Light Chain Usage in Anti–double-stranded DNA B Cell Subsets: Role in Cell Fate Determination

Spatz, Linda; Saenko, Vladimir; Iliev, Andrey; Jones, Lori; Geskin, Larisa J.; Diamond, Betty

doi:10.1084/jem.185.7.1317

Cited by 62 publications

(74 citation statements)

References 40 publications

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“…The 3-32-Tg also did not include C ␦ and could not be switched to C ␥ . B cells in R4A-␥2b conventional Tg BWF 1 , in contrast, were not anergic and produced Tg-encoded serum anti-DNA at higher titers than in normal, non-Tg BWF 1 mice (30). Although it is not clear why expression of the R4A-␥2b Tg in BWF 1 mice would have a different influence on B cell development and activation than 3H9-or 3-32-, the effect may be due to the effects of expression of C ␥ vs C during B cell development (40).…”

Section: Anergy In Igm Aϩ B Cells In Conventional 3⌯9-and Knock-in 3hmentioning

confidence: 99%

“…V H 3H9 with V8 produces an anti-DNA with ssDNA specificity (29), V H 3H9 with V4 produces an anti-DNA with dsDNA specificity, and V H NP-V8 yields an Ab with unknown specificity. Previous studies have used BWF 1 mice Tg only for the H chain of an anti-DNA Ab (30,31) or a knock-in of the V H for an anti-DNA (32), and each of the previous studies used a different anti-DNA V H Tg. The present study is the first to compare B cell development and anti-DNA Ab production in autoimmuneprone BWF 1 mice Tg for the V H of an anti-DNA Ab inherited either as a J H knock-in or as a conventional H chain Tg.…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

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Tolerance to DNA in (NZB × NZW)F1 Mice That Inherit an Anti-DNA VH as a Conventional μ H Chain Transgene but Not as a VH Knock-in Transgene

Steeves

Marion

2004

The Journal of Immunology

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Lupus-prone (NZB × NZW)F1 (BWF1) mice were made transgenic (Tg) for an anti-DNA Ab inherited either as a conventional VH3H9-μ H chain Tg (3H9-μ) with or without a conventional Vκ8-κ Tg, or a VH3H9 VH knock-in Tg allele (3H9R) with or without a Vκ4 Vκ knock-in Tg allele (Vκ4R). VH3H9 yields an anti-DNA Ab with most L chains including an anti-ssDNA with the Vκ8 Tg and an anti-dsDNA with the Vκ4 Tg. BWF1 mice that inherited the conventional 3H9-μ had normal serum IgM, little to none of which was encoded by 3H9-μ, and only a small percentage of those mice had serum anti-DNA, none of which was transgene encoded. B cells expressing the conventional 3H9-μ Tg were anergic. BWF1 mice that inherited the knock-in 3H9R Tg allele also had normal serum IgM, one-half of which was encoded by 3H9R, and produced anti-DNA encoded by the Tg allele. Most B cells expressing the knock-in 3H9R Tg also had an anergic phenotype. The results indicate that autoimmune-prone BWF1 mice initially develop effective B cell tolerance to DNA through anergy, and anergy was sustained in 3H9-μ Tg peripheral B cells but not in 3H9R Tg B cells. B cells expressing the 3H9R knock-in Tg allele were able to achieve an activation threshold that B cells expressing the 3H9-μ conventional Tg could not. The maintenance of B cell tolerance to DNA in autoimmune-prone BWF1 mice appears to differ from both normal mice and autoimmune-prone MRLlpr/lpr mice.

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Section: Anergy In Igm Aϩ B Cells In Conventional 3⌯9-and Knock-in 3hmentioning

confidence: 99%

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

Tolerance to DNA in (NZB × NZW)F1 Mice That Inherit an Anti-DNA VH as a Conventional μ H Chain Transgene but Not as a VH Knock-in Transgene

Steeves

Marion

2004

The Journal of Immunology

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“…R4A-␥2b transgenic BALB/c mice were bred at the animal facility of the Albert Einstein College of Medicine. The R4A-␥2b mice are transgenic for the H chain of the nephritogenic R4A anti-DNA Ab (21,22). Eight 16-wk-old female mice were included in the experiments.…”

Section: Transgenic Micementioning

confidence: 99%

“…Total RNA was extracted from all transgene-expressing clones regardless of their Vk usage. RT-PCR was performed using a 5Ј FR1 Vk primer and a 3Ј constant region primer as described elsewhere (21). The PCR products were purified by Qiaquick purification kit (Qiagen).…”

Section: B Cell Hybridomasmentioning

confidence: 99%

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Tamoxifen Blocks Estrogen-Induced B Cell Maturation but Not Survival

Peeva

Jeganathan

Diamond

2005

The Journal of Immunology

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Estrogen treatment has been shown not only to exacerbate disease activity and accelerate death in spontaneous murine models of lupus but also to induce a lupus-like phenotype in nonspontaneously autoimmune mice. In mice transgenic for the H chain of an anti-DNA Ab, estrogen rescues naive autoreactive B cells that normally are deleted and causes them to mature to a marginal zone phenotype. Estrogen further leads to the activation of this population causing an elevation of serum anti-DNA Ab titers and renal disease. This study was designed to evaluate the therapeutic potential of tamoxifen, a selective estrogen receptor modulator, on estrogen-induced lupus. Mice treated with both estradiol and tamoxifen showed no elevation in anti-DNA Ab titers and consequently no glomerular IgG. The DNA-reactive B cell population that is rescued by estrogen was present in an anergic state in mice treated with both estradiol and tamoxifen. Estradiol enhances transitional B cell resistance to apoptosis and expands the population of marginal zone B cells; tamoxifen did not impede the enhanced resistance to apoptosis, but prevented the development of autoreactive cells as marginal zone B cells. Thus, estrogen-induced autoimmunity proceeds through two distinct molecular pathways, one affecting survival and the other maturation. Activation, but not survival, of autoreactive B cells can be abrogated by tamoxifen. Drugs that modulate even some of the effects of estrogen may be beneficial in patients with lupus. Eventually, understanding the pathways involved in survival and activation of autoreactive B cells will permit the development of therapeutics that target all relevant pathways.

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Characterization of anti-DNA B cells that escape negative selection

1999

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One of the challenges in the study of autoimmunity is to understand which autoreactive cells are subject to regulation and what mechanisms of regulation are operative. In mice transgenic for the R4A-gamma2b heavy chain of an anti-double stranded (ds) DNA antibody, the gamma2b heavy chain can pair with the full spectrum of endogenous light chains to produce a multitude of antibodies, including anti-dsDNA antibodies of different affinities and fine specificities. We have previously demonstrated the existence of two populations of anti-DNA B cells in non-autoimmune hosts: a high-affinity population which is rendered anergic in vivo, and a second high-affinity population which is deleted. We have now identified a third population of dsDNA-binding B cells. These cells produce germ-line-encoded antibodies with an apparent affinity for dsDNA that is 1 to 4 logs lower than the apparent affinities of antibodies made by anergic or deleted B cells, and represent a non-tolerized population which escapes regulation. Based on its characterization, we can define a molecular threshold for tolerance induction, and can speculate on the fate of these B cells when they are recruited to an immune response and undergo somatic mutation to become high-affinity anti-DNA B cells.

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Light Chain Usage in Anti–double-stranded DNA B Cell Subsets: Role in Cell Fate Determination

Cited by 62 publications

References 40 publications

Tolerance to DNA in (NZB × NZW)F1 Mice That Inherit an Anti-DNA VH as a Conventional μ H Chain Transgene but Not as a VH Knock-in Transgene

Tolerance to DNA in (NZB × NZW)F1 Mice That Inherit an Anti-DNA VH as a Conventional μ H Chain Transgene but Not as a VH Knock-in Transgene

Tamoxifen Blocks Estrogen-Induced B Cell Maturation but Not Survival

Characterization of anti-DNA B cells that escape negative selection

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