Induction of excessive B cell proliferation and differentiation by an in vitro stimulus in culture in human systemic lupus erythematosus.

Suzuki, Noriaki; Sakane, Tsuyoshi

doi:10.1172/jci113979

Cited by 35 publications

(18 citation statements)

References 40 publications

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“…First, the increased costimulatory molecule expression could result from the B cell hyperresponsiveness to BCR stimuli reported in lupus patients (1)(2)(3)(4). This could lead to a decreased threshold for the activation of naive self-reactive B cells that have escaped anergy induction, and would not normally be activated by virtue of their low BCR affinity or poor availability of self-Ag, or could overcome the relative block in costimulatory molecule induction in anergic self-reactive B cells.…”

Section: Discussionmentioning

confidence: 99%

“…Although disease manifestations in SLE are due predominantly to high avidity somatically mutated class-switched IgG autoantibodies, indicating that T cell-B cell collaboration is essential for the development of autoimmunity, increasing evidence suggests that intrinsically abnormal B cells may drive this process. Indeed, B cells from lupus patients are hyperresponsive to a variety of stimuli demonstrating enhanced proliferation to polyclonal activators (1,2), increased anti-IgM and -IgD mediated intracellular Ca 2ϩ concentration responses (3), increased anti-IgM-induced protein tyrosine phosphorylation (3), and decreased Fc␥RIIb1 inhibition of BCR signaling (4). A hallmark of B cell activation is up-regulation of the costimulatory molecules CD80 and CD86.…”

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confidence: 99%

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Expanded Population of Activated Antigen-Engaged Cells within the Naive B Cell Compartment of Patients with Systemic Lupus Erythematosus

Chang

McKenzie

Bonventi

et al. 2008

The Journal of Immunology

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Polyclonal B cell activation is a well-described feature of systemic lupus erythematosus (SLE), but the immune mechanisms leading to this activation are unclear. To gain insight into these processes, we extensively characterized the activated peripheral blood B cell populations in SLE. PBMC from lupus patients and healthy controls were stained with various combinations of conjugated Ab to identify distinct peripheral B cell subsets, and activation was assessed by measurement of forward scatter and CD80 or CD86 expression using flow cytometry. SLE patients had altered proportions of several B cell subsets, many of which demonstrated increased activation as assessed by forward scatter. This activation occurred at an early developmental stage, as B cells in the transitional (T2) stage were already significantly larger than those seen in controls. Increased proportions of CD80- or CD86-expressing cells were also seen in multiple B cell subsets, with the most striking differences observed in the naive CD27−CD23+ population. Within the CD23+ subset, increased costimulatory molecule expression was most pronounced in an IgD+IgMlow population, suggesting that activation follows Ag engagement. Although controls also had IgD+IgMlowCD23+ cells, they were reduced in number and not activated. Thus, there is an altered response to Ig receptor engagement with self-Ags in lupus.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Expanded Population of Activated Antigen-Engaged Cells within the Naive B Cell Compartment of Patients with Systemic Lupus Erythematosus

Chang

McKenzie

Bonventi

et al. 2008

The Journal of Immunology

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“…The mean age (±SD) of these patients was 33.7±10.7 yr (range 19-56 yr) (Table I). Disease activity was assessed at the time ofphlebotomy on the basis of clinical and laboratory findings (fever, arthralgias, rash, oral ulcers or alopecia, elevated erythrocyte sedimentation rate (> 30 mm/h), leukopenia (< 4,000/,ul), hypoalbuminemia (< 3.5 g/dl), hypocomplementemia (CH5e < 20 U/ml), and presence of antinuclear antibody (titer > 1:80) (36 (42)(43)(44)(45). To calculate the number ofantigen-specific spots, the number of spots on antigen uncoated control wells were subtracted from the number on antigen-coated wells.…”

Section: Introductionmentioning

confidence: 99%

Anti-DNA antibody production by CD5+ and CD5- B cells of patients with systemic lupus erythematosus.

Suzuki¹,

Sakane²,

Engleman³

1990

J. Clin. Invest.

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Although the presence of anti-DNA antibody is a hallmark of systemic lupus erythematosus (SLE), neither the subsets of B cells that secrete anti-DNA antibody nor the stimuli responsible for the induction of anti-DNA secretion is known. In particular, the role of CD5+ B cells in human SLE, a distinct subpopulation of antibody-secreting cells shown previously to be a source of anti-DNA antibody in murine models of SLE, is unknown. To approach these questions, we developed a sensitive enzyme-linked immunospot (ELIspot) assay to measure spontaneous secretion of antibody to single-stranded (ss) DNA, double-stranded (ds) DNA, tetanus toxoid, and polyclonal immunoglobulin (Ig) by purified CD5+ and CD5-B cells of 15 SLE patients and 15 healthy control subjects. The B cells of only 1 of 15 healthy subjects secreted a significant level of anti-ssDNA antibody, and none secreted anti-dsDNA. By contrast, in the majority of SLE patients both CD5+ and CD5-B cells secreted IgG and/or IgM anti-ssDNA as well as antidsDNA antibody. Further analysis of the anti-ssDNA response revealed that the level of IgG and IgM anti-DNA antibody secretion by CD5-B cells correlated closely with the level of polyclonal Ig ptoduction by the same subpopulation (r = 0.81 and 0.70, respectively). In contrast, production of anti-DNA by CD5+ B cells occurred independently of polyclonal Ig production by both CD5+ and CD5-B cell subpopulations. These results suggest that in human SLE there exist two anti-DNA antibody-producing B cell subpopulations with distinct induction mechanisms: one (CD5+), which independently secretes anti-DNA, and another (CD5-), which produces anti-DNA as an apparent consequence of polyclonal B cell activation. (J. Clin. Invest. 1990. 85:238-247.) anti-DNA antibody .

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“…An intrinsic propensity of lupus B cells to proliferate and undergo accelerated class switch DNA recombination (CSR) has been suggested by experiments that documented increased numbers of IgG-secreting cells among high density peripheral blood B cells, even when cultured in the absence of mitogens or exogenous cytokines. [32,33] Genetic factors may contribute to accelerated Ig class switching, as suggested by the development of IgG antihistone/DNA autoantibodies and drug-induced lupus in only a subset of procainamidetreated individuals. [34] In the NZB × NZW F1 murine lupus model, the accelerated Ig class switching observed is controlled by the NZW genome.…”

Section: Introductionmentioning

confidence: 99%

Ongoing Immunoglobulin Class Switch DNA Recombination in Lupus B Cells: Analysis of Switch Regulatory Regions

et al. 2004

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Inflammation and tissue damage in systemic lupus erythematosus (SLE) are mediated by classswitched autoantibodies reactive with nucleic acids, nucleic acid-binding proteins, phospholipids and other self-antigens. While some healthy individuals produce IgM antibodies with specificities similar to those of lupus patients, immunoglobulin class switching to mature downstream isotypes appears to be required for the generation of pathogenic autoantibodies. To characterize the cellular and molecular basis of pathogenic autoantibody production in SLE, we studied the capacity of peripheral blood B cells of naïve phenotype from patients with SLE, rheumatoid arthritis (RA) or healthy control subjects to spontaneously switch to IgG and IgA. In addition, we determined the DNA sequences of the upstream evolutionary conserved sequence (ECS)-Iγ promoter regulatory regions that control germline I H -C H transcription and class switch DNA recombination (CSR) to IgG 1 , IgG 2 and IgG 4 . IgM + IgD + B cells from patients with SLE, but not those from RA or healthy control subjects, underwent spontaneous CSR, as assessed by expression of germline Iγ1-Cγ1, Iγ2-Cγ2, Iγ3-Cγ3, Iγ4-Cγ4 and Iα1-Cα1 transcripts, mature (switched) V H DJ H -Cγ1, V H DJ H -Cγ2, V H DJ H -Cγ3 and V H DJ H -Cα1 transcripts and secreted IgG and IgA. Although polymorphic DNA sequences were identified in the ECS-Iγ1, ECS-Iγ2 and ECS-Iγ4 promoter regions, the transcription factor-binding sites that mediate germline Iγ-Cγ transcription were conserved in patients and controls. However, distinct patterns of nuclear protein binding to an ECS-Iγ promoter sequence that contains both positive and negative regulatory elements were observed in SLE patients and controls. These results support a role for exogenous signals, such as through CD40 ligation, rather than altered genomic sequence, in the increased production of class switched autoantibodies in SLE. ‡

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Induction of excessive B cell proliferation and differentiation by an in vitro stimulus in culture in human systemic lupus erythematosus.

Cited by 35 publications

References 40 publications

Expanded Population of Activated Antigen-Engaged Cells within the Naive B Cell Compartment of Patients with Systemic Lupus Erythematosus

Expanded Population of Activated Antigen-Engaged Cells within the Naive B Cell Compartment of Patients with Systemic Lupus Erythematosus

Anti-DNA antibody production by CD5+ and CD5- B cells of patients with systemic lupus erythematosus.

Ongoing Immunoglobulin Class Switch DNA Recombination in Lupus B Cells: Analysis of Switch Regulatory Regions

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