Development and Selection of Edited B Cells in B6.56R Mice

Sekiguchi, Debora R.; Yunk, Lenka; Gary, David; Charan, Deepshikha; Bhaskar, Suryanarayanan; Allman, David; Weigert, Martin; Prak, Eline T. Luning

doi:10.4049/jimmunol.176.11.6879

Cited by 45 publications

(110 citation statements)

References 56 publications

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“…Overrepresentation of T3 splenic B cells has also been observed in transgenic B6.56R mice (85) and in two other Ig-transgenic models with autoreactive B cells (20,86). In the latter two models, anti-Ars/A1 and anti-HEL/sHEL-transgenic mice, maintenance of the T3 phenotype was found to depend on continuous exposure to self-Ag.…”

Section: Autoreactive T3 Splenic B Cellsmentioning

confidence: 77%

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

Kiefer

Nakajima

Oshinsky

et al. 2008

The Journal of Immunology

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In response to encounter with self-Ag, autoreactive B cells may undergo secondary L chain gene rearrangement (receptor editing) and change the specificity of their Ag receptor. Knowing at what differentiative stage(s) developing B cells undergo receptor editing is important for understanding how self-reactive B cells are regulated. In this study, in mice with Ig transgenes coding for anti-self (DNA) Ab, we report dsDNA breaks indicative of ongoing secondary L chain rearrangement not only in bone marrow cells with a pre-B/B cell phenotype but also in immature/transitional splenic B cells with little or no surface IgM (sIgM−/low). L chain-edited transgenic B cells were detectable in spleen but not bone marrow and were still found to produce Ab specific for DNA (and apoptotic cells), albeit with lower affinity for DNA than the unedited transgenic Ab. We conclude that L chain editing in anti-DNA-transgenic B cells is not only ongoing in bone marrow but also in spleen. Indeed, transfer of sIgM−/low anti-DNA splenic B cells into SCID mice resulted in the appearance of a L chain editor (Vλx) in the serum of engrafted recipients. Finally, we also report evidence for ongoing L chain editing in sIgMlow transitional splenic B cells of wild-type mice.

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Section: Autoreactive T3 Splenic B Cellsmentioning

confidence: 77%

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

Kiefer

Nakajima

Oshinsky

et al. 2008

The Journal of Immunology

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“…Previous studies demonstrated that dsDNA specificity and differentiation into Ab-producing cells of 56R + B cells depend on the background genomes (13,14); B6.56R mice spontaneously produce both IgM and IgG anti-dsDNA Abs, whereas BALB/c.56R mice exhibit enhanced levels of IgM anti-dsDNA Abs compared with those in wild-type mice but lower levels than those in B6.56R mice. In particular, lupus-prone MRL/lpr.56R mice produce 20-fold more IgG-type Abs than do B6.56R mice (14).…”

Section: S Ystemic Lupus Erythematosus (Sle; or Lupus) Is A Chronicmentioning

confidence: 99%

“…B6.Sle1 mice, bearing NZM2410-derived lupussusceptibility intervals, were described previously (19). B6.56R mice were 56R anti-DNA HC KI mice, and the heterozygous mice have two HC alleles differentiated by using anti-allotype Abs: anti-IgM a binds Abs expressed by the 56R allele, and anti-IgM b binds Abs expressed by the endogenous allele (14,15). These transgenic mice were kind gifts from Dr. Martin Weigert (University of Chicago, Chicago, IL).…”

Section: Methodsmentioning

confidence: 99%

“…Hybridoma studies using 56R mice demonstrate that dsDNA binding affinity of 56R + B cells can be avoided by HC editing (replacement of 56R with the upstream region of the HC V region [VH] on the 56R + allele or with HC on the endogenous allele) or pairing with L chain (LC) editors, such as Vk21D (14). The manner and timing of HC editing are still controversial.…”

Section: S Ystemic Lupus Erythematosus (Sle; or Lupus) Is A Chronicmentioning

confidence: 99%

“…The anti-dsDNA H chain (HC) (56R) knock-in (KI) mouse (13)(14)(15)) is a useful model to track the fate of autoreactive B cells in the primary repertoire during peripheral differentiation. Previous studies demonstrated that dsDNA specificity and differentiation into Ab-producing cells of 56R + B cells depend on the background genomes (13,14); B6.56R mice spontaneously produce both IgM and IgG anti-dsDNA Abs, whereas BALB/c.56R mice exhibit enhanced levels of IgM anti-dsDNA Abs compared with those in wild-type mice but lower levels than those in B6.56R mice.…”

Section: S Ystemic Lupus Erythematosus (Sle; or Lupus) Is A Chronicmentioning

confidence: 99%

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The Lupus Susceptibility Locus Sle1 Facilitates the Peripheral Development and Selection of Anti-DNA B Cells through Impaired Receptor Editing

Chang

Kim

et al. 2014

The Journal of Immunology

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Systemic lupus erythematosus is characterized by the spontaneous production of IgG autoantibodies in patients and lupus-prone mice. In this study, we investigated the effect of the Sle1 lupus susceptibility locus on the peripheral development of 56R+ anti-DNA transgenic B cells by tracking 56R+ B cells in mice without (B6.56R) or with (B6.Sle1.56R) the Sle1 locus. Compared with B6.56R mice, B6.Sle1.56R mice exhibited increased class-switched IgG2a anti-DNA Abs in their serum, encoded by the transgene. Interestingly, within the spleen, Sle1 facilitated the development of these cells into clusters of IgG2a class-switched B cells juxtaposed to CD4+ T cells within extrafollicular sites. Through sequence analysis of B cell hybridomas, we also found that B cells from B6.Sle1.56R mice are inefficient at Ig H and L chain editing. Thus, the Ig H chains in Sle1.56R+ B cells are partnered more often with cationic L chains that facilitate DNA binding. Taken together, these findings indicate that the Sle1 lupus-susceptibility locus may facilitate the emergence of anti-DNA B cells by subduing BCR revision and possibly by shaping the extrafollicular development of effector B cells, although the precise molecular mechanisms await further study.

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Caspase‐activated DNase is required for maintenance of tolerance to lupus nuclear autoantigens

Jog¹,

Frisoni²,

Shi³

et al. 2012

Arthritis & Rheumatism

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Objective Caspase Activated DNase (CAD) is an endonuclease that is activated by active caspase 3 during apoptosis and is responsible for degradation of chromatin into nucleosomal units. These nucleosomal units are then included in apoptotic bodies. The presence of apoptotic bodies is considered important for the generation of auto-antigens in autoimmune diseases such as lupus, which are characterized by the presence of anti-nuclear antibodies. Methods The present study was carried out to determine the role of CAD in Sle1, Sle123 and 3H9 spontaneous models of lupus, where autoimmunity is genetically pre-determined. We also determined the ability of lupus auto-antibodies to bind to CAD deficient or sufficient apoptotic cells. Results The deficiency of CAD resulted in higher anti-dsDNA antibody titers in lupus-prone mice. Surprisingly, the absence of CAD only exacerbated genetically pre-determined autoimmune responses. To further determine whether nuclear modifications are required to maintain tolerance to nuclear auto-antigens, we used the 3H9 mouse, an anti-DNA heavy chain knock-in. In this model, the autoreactive B cells are tolerized by anergy. In line with the Sle1 and Sle123 CAD mutant mice, CAD deficient 3H9 mice spontaneously generated anti-DNA antibodies. We finally show that auto-antibodies with specificities towards histone/DNA complexes bind more to CAD deficient apoptotic cells compared to CAD sufficient apoptotic cells. Conclusions We propose that in mice genetically predisposed to lupus, nuclear apoptotic modifications are required to maintain tolerance. In the absence of these modifications, apoptotic chromatin is abnormally exposed, facilitating the autoimmune response.

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Development and Selection of Edited B Cells in B6.56R Mice

Cited by 45 publications

References 56 publications

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

Antigen Receptor Editing in Anti-DNA Transitional B Cells Deficient for Surface IgM

The Lupus Susceptibility Locus Sle1 Facilitates the Peripheral Development and Selection of Anti-DNA B Cells through Impaired Receptor Editing

Caspase‐activated DNase is required for maintenance of tolerance to lupus nuclear autoantigens

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