Faculty Opinions recommendation of The AID enzyme induces class switch recombination in fibroblasts.
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Abstract:
The switch of the immunoglobulin isotype from IgM to IgG, IgE or IgA is mediated by class switch recombination (CSR). CSR changes the immunoglobulin heavy chain constant region (CH) gene from Cmu to one of the other CH genes. Somatic hypermutation introduces massive numbers of point mutations in the immunoglobulin variable (V) region gene, giving rise to immunoglobulin with higher affinity. Activation-induced cytidine deaminase (AID), a putative RNA-editing cytidine deaminase, is expressed strictly in activated B cells and is indispensable in both CSR and somatic hypermutation. But the exact function of AID is unknown. Here we show that ectopic expression of AID induces CSR in an artificial switch construct in fibroblasts at a level comparable to that in stimulated B cells. Sequences around recombination junctions in the artificial substrate have features similar to endogenous CSR junctions. Furthermore, AID-induced CSR in fibroblasts is dependent on transcription of the target S region, as shown in endogenous CSR in B cells. The results show that AID is the only B-cell-specific factor required for initiation of the CSR reaction in the activated locus. PMID: 11875397Keywords:
Activation-induced (cytidine) deaminase
Isotype
Immunoglobulin gene
Activation-induced (cytidine) deaminase
Gene conversion
Isotype
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Activation-induced (cytidine) deaminase
Deamination
Cytidine
Immunoglobulin gene
Gene conversion
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Activation-induced (cytidine) deaminase
Cytidine
Gene conversion
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Purpose of review Elucidation of the molecular basis of hyper-immunoglobulin-M syndromes has provided considerable insight into the molecular events involved in antibody maturation, including immunoglobulin class switch recombination and the generation of somatic hypermutation. Recent findings The identification of activation-induced cytidine deaminase deficiency (hyper-immunoglobulin-M syndrome 2) has revealed the key role played by this inducible B cell-specific molecule in both class switch recombination and somatic hypermutation. Data from Escherichia coli and in-vitro assays have strongly suggested that activation-induced cytidine deaminase acts as a DNA-editing enzyme in these processes. The recent description of a new hyper-immunoglobulin-M syndrome caused by mutations in the gene encoding the uracil-N glycosylase provided further evidence that activation-induced cytidine deaminase acts on deoxycytidine in the switch and variable regions. Indeed, uracil-N glycosylase is required to remove the uracil residues integrated into DNA following deoxycytidine deamination by activation-induced cytidine deaminase. Another hyper-immunoglobulin-M condition has recently been described (hyper-immunoglobulin-M syndrome 4). Its molecular basis is unknown, but it appears to be a homogeneous entity characterized by an intrinsic B cell defective class switch recombination but normal generation of somatic hypermutation. It is probably caused by a class switch recombination-specific DNA repair defect because class switch recombination-induced DNA breaks in S regions are normally detected in patients with this condition. Summary The heterogeneity in hyper-immunoglobulin-M syndromes will continue to shed light on the molecular mechanisms of class switch recombination and somatic hypermutation. The description of hyper-immunoglobulin-M syndromes may therefore lead to improvements in the care of these patients.
Activation-induced (cytidine) deaminase
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Abstract Maturation of the antibody repertoire is mediated by two different mechanisms: class‐switch recombination (CSR) and somatic hypermutation (SHM). These two processes are T cell dependent and occur in the germinal centers of secondary lymphoid organs. CSR leads to the production of antibodies of different isotypes whereas SHM leads to the selection of B cells expressing a BCR with high affinity for antigen. The activation‐induced cytidine deaminase (AID) was recently shown to play a key role in these two mechanisms, demonstrating for the first time that these maturation processes share a common mechanism. There is evidence that AID is involved in the somatic DNA alterations required for CSR and SHM. The mechanism of action of AID is unclear. As AID and APOBEC‐1 display a sequence similarity, AID may act as an RNA‐editing enzyme. However, the immunological abnormalities observed in uracil‐N glycosylase deficiency in a recent study indirectly suggest that AID may edit DNA directly.
Activation-induced (cytidine) deaminase
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In B-cells, activation-induced cytidine deaminase (AID) is required for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes. AID introduces mutations in immunoglobulin variable regions (IGV) during B-cell receptor affinity maturation, but may also introduce aberrant mutations into non-immunoglobulin genes, most commonly BCL6. Follicular lymphoma (FL) B-cells constitutively express AID and undergo CSR, SHM and aberrant SHM. We have studied AID expression, the presence of SHM mutations, CSR, and aberrant SHM in BCL6 in a cohort of 75 FL patients. Whereas IgM-expressing (non-switched) FL were characterized by an expected positive correlation between AID and IGV and BCL6 mutations, isotype-switched FL showed dissociation between AID expression and aberrant SHM, and inverse correlation between SHM and AID expression. Our results unveil two manifest biological subgroups of FL and indicate that the specific dissociation between AID and SHM after isotype switch may correlate with the clinical outcome of this heterogeneous disease.
Activation-induced (cytidine) deaminase
BCL6
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Affinity maturation
Immunoglobulin gene
Follicular lymphoma
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Activation-induced (cytidine) deaminase
Cytidine
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The regulation of activation induced cytidine deaminase (AID) gene ( aicda ) expression and the modulation of immunoglobulin gene class switch DNA recombination (CSR) and somatic hypermutation (SHM) remain to be defined. We found that the HoxC4 homeodomain protein is preferentially expressed in germinal center B cells and upregulated by stimuli that induce AID expression and CSR. In HoxC4‐deficient mice, the mutation frequency in the intronic J H ‐iEμ region of IgH DNA and the serum IgG1 levels were decreased by about 60%. Accordingly, the high affinity anti‐NP response was significantly compromised in hoxC4 −/− mice, and CSR to IgG1, IgG2a, IgG2b, IgG3 and IgA in in vitro stimulated hoxC4 −/− B cells was impaired. This was not due to altered hoxC4 −/− B cell proliferation or germinal center formation in hoxC4 −/− mice. Rather, it resulted from a defective induction of AID expression. Indeed, by performing in vitro promoter bashing experiments using luciferase gene reporter assays and ChIP, we showed that HoxC4 activates aicda by binding to an evolutionarily conserved HoxC4/Oct‐binding ATTT(GCAT) motif in the promoter for this gene. Enforced expression of AID in HoxC4‐deficient B cells restored CSR. Thus, these findings show that by regulating AID expression through direct activation of the aicda promoter, HoxC4 plays a critical role in modulating CSR and SHM. Supported by NIH grants, AI 45011, AI 60573 and AR 40908.
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Activation-induced (cytidine) deaminase
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Activation-induced (cytidine) deaminase
Cytidine
Gene conversion
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