Overexpression of bcl-2 alters usage of mutational hot spots in germinal center B cells

Kuo, Philip; Alban, Alvaro; Gebhard, David F.; Diamond, Betty

doi:10.1016/s0161-5890(97)00117-x

Cited by 18 publications

(14 citation statements)

References 33 publications

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“…These results are similar to other studies in our laboratory which found that germinal center B cells of mice constitutively expressing bcl-2 show no decrease in frequency of somatic mutation of Ig genes, but a decreased targeting of mutation to putative mutational hot spots (41). Recent studies have shown that expression of bcl-2 inhibits progression through the cell cycle (42,43).…”

Section: Discussionsupporting

confidence: 91%

Lupus-specific antibodies reveal an altered pattern of somatic mutation.

Manheimer-Lory

Zandman‐Goddard²,

Davidson³

et al. 1997

J. Clin. Invest.

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The F4 idiotype is a heavy chain determinant expressed almost exclusively on IgG immunoglobulins and is highly associated with specificity for double-stranded DNA. Since high-titered F4 expression is present predominantly in sera of patients with systemic lupus erythematosus (SLE), we thought F4ϩ IgG antibodies might constitute a useful subset of immunoglobulins in which to investigate lupus-specific alterations in variable (V) region gene expression or in the process of somatic mutation. This molecular analysis of F4 ϩ B cell lines generated from lupus patients demonstrates that despite the strong association of F4 reactivity with specificity for native DNA, there is no apparent V H gene restriction. Furthermore, V H gene segments encoding these antibodies are also used in protective immune responses.An examination of the process of somatic mutation in F4 ϩ antibodies showed no abnormality in frequency of somatic mutation nor in the distribution of mutations in complementarity-determining regions or framework regions. However, there was a decrease in targeting of mutations to putative mutational hot spots. This subtle difference in mutations present in these antibodies may reflect an intrinsic defect in mutational machinery or, more likely, altered state of B cell activation that affects the mutational process and perhaps also negative selection. (

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Section: Discussionsupporting

confidence: 91%

Lupus-specific antibodies reveal an altered pattern of somatic mutation.

Manheimer-Lory

Zandman‐Goddard²,

Davidson³

et al. 1997

J. Clin. Invest.

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“…Although these genes only temporarily extend cell viability, the dual level of protection thus generated (against cell-intrinsic and cell-extrinsic apoptosis) may play a role in the maturation of the B cell response. Altered patterns of SHM in Bcl-2 transgenic mice is consistent with reduced selective pressure in the absence of cell-intrinsic death (Hande et al, 1998;Kuo et al, 1997). However, affinity maturation does occur in these mice, indicating that other forms of cell death must be overcome if high-avidity BCRs are to be selected.…”

Section: Nf-kb Function In the Germinal Centermentioning

confidence: 72%

Control of B Lymphocyte Apoptosis by the Transcription Factor NF-κB

Sen

2006

Immunity

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B cells maintain homeostasis by balancing cell viability and cell death. B lymphocytes are susceptible to mitochondria- and receptor-initiated cell death at various stages of peripheral differentiation and during immune responses. The inducible transcription factor NF-kappaB enhances cell viability by activating genes that counteract both cell-death pathways. This review uses characteristic features of NF-kappaB activation and downregulation to provide insight into the regulation of B cell apoptosis in the periphery. In particular, the temporal patterns of NF-kappaB induction, differences between Rel family members, and the intersection between canonical and noncanonical signaling pathways in keeping B cells alive are discussed.

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“…Significantly, of the 94 mutations in productive rearrangements, 41 (43%) were found at the "hotspots" targeted in normal germinal center cells ( Figure 7; Table 2). A previous study of S107 sequences from phosphorylcholine-immunized E-Bcl2 22 mice, which analyzed 33 mutations, 37 failed to detect such targeting. The apparent disparity may reflect experimental differences in the latter study-the B-cell-specific expression of the E-Bcl2 transgene, the different genetic background (BALB/c rather than C57BL/6), and prior immunization.…”

Section: Discussionmentioning

confidence: 93%