Somatic hypermutation of immunoglobulin genes is independent of the Bloom's syndrome DNA helicase

Sack, Stephen Z; Liu, Y; German, James; Green, Nancy

doi:10.1046/j.1365-2249.1998.00575.x

Cited by 17 publications

(10 citation statements)

References 36 publications

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“…However, the frequency of abnormal rearrangement in the PBL of the patients with BS was lower than that in the PBL of patients with A-T. Consistent with previous reports [9][10][11], the sequences of the CDR3 region VDJ rearrangement in the peripheral B cells of patients with BS were in-frame and the N-region insertion was also present. These results suggest that the DNA helicase activity of BLM is not directly involved in VDJ recombination.…”

Section: Discussionsupporting

confidence: 90%

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Expression of the BLM gene in human haematopoietic cells

Kaneko

Matsui

Fukao

et al. 1999

Clinical and Experimental Immunology

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Bloom's syndrome (BS) is a rare autosomal recessive disorder characterized by stunted growth, sun-sensitive erythema and immunodeficiency. Chromosomal abnormalities are often observed. Patients with BS are highly predisposed to cancers. The causative gene for BS has been identified as BLM. The former encodes a protein, which is a homologue of the RecQ DNA helicase family, a family which includes helicases such as Esherichia coli RecQ, yeast Sgs1, and human WRN. WRN is encoded by the gene that when mutated causes Werner's syndrome. The function of BLM in DNA replication and repair has not yet been determined, however. To understand the function of BLM in haematopoietic cells and the cause of immunodeficiency in BS, expression of the BLM gene in various human tissues and haematopoietic cell lines was analysed and the involvement of BLM in immunoglobulin rearrangement examined. In contrast to WRN, BLM was expressed strongly in the testis and thymus. B, T, myelomonocytic and megakaryocytic cell lines also expressed BLM. All of the examined sequences at the junction of the variable (V), diversity (D) and joining (J) regions of the immunoglobulin heavy-chain genes were in-frame, and N-region insertions were also present. The frequency of abnormal rearrangements of the T cell receptor was slightly elevated in the peripheral T cells of patients with BS compared with healthy individuals, whereas a higher frequency of abnormal rearrangements was observed in the cells of patients with ataxia-telangiectasia (A-T). In DND39 cell lines, the induction of sterile transcription, which is required for class switching of immunoglobulin heavy-chain constant genes, was correlated with the induction of the BLM gene. Taking into consideration all these results, BLM may not be directly involved in VDJ recombination, but is apparently involved in the maintenance of the stability of DNA.

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Section: Discussionsupporting

confidence: 90%

“…Phung et al [8] reported that MSH2-dependent mismatch repair did not cause hypermutation in immunoglobulin variable genes. Several studies in BS cells have shown that recombination and somatic hypermutation of immunoglobulin variable genes is independent of BLM [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Expression of the BLM gene in human haematopoietic cells

Kaneko

Matsui

Fukao

et al. 1999

Clinical and Experimental Immunology

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“…However, the frequency of abnormal rearrangement in the PBL of patients with BS is lower than the PBL in ataxia-telangiectasia. Consistent with a previous report on peripheral B-cells from patients with BS, the sequences of the CDR3 region in the VDJ rearrangement were in-frame and insertion of the N region was also detected [15][16][17]. These results suggested that the DNA helicase function of BLM is not involved in VDJ recombination directly.…”

Section: Ig Gene Rearrangement In Bs Lymphocytessupporting

confidence: 91%

Clinical features of Bloom syndrome and function of the causative gene, BLM helicase

Kaneko¹,

Kondo

2004

Expert Review of Molecular Diagnostics

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Bloom syndrome is a rare autosomal recessive genetic disorder characterized by growth deficiency, unusual facies, sun-sensitive telangiectatic erythema, immunodeficiency and predisposition to cancer. The causative gene for Bloom syndrome is BLM, which encodes the BLM RecQ helicase homolog protein. The first part of this review describes a long-term follow-up study of two Bloom syndrome siblings. Subsequently, the focus is placed on the functional domains of BLM. Laboratory diagnosis of Bloom syndrome by detecting mutations in BLM is laborious and impractical, unless there are common mutations in a population. Immunoblot and immunohistochemical analyses for the detection of the BLM protein using a polyclonal BLM antibody, which are useful approaches for clinical diagnosis of Bloom syndrome, are also described. In addition, a useful adjunct for the diagnosis of Bloom syndrome in terms of the BLM function is investigated, since disease cells must have the defective BLM helicase function. This review also discusses the nuclear localization signal of BLM, the proteins that interact with BLM and tumors originating from Bloom syndrome.

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“…Total RNA was obtained from 1–2 × 10 6 PBMCs from pretreatment and the first posttreatment sample and reverse transcribed into complementary DNA (cDNA) using random hexamers (Gibco BRL, Gaithersburg, MD). IgG VH‐26 (3‐23, DP‐47) cDNA libraries were obtained by polymerase chain reaction (PCR) using 5′ VH‐26 FR1 primer and a 3′ IgG specific primer, as previously described (17, 18). One round of 35 cycles of PCR was performed using Pfu I polymerase (Stratagene, La Jolla, CA) followed by a 10‐minute extension with Taq polymerase (Roche Molecular Systems, Branchburg, NJ).…”

Section: Methodsmentioning

confidence: 99%

The effect of anti‐CD40 ligand antibody on B cells in human systemic lupus erythematosus

Huang¹,

Sinha²,

Newman³

et al. 2002

Arthritis & Rheumatism

153

106

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Objective. To determine the immunologic effects of anti-CD40 ligand (anti-CD40L) therapy in 5 patients with systemic lupus erythematosus nephritis who participated in an open-label study of a humanized anti-CD40L monoclonal antibody.Methods. Serum and peripheral blood mononuclear cells were obtained before, during, and after treatment, and the frequency of Ig and anti-DNA antibody-secreting B cells was analyzed by enzymelinked immunospot assay and by analysis of EpsteinBarr virus (EBV)-transformed B cell lines. To determine the effect of treatment on somatic mutation of Ig genes, reverse transcriptase-polymerase chain reaction was performed on messenger RNA from 4 patients, using primers specific for the DP-47 heavy chain gene and for IgG. Finally, B cell phenotype was investigated using flow cytometry.Results. Even a brief period of treatment with anti-CD40L markedly reduced the frequency of IgG and IgG anti-DNA antibody-producing B cells, and these changes persisted for several months after cessation of treatment. To confirm these findings, EBV-transformed B cell lines were screened from each of 3 patients, and a 10-fold decrease in anti-DNA antibody-secreting cell lines was found after treatment in all 3 patients. Few differences in mutation patterns were observed before and after treatment; however, the frequency of germlineencoded DP-47 sequences was significantly increased before treatment and normalized following treatment. Flow cytometric analysis of B cells revealed expansion of a CD27؊/IgD؊ B cell subset in some of the patients, which did not change with treatment.Conclusion. These are the first mechanistic studies of the effect of anti-CD40L therapy in human autoimmune disease. The results suggest that further studies of CD40L blockade are warranted.

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Somatic hypermutation of immunoglobulin genes is independent of the Bloom's syndrome DNA helicase

Cited by 17 publications

References 36 publications

Expression of the BLM gene in human haematopoietic cells

Expression of the BLM gene in human haematopoietic cells

Clinical features of Bloom syndrome and function of the causative gene, BLM helicase

The effect of anti‐CD40 ligand antibody on B cells in human systemic lupus erythematosus

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