Cat dander extract directly stimulates BAFF-dependent class switch recombination to IgE in B cells without T-cell help

AbstractClass-switched IgG autoantibodies but not unswitched IgM autoantibodies play a crucial role in the development of systemic lupus erythematosus (SLE). Bach2 is known to be essential for class switch recombination of Ig genes, but recent genomic and clinical studies have suggested an association of Bach2 deficiency with SLE. This study was undertaken to examine the mechanism by which Bach2 regulates the development of SLE. Despite defects in Ig class switch recombination and germinal center formation when actively immunized, Bach2−/− mice spontaneously accumulated IgG autoantibody-secreting cells without germinal center reactions in a regulatory T cell-independent manner, and this phenomenon was accompanied by manifestations akin to SLE. Transcriptome analyses revealed that Bach2 regulated the expression of genes related to germinal center formation and SLE pathogenesis in B cells. B cell-specific deletion of Bach2 was sufficient to impair the development of germinal center B cells but insufficient to promote the production of IgG autoantibodies. Bach2 deficiency caused CD4+ T cells to overexpress Icos and differentiate into extrafollicular helper T cells in a cell-autonomous manner. These findings suggest that Bach2-deficient autoreactive B cells preferentially react at extrafollicular sites to give rise to IgG class-switched pathogenic plasma cells and that this effect requires the help of Bach2-Icoshi helper T cells. Thus, the cell-autonomous roles of Bach2 in B cells and in their cognate CD4+ T cells are required to maintain self-tolerance against SLE.

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A brief history of T cell help to B cells

Nature Reviews Immunology ◽

10.1038/nri3803 ◽

2015 ◽

Vol 15 (3) ◽

pp. 185-189 ◽

Cited By ~ 238

Author(s):

Shane Crotty

Keyword(s):

T Cell ◽

B Cells ◽

History Of ◽

T Cell Help

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Arachidonate 5-Lipoxygenase Establishes Adaptive Humoral Immunity by Controlling Primary B Cells and Their Cognate T-Cell Help

American Journal Of Pathology ◽

10.1016/j.ajpath.2010.11.033 ◽

2011 ◽

Vol 178 (1) ◽

pp. 222-232 ◽

Cited By ~ 16

Author(s):

Tsutomu Nagashima ◽

Shingo Ichimiya ◽

Tomoki Kikuchi ◽

Yoshiyuki Saito ◽

Hiroshi Matsumiya ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Humoral Immunity ◽

T Cell Help

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Genomic deletion of the whole IgH 3′ regulatory region (hs3a, hs1,2, hs3b, and hs4) dramatically affects class switch recombination and Ig secretion to all isotypes

Blood ◽

10.1182/blood-2010-01-264689 ◽

2010 ◽

Vol 116 (11) ◽

pp. 1895-1898 ◽

Cited By ~ 99

Author(s):

Christelle Vincent-Fabert ◽

Remi Fiancette ◽

Eric Pinaud ◽

Véronique Truffinet ◽

Nadine Cogné ◽

...

Keyword(s):

Cell Differentiation ◽

B Cells ◽

Plasma Cell ◽

Regulatory Region ◽

Class Switch Recombination ◽

B Cell Differentiation ◽

Plasma Cell Differentiation ◽

Heavy Chains ◽

Class Switch ◽

Transcriptional Changes

Abstract The immunoglobulin heavy chain locus (IgH) undergoes multiple changes along B-cell differentiation. In progenitor B cells, V(D)J assembly allows expression of μ heavy chains. In mature B cells, class switch recombination may replace the expressed constant (C)μ gene with a downstream CH gene. Finally, plasma cell differentiation strongly boosts IgH transcription. How the multiple IgH transcriptional enhancers tune these changes is unclear. Here we demonstrate that deletion of the whole IgH 3′ regulatory region (3′RR) allows normal maturation until the stage of IgM/IgD expressing lymphocytes, but nearly abrogates class switch recombination to all CH genes. Although plasma cell numbers are unaffected, we reveal the role of the 3′RR into the transcriptional burst normally associated with plasma cell differentiation. Our study shows that transcriptional changes and recombinations occurring after antigen-encounter appear mainly controlled by the 3′RR working as a single functional unit.

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Single Round of Antigen Receptor Signaling Programs Naive B Cells to Receive T Cell Help

Immunity ◽

10.1016/j.immuni.2010.02.013 ◽

2010 ◽

Vol 32 (3) ◽

pp. 355-366 ◽

Cited By ~ 38

Author(s):

Bazarragchaa Damdinsuren ◽

Yongqing Zhang ◽

Ashraf Khalil ◽

William H. Wood ◽

Kevin G. Becker ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Antigen Receptor ◽

Receptor Signaling ◽

Antigen Receptor Signaling ◽

T Cell Help ◽

To Receive

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Germinal center reutilization by newly activated B cells

Journal of Experimental Medicine ◽

10.1084/jem.20091225 ◽

2009 ◽

Vol 206 (13) ◽

pp. 2907-2914 ◽

Cited By ~ 65

Author(s):

Tanja A. Schwickert ◽

Boris Alabyev ◽

Tim Manser ◽

Michel C. Nussenzweig

Keyword(s):

B Cells ◽

Immune Responses ◽

Somatic Hypermutation ◽

Affinity Maturation ◽

Anatomical Structures ◽

Class Switch ◽

Cell Clones ◽

T Cell Help ◽

Activated B Cells

Germinal centers (GCs) are specialized structures in which B lymphocytes undergo clonal expansion, class switch recombination, somatic hypermutation, and affinity maturation. Although these structures were previously thought to contain a limited number of isolated B cell clones, recent in vivo imaging studies revealed that they are in fact dynamic and appear to be open to their environment. We demonstrate that B cells can colonize heterologous GCs. Invasion of primary GCs after subsequent immunization is most efficient when T cell help is shared by the two immune responses; however, it also occurs when the immune responses are entirely unrelated. We conclude that GCs are dynamic anatomical structures that can be reutilized by newly activated B cells during immune responses.

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Germinal center B cell development has distinctly regulated stages completed by disengagement from T cell help

eLife ◽

10.7554/elife.19552 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 20

Author(s):

Ting-ting Zhang ◽

David G Gonzalez ◽

Christine M Cote ◽

Steven M Kerfoot ◽

Shaoli Deng ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

B Cell Differentiation ◽

B Cell Maturation ◽

Germinal Center B Cell ◽

T Cell Help ◽

Dose Dependent

To reconcile conflicting reports on the role of CD40 signaling in germinal center (GC) formation, we examined the earliest stages of murine GC B cell differentiation. Peri-follicular GC precursors first expressed intermediate levels of BCL6 while co-expressing the transcription factors RelB and IRF4, the latter known to repress Bcl6 transcription. Transition of GC precursors to the BCL6hi follicular state was associated with cell division, although the number of required cell divisions was immunogen dose dependent. Potentiating T cell help or CD40 signaling in these GC precursors actively repressed GC B cell maturation and diverted their fate towards plasmablast differentiation, whereas depletion of CD4+ T cells promoted this initial transition. Thus while CD40 signaling in B cells is necessary to generate the immediate precursors of GC B cells, transition to the BCL6hi follicular state is promoted by a regional and transient diminution of T cell help.

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Mapping of a Functional Recombination Motif that Defines Isotype Specificity for μ→γ3 Switch Recombination Implicates NF-κB p50 as the Isotype-specific Switching Factor

Journal of Experimental Medicine ◽

10.1084/jem.20031935 ◽

2004 ◽

Vol 199 (5) ◽

pp. 617-627 ◽

Cited By ~ 22

Author(s):

Amy L. Kenter ◽

Robert Wuerffel ◽

Carmen Dominguez ◽

Ananth Shanmugam ◽

Hongmei Zhang

Keyword(s):

B Cells ◽

Binding Site ◽

Class Switch Recombination ◽

Interleukin 4 ◽

Specific Factor ◽

Wild Type ◽

Class Switch ◽

Activation Induced Deaminase ◽

Necessary And Sufficient

Ig class switch recombination (CSR) requires expression of activation-induced deaminase (AID) and production of germline transcripts to target S regions for recombination. However, the mechanism of CSR remains unclear. Here we show that an extrachromosomal S plasmid assay is AID dependent and that a single consensus repeat is both necessary and sufficient for isotype-specific CSR. Transfected switch substrates specific for μ→γ3 and μ→γ1 are stimulated to switch with lipopolysaccharide (LPS) alone or LPS and interleukin-4, respectively. An Sγ3/Sγ1 substrate containing only three Sγ3-associated nucleotides reconstituted LPS responsiveness and permitted mapping of a functional recombination motif specific for μ→γ3 CSR. This functional recombination motif colocalized with a binding site for NF-κB p50, and p50 binding to this site was previously established. We show a p50 requirement for plasmid-based μ→γ3 CSR using p50-deficient B cells. Switch junctions from p50-deficient B cells showed decreased lengths of microhomology between Sμ and Sγ3 relative to wild-type cells, indicating a function for p50 in the mechanics of CSR. We note a striking parallel between the affects of p50 and Msh2 deficiency on Sμ/Sγ3 junctions. The data suggest that p50 may be the isotype-specific factor in μ→γ3 CSR and epistatic with Msh2.

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MicroRNA-directed pathway discovery elucidates an miR-221/222–mediated regulatory circuit in class switch recombination

Journal of Experimental Medicine ◽

10.1084/jem.20201422 ◽

2021 ◽

Vol 218 (11) ◽

Author(s):

Eric J. Wigton ◽

Yohei Mikami ◽

Ryan J. McMonigle ◽

Carlos A. Castellanos ◽

Adam K. Wade-Vallance ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Fate ◽

Cell Activation ◽

Class Switch Recombination ◽

Cell Fate Decisions ◽

Class Switch ◽

Mrna Targets ◽

Regulatory Circuit ◽

Pathway Discovery

MicroRNAs (miRNAs, miRs) regulate cell fate decisions by post-transcriptionally tuning networks of mRNA targets. We used miRNA-directed pathway discovery to reveal a regulatory circuit that influences Ig class switch recombination (CSR). We developed a system to deplete mature, activated B cells of miRNAs, and performed a rescue screen that identified the miR-221/222 family as a positive regulator of CSR. Endogenous miR-221/222 regulated B cell CSR to IgE and IgG1 in vitro, and miR-221/222–deficient mice exhibited defective IgE production in allergic airway challenge and polyclonal B cell activation models in vivo. We combined comparative Ago2-HITS-CLIP and gene expression analyses to identify mRNAs bound and regulated by miR-221/222 in primary B cells. Interrogation of these putative direct targets uncovered functionally relevant downstream genes. Genetic depletion or pharmacological inhibition of Foxp1 and Arid1a confirmed their roles as key modulators of CSR to IgE and IgG1.

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Noncoding RNA transcription alters chromosomal topology to promote isotype-specific class switch recombination

Science Immunology ◽

10.1126/sciimmunol.aay5864 ◽

2020 ◽

Vol 5 (44) ◽

pp. eaay5864 ◽

Cited By ~ 4

Author(s):

Gerson Rothschild ◽

Wanwei Zhang ◽

Junghyun Lim ◽

Pankaj Kumar Giri ◽

Brice Laffleur ◽

...

Keyword(s):

B Cells ◽

Regulatory Region ◽

Noncoding Rnas ◽

Class Switch Recombination ◽

Regulatory Elements ◽

Specific Class ◽

Antibody Diversity ◽

Variable Regions ◽

Class Switch ◽

Super Enhancer

B cells undergo two types of genomic alterations to increase antibody diversity: introduction of point mutations into immunoglobulin heavy- and light-chain (IgH and IgL) variable regions by somatic hypermutation (SHM) and alteration of antibody effector functions by changing the expressed IgH constant region exons through IgH class switch recombination (CSR). SHM and CSR require the B cell–specific activation-induced cytidine deaminase (AID) protein, the transcription of germline noncoding RNAs, and the activity of the 3′ regulatory region (3′RR) super-enhancer. Although many transcription regulatory elements (e.g., promoters and enhancers) reside inside the IgH and IgL sequences, the question remains whether clusters of regulatory elements outside IgH control CSR. Using RNA exosome–deficient mouse B cells where long noncoding RNAs (lncRNAs) are easily detected, we identified a cluster of three RNA-expressing elements that includes lncCSRIgA (that expresses lncRNA-CSRIgA). B cells isolated from a mouse model lacking lncRNA-CSRIgA transcription fail to undergo normal levels of CSR to IgA both in B cells of the Peyer’s patches and grown in ex vivo culture conditions. lncRNA-CSRIgA is expressed from an enhancer site (lncCSRIgA) to facilitate the recruitment of regulatory proteins to a nearby CTCF site (CTCFlncCSR) that alters the chromosomal interactions inside the TADlncCSRIgA and long-range interactions with the 3′RR super-enhancer. Humans with IgA deficiency show polymorphisms in the lncCSRIgA locus compared with the normal population. Thus, we provide evidence for an evolutionarily conserved topologically associated domain (TADlncCSRIgA) that coordinates IgA CSR in Peyer’s patch B cells through an lncRNA (lncRNA-CSRIgA) transcription-dependent mechanism.

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