scholarly journals Epigenetic Modulation of Class-Switch DNA Recombination to IgA by miR-146a Through Downregulation of Smad2, Smad3 and Smad4

2021 ◽  
Vol 12 ◽  
Author(s):  
Paolo Casali ◽  
Shili Li ◽  
Grecia Morales ◽  
Cassidy C. Daw ◽  
Daniel P. Chupp ◽  
...  
Keyword(s):  
B Cells ◽  
Antibody Response ◽  
B Cell ◽  
Critical Role ◽  
Dna Recombination ◽  
Antibody Isotype ◽  
Class Switch ◽  
Iga Antibody ◽  
Class Switch Dna Recombination

IgA is the predominant antibody isotype at intestinal mucosae, where it plays a critical role in homeostasis and provides a first line of immune protection. Dysregulation of IgA production, however, can contribute to immunopathology, particularly in kidneys in which IgA deposition can cause nephropathy. Class-switch DNA recombination (CSR) to IgA is directed by TGF-β signaling, which activates Smad2 and Smad3. Activated Smad2/Smad3 dimers are recruited together with Smad4 to the IgH α locus Iα promoter to activate germline Iα-Cα transcription, the first step in the unfolding of CSR to IgA. Epigenetic factors, such as non-coding RNAs, particularly microRNAs, have been shown to regulate T cells, dendritic cells and other immune elements, as well as modulate the antibody response, including CSR, in a B cell-intrinsic fashion. Here we showed that the most abundant miRNA in resting B cells, miR-146a targets Smad2, Smad3 and Smad4 mRNA 3’UTRs and keeps CSR to IgA in check in resting B cells. Indeed, enforced miR-146a expression in B cells aborted induction of IgA CSR by decreasing Smad levels. By contrast, upon induction of CSR to IgA, as directed by TGF-β, B cells downregulated miR-146a, thereby reversing the silencing of Smad2, Smad3 and Smad4, which, once expressed, led to recruitment of Smad2, Smad3 and Smad4 to the Iα promoter for activation of germline Iα-Cα transcription. Deletion of miR-146a in miR-146a–/– mice significantly increased circulating levels of steady state total IgA, but not IgM, IgG or IgE, and heightened the specific IgA antibody response to OVA. In miR-146a–/– mice, the elevated systemic IgA levels were associated with increased IgA+ B cells in intestinal mucosae, increased amounts of fecal free and bacteria-bound IgA as well as kidney IgA deposition, a hallmark of IgA nephropathy. Increased germline Iα-Cα transcription and CSR to IgA in miR-146a–/– B cells in vitro proved that miR-146a-induced Smad2, Smad3 and Smad4 repression is B cell intrinsic. The B cell-intrinsic role of miR-146a in the modulation of CSR to IgA was formally confirmed in vivo by construction and OVA immunization of mixed bone marrow μMT/miR-146a–/– chimeric mice. Thus, by inhibiting Smad2, Smad3 and Smad4 expression, miR-146a plays an important and B cell intrinsic role in modulation of CSR to IgA and the IgA antibody response.

Mucosal Epithelial Cells Initiate Frontline Immunoglobulin Class Switching through an SLPI-Regulated Pathway.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3898-3898
Author(s):  
Andrea Cerutti ◽  
Bing He ◽  
April Chiu ◽  
Meimei Shan ◽  
Paul Santini ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Cells ◽  
Epithelial Cells ◽  
B Cell ◽  
Antibody Production ◽  
Cytidine Deaminase ◽  
Dna Recombination ◽  
Class Switching ◽  
Class Switch

Abstract Introduction. Class switching from IgM to IgG and IgA is central to immunity against microbes and usually occurs in draining lymph nodes and requires activation of B cells by CD4+ T cells expressing CD40 ligand. Growing evidence indicates that B cells can mount frontline IgG and IgA responses at mucosal sites of entry through an alternative CD40-independent pathway involving B cell-activating factor of the TNF family (BAFF, also known as BLyS) and a proliferation-inducing ligand (APRIL). These innate factors are usually produced by dendritic cells and stimulate B cells through at least three distinct receptors. Together with dendritic cells, epithelial cells have a key position at the host-environment interface. Therefore, we asked whether epithelial cells play a role in frontline antibody production. Methods. Tonsillar tissue sections from healthy donors were analyzed for expression of activation-induced cytidine deaminase (AID) by immunohistochemistry and in situ hybridization. A simplified in vitro model reproducing the geometry of mucosal surfaces was used to evaluate the role of epithelial cells in class switching. Briefly, primary epithelial cells and B cells were cultured in the upper and lower chambers, respectively, of a trans-well system. Monocyte-derived dendritic cells were positioned on a filter separating the two chambers. Various microbial product analogues were used to mimic infection. RNA interference was performed to knockdown BAFF in epithelial cells. AID expression, CSR, antibody production and signaling were evaluated in B cells as reported (Litinsky et al., Nat. Immunol.2002, 3:822–829; Qiao et al., Nat. Immunol.2006, 7:302–310). Results. We found that the upper respiratory mucosa of healthy subjects comprised intraepithelial pockets filled with B cells expressing AID, a DNA-editing enzyme associated with ongoing class switch DNA recombination (CSR). Epithelial cells released innate class switch-inducing factors, including BAFF, after sensing microbial products through TLRs, thereby inducing AID expression, CSR, and ultimately IgG and IgA production in neighboring B cells. Epithelial cell-induced antibodies comprised polyreactive IgG and IgA capable of recognizing multiple microbial determinants. Intraepithelial class switching was enhanced by thymic stromal lymphopoietin (TSLP), an epithelial IL-7-like cytokine that augments the innate B cell-licensing functions of dendritic cells, and restrained by secretory leukocyte protease inhibitor (SLPI), an epithelial alarm antiprotease that suppresses AID expression in activated B cells. Conclusions. The present findings indicate that epithelial cells function as non-immune sentinels capable to autonomously orchestrate compartmentalized IgG and IgA responses at the interface between host and environment. This implies that mucosal vaccines should activate both epithelial and immune cells to elicit optimal antibody production.

scholarly journals Rad52 mediates class-switch DNA recombination to IgD

2021 ◽  
Author(s):  
Yijiang Xu ◽  
Hang Zhou ◽  
Ginell Post ◽  
Hong Zan ◽  
Paolo Casali
Keyword(s):  
B Cells ◽  
Short Range ◽  
Dna Recombination ◽  
Dna Breaks ◽  
Class Switch ◽  
Rad52 Protein ◽  
Class Switch Dna Recombination

While the biology of IgD begins to be better understood, the mechanism of expression of this phylogenetically old and highly conserved Ig class remains unknown. In B cells, IgD is expressed together with IgM as transmembrane receptor for antigen through alternative splicing of long primary VHDJH-Cμ-s-m-Cδ-s-m RNA, which also underpins the secreted form of IgD. IgD is also expressed through class switch DNA recombination (CSR), as initiated by AID-mediated double-strand DNA breaks (DSBs) in Sμ and σδ and resolution of such DSBs by a yet unknown alternative endjoining (A-EJ) mechanism. This synapses Sμ with σδ region DSB resected ends leading to insertion of extensive S-S junction microhomologies, unlike the Ku70/Ku86-dependent NHEJ which resolves DSB blunt ends in CSR to IgG, IgA and IgE with little or no microhomologies. We previously demonstrated a novel role of DNA annealing homologous recombination Rad52 protein in 'short-range' microhomology-mediated synapsis of intra-Sδ region DSBs. This led us to hypothesize that Rad52 is also involved in the short-range microhomology-mediated A-EJ recombination of Sμ with σδ. We found that induction of IgD CSR by T-dependent or T-independent stimuli downregulated Zfp318 (the suppressor of Cδ-s-m transcription termination), promoted Rad52 phosphorylation, recruitment of Rad52 to Sμ and σδ leading to Sμ-σδ recombination with extensive microhomologies, VHDJH-Cδs transcription and sustained IgD secretion. Rad52 ablation in mouse Rad52-/- B cells aborted IgD CSR in vitro and in vivo and dampened the specific IgD antibody response to OVA. Further, Rad52 knockdown in human B cells virtually abrogated IgD CSR. Finally, Rad52 phosphorylation was associated with high levels IgD CSR and anti-nuclear IgD autoantibodies in lupus-prone mice and lupus patients. Thus, Rad52 mediates CSR to IgD by synapsing Sμ-σδ resected DSB ends through microhomology-mediated A-EJ and in concert with Zfp318 modulation. This is a previously unrecognized, critical and dedicated role of Rad52 in mammalian DNA repair.

scholarly journals Correction: Scaffold Functions of 14-3-3 Adaptors in B Cell Immunoglobulin Class Switch DNA Recombination

PLoS ONE ◽  
2017 ◽  
Vol 12 (3) ◽  
pp. e0174195
Author(s):  
Tonika Lam ◽  
Lisa M. Thomas ◽  
Clayton A. White ◽  
Guideng Li ◽  
Egest J. Pone ◽  
...  
Keyword(s):  
B Cell ◽  
Dna Recombination ◽  
Immunoglobulin Class ◽  
Class Switch ◽  
Class Switch Dna Recombination

scholarly journals Engagement of CD153 (CD30 Ligand) by CD30+T Cells Inhibits Class Switch DNA Recombination and Antibody Production in Human IgD+IgM+B Cells

2000 ◽  
Vol 165 (2) ◽  
pp. 786-794 ◽  
Author(s):  
Andrea Cerutti ◽  
Andràs Schaffer ◽  
Raymond G. Goodwin ◽  
Shefali Shah ◽  
Hong Zan ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Antibody Production ◽  
Dna Recombination ◽  
Class Switch ◽  
Class Switch Dna Recombination

scholarly journals How the Signaling Crosstalk of B Cell Receptor (BCR) and Co-Receptors Regulates Antibody Class Switch Recombination: A New Perspective of Checkpoints of BCR Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhangguo Chen ◽  
Jing H. Wang
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Dna Recombination ◽  
Class Switch Recombination ◽  
Cell Receptor ◽  
Signaling Crosstalk ◽  
Class Switch ◽  
Antibody Class ◽  
New Perspective

Mature B cells express B cell antigen receptor (BCR), toll-like receptors (TLR) and TNF family receptors including CD40 and B-cell activating factor receptor (BAFFR). These receptors transduce cellular signals to govern the physiological and pathological processes in B cells including B cell development and differentiation, survival, proliferation, and antibody-mediated immune responses as well as autoimmune diseases and B cell lymphomagenesis. Effective antibody-mediated immune responses require class switch recombination (CSR), a somatic DNA recombination event occurring at the immunoglobulin heavy chain (Igh) gene locus. Mature B cells initially express IgM as their BCR, and CSR enables the B cells to switch from expressing IgM to expressing different classes of antibodies including IgG, IgA or IgE that exhibit distinct effector functions. Here, we briefly review recent findings about how the signaling crosstalk of the BCR with TLRs, CD40 and BAFFR regulates CSR, antibody-mediate immune responses, and B cell anergy.

scholarly journals Blimp-1-Dependent Repression of Pax-5 Is Required for Differentiation of B Cells to Immunoglobulin M-Secreting Plasma Cells

2002 ◽  
Vol 22 (13) ◽  
pp. 4771-4780 ◽  
Author(s):  
Kuo-I Lin ◽  
Cristina Angelin-Duclos ◽  
Tracy C. Kuo ◽  
Kathryn Calame
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Critical Role ◽  
Cell Lineage ◽  
Immunoglobulin M ◽  
Dependent Manner ◽  
Plasmacytic Differentiation

ABSTRACT B-cell lineage-specific activator protein (BSAP), encoded by the Pax-5 gene, is critical for B-cell lineage commitment and B-cell development but is not expressed in terminally differentiated B cells. We demonstrate a direct connection between BSAP and B-lymphocyte-induced maturation protein 1 (Blimp-1), a transcriptional repressor that is sufficient to drive plasmacytic differentiation. Blimp-1 binds a site on the Pax-5 promoter in vitro and in vivo and represses the Pax-5 promoter in a binding-site-dependent manner. By ectopically expressing Blimp-1 or a competitive inhibitor of Blimp-1, we show that Blimp-1 is both necessary and sufficient to repress Pax-5 during plasmacytic differentiation of primary splenic B cells. Blimp-1-dependent repression of Pax-5 is sufficient to regulate BSAP targets CD19 and J chain and is necessary but not sufficient to induce XBP-1. We further show that repression of Pax-5 is required for Blimp-1 to drive differentiation of splenocytes to immunoglobulin M-secreting cells. Thus, repression of Pax-5 plays a critical role in the Blimp-1-dependent program of plasmacytic differentiation.

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