mechanism

Merluzzi, Sonia; Moretti, Massimo; Altamura, Sandro; Zwollo, Patty; Sigvardsson, Mikael; Vitale, Gaetano; Pucillo, Carlo

doi:10.1074/jbc.m305418200

Cited by 41 publications

(28 citation statements)

References 64 publications

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“…Pax5 controls the expression of many B lineagespecific genes, including cd19, cd79a and the B cell linker protein-encoding gene blnk, through binding to their promoters and/or other regulatory elements 140 . In human and mouse germinal centers, the pax5 transcription level is significantly upregulated in centroblasts 141 ( Figure 2), possibly as a result of activated CD40 and/or IL-4 receptor signal transduction pathways, as suggested by the efficient Pax5 induction in murine spleen B cells stimulated with an agonistic anti-CD40 mAb 142 . In mouse spleen B cells stimulated with LPS, pax5 mRNA level increases by day 2, coincident with the initiation of aicda expression, and then decreases by day 4, with concomitant decrease of aicda expression 38,141 .…”

Section: Pax5-pax5mentioning

confidence: 99%

Regulation of aicda Expression and AID Activity: Relevance to Somatic Hypermutation and Class Switch DNA Recombination

Pone

Al‐Qahtani

et al. 2007

Crit Rev Immunol

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Expression and activity of activation-induced cytidine deaminase (AID) encoded by the aicda gene are essential for immunoglobulin (Ig) gene somatic hypermutation (SHM) and class switch DNA recombination (CSR). SHM and CSR unfold in general in germinal centers and are central to the maturation of effective antibody responses. AID expression is induced by activated B cell CD40 signaling, which is critical for the germinal center reaction, and is further enhanced by other stimuli, including interleukin-4 (IL-4) secreted from CD4 + T cells or Toll-like receptor (TLR)-activating bacterial and/or viral molecules. Integration of different intracellular signal transduction pathways, as activated by these stimuli, leads to a dynamic aicda-regulating program, which involves both positively acting trans-factors, such as Pax5, HoxC4, E47 and Irf8, and negative modulators, such as Blimp1 and Id2, to restrict aicda expression primarily to germinal center B cells. The phosphatidylinositol 3-kinase (PI 3-K), which functions downstream of activated B cell receptor (BCR) signaling, likely plays an important role in triggering the downregulation of aicda expression in post-germinal center B cells and throughout plasmacytoid differentiation. In B cells undergoing SHM and CSR, AID activity and, possibly, AID targeting to the Ig locus are regulated at a post-translational level, including AID dimerization/oligomerization, nuclear/cytoplasmic AID translocation and phosphorylation of the AID Ser38 residue by protein kinase A (PKA). Here, we will discuss the role of B cell activation signals, transcription regulation programs and posttranslational modifications in controlling aicda expression and AID activity, thereby delineating an integrated model of modulation of SHM and CSR in the germinal center reaction.Keywords activation-induced cytidine deaminase (AID); B cell; class switch DNA recombination (CSR); enhanceosome; germinal center reaction; immunoglobulin (Ig); plasmacytoid differentiation; posttranslational modifications; signal transduction pathways; somatic hypermutation (SHM); transcription factors IntroductionThe ability of vertebrates to mount specific and effective responses to a broad range of pathogens and develop long-term memory is underpinned by the broad diversity and exquisite specificity of adaptive immunity. During B cell development in the bone marrow of mammals, rearrangement of germline V (variable), D (diversity) and J (joining) gene segments in the immunoglobulin heavy (H) chain locus and V and J gene segments in the Correspondence: Paolo Casali, Center for Immunology, 3028 Hewitt Hall, University of California, Irvine, CA 92697-4120; pcasali@uci.edu; phone: (949) 824-4456; fax: (949) 824-2305. NIH Public Access Author ManuscriptCrit Rev Immunol. Author manuscript; available in PMC 2010 November 30. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIgλ or Igκ light (L) chain locus yields a highly diverse BCR repertoire, which is available for antigen recognition in the ...

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Section: Pax5-pax5mentioning

confidence: 99%

Regulation of aicda Expression and AID Activity: Relevance to Somatic Hypermutation and Class Switch DNA Recombination

Pone

Al‐Qahtani

et al. 2007

Crit Rev Immunol

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“…Purified splenic B cells were obtained from 6-to 12-wk-old B6 mice as previously described (14). Bone marrow-derived MCs (BMMCs) were obtained by in vitro differentiation of bone marrow cells taken from femurs of B6 WT or Cd40l 2/2 mice as previously described (15).…”

Section: Cell Preparationmentioning

confidence: 99%

Mast Cells Control the Expansion and Differentiation of IL-10–Competent B Cells

Mion

D’Incà

Danelli

et al. 2014

The Journal of Immunology

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The discovery of B cell subsets with regulatory properties, dependent on IL-10 production, has expanded our view on the mechanisms that control inflammation. Regulatory B cells acquire the ability to produce IL-10 in a stepwise process: first, they become IL-10 competent, a poised state in which B cells are sensitive to trigger signals but do not actually express the Il-10 gene; then, when exposed to appropriate stimuli, they start producing IL-10. Even if the existence of IL-10–competent B cells is now well established, it is not yet known how different immune cell types cross talk with B cells and affect IL-10–competent B cell differentiation and expansion. Mast cells (MCs) contribute to the differentiation and influence the effector functions of various immune cells, including B lymphocytes. In this study, we explored whether MCs could play a role in the expansion of IL-10–competent B cells and addressed the in vivo relevance of MC deficiency on the generation of these cells. We show that MCs can expand IL-10–competent B cells, but they do not directly induce IL-10 production; moreover, the absence of MCs negatively affects IL-10–competent B cell differentiation. Noteworthy, our findings reveal that the CD40L/CD40 axis plays a significant role in MC-driven expansion of IL-10–competent B cells in vitro and highlight the importance of MC CD40L signaling in the colon.

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“…Murine B cells were isolated from spleen of C57BL/6 mice by a negative depletion method as previously described, 25 and the purity, as percentage of CD19 ϩ cells, was more than 95%. Primary cultures of bone marrow mast cells were obtained by in vitro differentiation of bone marrow cells taken from mouse femur as previously described.…”

Section: Cell Preparation and Culture Conditionsmentioning

confidence: 99%

Mast cells enhance proliferation of B lymphocytes and drive their differentiation toward IgA-secreting plasma cells

Merluzzi

Frossi

Gri

et al. 2010

Blood

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115

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CD40 Stimulation Induces Pax5/BSAP and EBF Activation through a APE/Ref-1-dependent Redox Mechanism

Cited by 41 publications

References 64 publications

Regulation of aicda Expression and AID Activity: Relevance to Somatic Hypermutation and Class Switch DNA Recombination

Regulation of aicda Expression and AID Activity: Relevance to Somatic Hypermutation and Class Switch DNA Recombination

Mast Cells Control the Expansion and Differentiation of IL-10–Competent B Cells

Mast cells enhance proliferation of B lymphocytes and drive their differentiation toward IgA-secreting plasma cells

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