<i>In vivo</i>and<i>in vitro</i>studies of immunoglobulin gene somatic hypermutation

Sale, Julian E.; Bemark, Mats; Williams, Gareth T.; Jolly, Christopher J.; Ehrenstein, Michael R.; Rada, Cristina; Milstein, C.; Neuberger, Michael S.

doi:10.1098/rstb.2000.0744

Cited by 20 publications

(13 citation statements)

References 82 publications

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“…The data from XRCC3 −/− cells also demonstrated the ability of our mathematical modeling [42] to estimate changes in mutation rate. The 21× increase in the rate of sIg loss estimated for XRCC3 −/− cells (Table 1) corresponds well to their rate of point mutation determined by sequencing [43]. …”

Section: Resultssupporting

confidence: 57%

“…Note: lack of surface Ig-expression in the XRCC3 −/− founder clones was due to Ig V(D)J point mutations and not due to the canonical CL18 frame shift carried by the control, Ku70 −/− , and DNA-PKcs −/−/− clones (unpublished data). Thus, the reduced rate of Ig V gene conversion known to exist in these cells [43,45] did not significantly reduce their rate of surface Ig gain.…”

Section: Resultsmentioning

confidence: 99%

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DNA-Dependent Protein Kinase Inhibits AID-Induced Antibody Gene Conversion

et al. 2007

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Affinity maturation and class switching of antibodies requires activation-induced cytidine deaminase (AID)-dependent hypermutation of Ig V(D)J rearrangements and Ig S regions, respectively, in activated B cells. AID deaminates deoxycytidine bases in Ig genes, converting them into deoxyuridines. In V(D)J regions, subsequent excision of the deaminated bases by uracil-DNA glycosylase, or by mismatch repair, leads to further point mutation or gene conversion, depending on the species. In Ig S regions, nicking at the abasic sites produced by AID and uracil-DNA glycosylases results in staggered double-strand breaks, whose repair by nonhomologous end joining mediates Ig class switching. We have tested whether nonhomologous end joining also plays a role in V(D)J hypermutation using chicken DT40 cells deficient for Ku70 or the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Inactivation of the Ku70 or DNA-PKcs genes in DT40 cells elevated the rate of AID-induced gene conversion as much as 5-fold. Furthermore, DNA-PKcs-deficiency appeared to reduce point mutation. The data provide strong evidence that double-strand DNA ends capable of recruiting the DNA-dependent protein kinase complex are important intermediates in Ig V gene conversion.

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Section: Resultssupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

DNA-Dependent Protein Kinase Inhibits AID-Induced Antibody Gene Conversion

et al. 2007

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“…[31][32][33][34][35][36] Sufficient binding of antibody to a given pathogen should therefore be possible with much less affinity-maturated antibody than with the unmutated version. Because the total levels of circulating immunoglobulins are restricted, SHM allows for more specificities in the immune antibody repertoire or for longer duration of antibody-mediated memory or both.…”

Section: Discussionmentioning

confidence: 99%

“…By this process affinity may increase 10-to 1000-fold. [31][32][33][34][35][36] The finding that IgG-secreting cells in some patients lack somatic mutations indicates that the IgG produced in these patients is of reduced quality with low affinity for the eliciting antigens. However, affinity maturation by SHM does not depend on isotype switching and may occur in B cells producing IgM.…”

Section: Introductionmentioning

confidence: 99%

Deficiency of somatic hypermutation of the antibody light chain is associated with increased frequency of severe respiratory tract infection in common variable immunodeficiency

Andersen

Permin

Andersen

et al. 2005

Blood

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Reduced levels of somatic hypermutation (SHM) have recently been described in IgG-switched immunoglobulin genes in a minority of patients with common variable immunodeficiency (CVID), demonstrating a disruption of the normal linkage between isotype switch and SHM. To see if, irrespective of isotype, there is a tendency to use unmutated immunoglobulin genes in CVID, we studied SHM in light-chain transcripts using a V A27-specific restriction enzyme-based hot-spot mutation assay (IgREHMA). Hot-spot mutations were found in 48% (median; reference interval, 28%-62%) of transcripts from 53 healthy controls. Values were significantly lower in 31 patients (median, 7.5%; range, 0%-73%; P < .0000001) of whom 24 (77%) had levels below the reference interval. Low levels of SHM correlated with increased frequency of severe respiratory tract infection (SRTI; P < .005), but not with diarrhea (P ‫؍‬ .8). Mannose-binding lectin (MBL) deficiency also correlated with SRTI score (P ‫؍‬ .009). However, the correlation of SHM and SRTI was also seen when only patients with normal MBL genotypes were analyzed (n ‫؍‬ 18, P ‫؍‬ .006). A slight decline of mutated fractions over years was noted (P ‫؍‬ .01). This suggests that most patients with CVID fail to recruit affinity-maturated B cells, adding a qualitative deficiency to the quantitative deficiency characterizing these patients. (Blood. 2005;105:511-517)

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“…Another question that is not fully answered is how AID activity leads to C/G mutations in cell lines (199, 200, 201, 202, 203) or in CSR-activated B cells (194) versus spreading of the C/G mutations to A/T base pairs in GC B cells (204, 205). Error-prone DNA polymerases during BER and MMR in GC B cells have been implicated in the spreading process that generates mutations at A/T base pairs (206, 207), raising the possibility that differential expression of these enzymes or other related factors in GC B cells could contribute to SHM spreading (208).…”

Section: Perspectivementioning

confidence: 99%

Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination

2015

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The primary antibody repertoire is generated by mechanisms involving the assembly of the exons that encode the antigen-binding variable regions of immunoglobulin heavy (IgH) and light (IgL) chains during the early development of B lymphocytes. After antigen-dependent activation, mature B lymphocytes can further alter their IgH and IgL variable region exons by the process of somatic hypermutation (SHM), which allows the selection of B cells in which SHMs resulted in the production of antibodies with increased antigen affinity. In addition, during antigen-dependent activation, B cells can also change the constant region of their IgH chain through a DNA double-strand-break (DSB) dependent process referred to as IgH class switch recombination (CSR), which generates B cell progeny that produce antibodies with different IgH constant region effector functions that are best suited for a elimination of a particular pathogen or in a particular setting. Both the mutations that underlie SHM and the DSBs that underlie CSR are initiated in target genes by activation-induced cytidine deaminase (AID). This review describes in depth the processes of SHM and CSR with a focus on mechanisms that direct AID cytidine deamination in activated B cells and mechanisms that promote the differential outcomes of such cytidine deamination.

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In vivoandin vitrostudies of immunoglobulin gene somatic hypermutation

Cited by 20 publications

References 82 publications

DNA-Dependent Protein Kinase Inhibits AID-Induced Antibody Gene Conversion

DNA-Dependent Protein Kinase Inhibits AID-Induced Antibody Gene Conversion

Deficiency of somatic hypermutation of the antibody light chain is associated with increased frequency of severe respiratory tract infection in common variable immunodeficiency

Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination

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