Activation-induced deaminase-mediated class switch recombination is blocked by anti-IgM signaling in a phosphatidylinositol 3-kinase-dependent fashion

Heltemes-Harris, Lynn; Gearhart, Patricia J.; Ghosh, Paritosh; Longo, Dan L.

doi:10.1016/j.molimm.2007.09.020

Cited by 16 publications

(17 citation statements)

References 43 publications

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“…This is an important distinction that invites new consideration of existing findings. In contrast to our observation that high-affinity Ag induces upregulation of AID expression, it has previously been shown that AID mRNA expression is delayed and reaches a lower maximum at later days in in vitro murine B cell cultures stimulated with anti-IgM plus IL-4 compared with that in cultures stimulated with LPS and IL-4 (43). In fact, the addition of anti-IgM to cell cultures stimulated with LPS and IL-4 or anti-CD40 and IL-4 was shown to reduce the proportion of class-switched cells in these cultures.…”

Section: Discussioncontrasting

confidence: 99%

“…In fact, the addition of anti-IgM to cell cultures stimulated with LPS and IL-4 or anti-CD40 and IL-4 was shown to reduce the proportion of class-switched cells in these cultures. Furthermore, these authors reported that B cells stimulated with anti-IgM and IL-4 did not switch to either IgG1 or IgG3 compared with cells stimulated with LPS alone (IgG3 switched) or with LPS and IL-4 (IgG1 switched) (43). However, no difference was found in the levels of germline g1 transcripts of cells stimulated with IL-4 and LPS or anti-IgM, indicating that the inhibitory effect of anti-IgM on switching occurs at a stage subsequent to the formation of the germline transcript.…”

Section: Discussionmentioning

confidence: 99%

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High-Affinity B Cell Receptor Ligation by Cognate Antigen Induces Cytokine-Independent Isotype Switching

Turner

Corcoran

Brink

et al. 2010

The Journal of Immunology

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The selection of an appropriate Ig isotype is critical for an effective immune response against pathogens. Isotype regulation is sensitive to external signals, particularly cytokines secreted by Th cells. For example, IL-4 induces isotype switching to IgG1 via a STAT6-dependent signaling pathway. In this study, we show that BCR ligation also induces IgG1 switching in mouse B cells. The extent of switch induction by Ag is affinity-dependent, and high-affinity Ag binding leads to IgG1 switching levels comparable to those induced by saturating IL-4. However, the Ag-induced IgG1 switch does not require additional cytokine signals and occurs in a STAT6-independent manner. Thus, BCR ligation represents a novel pathway for direct isotype switching leading to IgG1 secretion.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

High-Affinity B Cell Receptor Ligation by Cognate Antigen Induces Cytokine-Independent Isotype Switching

Turner

Corcoran

Brink

et al. 2010

The Journal of Immunology

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“…4 This finding adds to the growing evidence for unique signaling pathways regulating AID expression through the BCR and other surface receptors. 38,39 These studies have shown that signaling through the BCR delays AID expression and down-regulates certain AID-induced processes, such as class-switching, while having no effect on total transcript and protein levels. Furthermore, costimulation of both the BCR and TLR-4 was enough to dampen CSR in a phosphatidylinositol 3-kinase-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, costimulation of both the BCR and TLR-4 was enough to dampen CSR in a phosphatidylinositol 3-kinase-dependent manner. 38 Phosphatidylinositol 3-kinase-signaling interferes with AID activity only when signaled through the BCR, therefore implying a distinct signaling cascade compared with TLR-4. Unlike the BCR and CD40, however, TLR-4 signaling is not known to induce GC formation in vivo; thus, the ex vivo defect reported here might explain why AID deficiency has a GC-specific phenotype regarding apoptosis.…”

Section: Discussionmentioning

confidence: 99%

AID constrains germinal center size by rendering B cells susceptible to apoptosis

Zaheen

Boulianne

Parsa

et al. 2009

Blood

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IntroductionA fundamental hallmark of humoral immunity is the ability to produce class-switched antibodies that have enhanced affinity for antigen. This process, termed affinity maturation, allows clonally selected B cells to refine their response to theoretically target any antigen with high specificity. After activation, B cells mutate the immunoglobulin (Ig) locus in a process known as somatic hypermutation (SHM). 1 Mutated clones that have acquired increased affinity for antigen preferentially expand over their low-affinity counterparts. The selection process occurs in the germinal center (GC), a transient microenvironment that forms in secondary lymphoid tissue shortly after antigen exposure. 2 The GC provides a competitive setting for B cells whereby ineffectual clones are actively cleared from the system via apoptosis, although the processes that govern this selection still remain vague.SHM and class switch recombination (CSR) are initiated by the enzyme activation-induced cytidine deaminase (AID), 3,4 which deaminates cytidines to uridines specifically at the Ig locus. 5-10 AID-generated uridines are then engaged by various DNA repair pathways that either lead to the generation of point mutations in the antibody variable region or recombinogenic events that lead to CSR. AID Ϫ/Ϫ mice lack mutations at their Ig locus and are incapable of producing class-switched antibodies. 4 Interestingly, these mice were previously shown to harbor an abnormally high proportion of splenic GC B cells. 11 This phenotype is also recapitulated in humans with AID deficiencies. 3 Although a link between reduced gut immunity (resulting from an inability to produce mucosal IgA) and peripheral GC formation was hypothesized to account for these abnormalities, this remains to be conclusively proven, and the possibility of a B cell-intrinsic effect that could explain the profound expansion of GC B cells has not been examined.GC B cells represent a unique lymphoid compartment of actively proliferating cells where numerous apoptotic factors must synergize to induce the elimination of nonproductive clones. Factors contributing to the intrinsic pathway of apoptosis, such as Bcl-2, Bcl-x L , and Bim, 12-17 and the extrinsic pathway, such as Fas, [18][19][20][21][22] have been implicated in GC selection. The unique physiology of these cells makes them highly susceptible to disease progression, often serving as etiologic sites for autoimmune and malignant B cells. 13,[23][24][25][26] Recent evidence has implicated AID as a fundamental contributor to the genetic aberrations that lead to these disease phenotypes. 24,[27][28][29] Given the importance of apoptosis as a parameter for both GC B-cell selection and lymphomagenesis, we investigated the relationship between AID-induced DNA mutation and cell death to understand how this enzyme may impinge on survival and death within the GC niche. Here we report that many of the potentially harmful AID-induced genetic alterations may indeed lead to the death of these cells within the GC. Methods Mice...

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“…Abundant AID expression and CSR occurs after stimulation with LPS, which binds to toll-like receptor 4, or with anti-CD40 antibody, which binds to the CD40 receptor. In contrast, AID expression is delayed and CSR is ablated when cells are stimulated with anti-IgM, which binds to the Ig receptor (Heltemes-Harris et al ., 2008; Jabara et al ., 2008). Furthermore, AID expression and CSR are actually suppressed when anti-IgM is added to cells stimulated with LPS or anti-CD40 (Heltemes-Harris et al ., 2008; Jabara et al ., 2008; Rush et al ., 2002).…”

Section: Aid the Master Catalystmentioning

confidence: 99%

AID and Somatic Hypermutation

Maul

Gearhart

2010

Advances in Immunology

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166

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In response to an assault by foreign organisms, peripheral B cells can change their antibody affinity and isotype by somatically mutating their genomic DNA. The ability of a cell to modify its DNA is exceptional in light of the potential consequences of genetic alterations to cause human disease and cancer. Thus, as expected, this mechanism of antibody diversity is tightly regulated and coordinated through one protein, activation induced deaminase (AID). AID produces diversity by converting cytosine to uracil within the immunoglobulin loci. The deoxyuracil residue is mutagenic when paired with deoxyguanosine, since it mimics thymidine during DNA replication. Additionally, B cells can manipulate the DNA repair pathways so that deoxyuracils are not faithfully repaired. Therefore, an intricate balance exists which is regulated at multiple stages to promote mutation of immunoglobulin genes, while retaining integrity of the rest of the genome. Here we discuss and summarize the current understanding of how AID functions to cause somatic hypermutation.

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Activation-induced deaminase-mediated class switch recombination is blocked by anti-IgM signaling in a phosphatidylinositol 3-kinase-dependent fashion

Cited by 16 publications

References 43 publications

High-Affinity B Cell Receptor Ligation by Cognate Antigen Induces Cytokine-Independent Isotype Switching

High-Affinity B Cell Receptor Ligation by Cognate Antigen Induces Cytokine-Independent Isotype Switching

AID constrains germinal center size by rendering B cells susceptible to apoptosis

AID and Somatic Hypermutation

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