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, Meredith A.; Marion, Tony N.

doi:10.4049/jimmunol.172.11.6568

Cited by 15 publications

(16 citation statements)

References 51 publications

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“…Sle3, the third NZW lupus susceptibility locus also promoted anti-DNA Ab production in response to prolactin in another anti-DNA BCR Tg model [121]. In contrast to these findings, and previous reports on this model [59,119], analyses of lupus-prone BWF1 mice bearing the anti-DNA ''3H9'' Tg revealed that B-cells from such mice displayed normal tolerance to DNA in that they were adequately anergized; the reasons for these differences are presently unknown [122].…”

Section: Molecules Involved In Lymphocyte Apoptosis/survivalcontrasting

confidence: 77%

Understanding B-cell tolerance through the use of immunoglobulin transgenic models

Kumar

Mohan

2007

Immunol Res

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The appearance of autoantibodies in autoimmune diseases such as lupus suggests that B-cell tolerance to self is breached. Hence it becomes important to unravel the precise cellular and molecular mechanisms that are responsible for violations in various B-cell tolerance checkpoints in autoimmune diseases. B-cell immunoglobulin or B-cell receptor transgenic models have been of immense aid in uncovering many of these key tolerance checkpoints during normal B-cell development. By breeding these transgenic models onto mice that are engineered to lack or hyperexpress various B-cell molecules, including signaling intermediates, researchers have delineated the role of these molecules in B-cell tolerance. These transgenic models have also been useful in delineating the impact of various lupus prone genomes and lupus susceptibility loci on B-cell tolerance. This review focuses on some of the more well-studied B-cell receptor transgenic models and the lessons they have taught us over the past two decades.

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Section: Molecules Involved In Lymphocyte Apoptosis/survivalcontrasting

confidence: 77%

Understanding B-cell tolerance through the use of immunoglobulin transgenic models

Kumar

Mohan

2007

Immunol Res

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“…To analyze the mechanisms for dysregulation of the autoantibody response in TLR7 over-expressing W/B males and for the loss of B cell tolerance following exogenous IFNα administration in females we generated W/B mice bearing the site directed anti-CL/DNA autoantibody V H transgene 3H9 (9). V H 3H9 is a heavy chain isolated from an anti-DNA antibody spontaneously produced in MRL/lpr mice; it pairs with a wide variety of V light chains to generate DNA and non-DNA binding antibodies as well as low affinity anti-CL antibodies (10).…”

Section: Introductionmentioning

confidence: 99%

TheYaaLocus and IFN-α Fine-Tune Germinal Center B Cell Selection in Murine Systemic Lupus Erythematosus

Moisini

Huang

Bethunaickan

et al. 2012

The Journal of Immunology

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Male NZW/BXSB.Yaa (W/B) mice express two copies of TLR7 and develop pathogenic autoantibodies whereas females with only one copy of TLR7 have attenuated disease. Our goal was to analyze the regulation of the autoantibody response in male and female W/B mice bearing the autoreactive site-directed heavy chain transgene 3H9. Serum anti-dsDNA antibodies appeared in males at 12 weeks and most had high titer IgG anti-dsDNA and anti-cardiolipin antibodies and developed >300mg/dl proteinuria by 8 months. Females had only low titer IgG anti-CL antibodies and none developed proteinuria by 1 year. Males had a smaller marginal zone (MZ) than females with a repertoire that was distinct from the follicular repertoire, indicating that the loss of MZ B cells was not due to diversion to the follicular compartment. Vk5-43 and Vk5-48, that were rare in the naïve repertoire, were markedly overrepresented in the GC repertoire of both males and females but the VJ junctions differed between males and females with higher affinity autoreactive B cells being selected into the GCs of males. Administration of IFNα to females induced anti-cardiolipin and anti-DNA autoantibodies and proteinuria and was associated with a male pattern of junctional diversity in Vk5-43 and Vk5-48. Our studies are consistent with the hypothesis that presence of the Yaa locus, that includes an extra copy of Tlr7, or administration of exogenous IFNα relaxes the stringency for selection in the germinal centers resulting in increased autoreactivity of the antigen driven B cell repertoire.

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“…The present results may explain why autoimmune female BWF1 transgenic for V H of the 3H9 anti-DNA mAb (33, 34) do not develop nephritis (35). 3H9 mAb binds DNA and chromatin (36) but does not bind BM.…”

Section: Discussionmentioning

confidence: 69%

“…BALB/c mice injected with the 3H9 hybridoma had relatively low glomerular immunofluorescence and disease scores compared with mice injected with 163p.77 or 163p.132 hybridomas (31). The majority of anti-DNA hybridomas from V H 3H9 transgenic BWF1 had V H 3H9 H chains (39). Likely those mAbs could not bind BM and could not initiate disease.…”

Section: Discussionmentioning

confidence: 99%

Anti-DNA autoantibodies initiate experimental lupus nephritis by binding directly to the glomerular basement membrane in mice

Krishnan

Wang

Marion

2012

Kidney International

Self Cite

117

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The strongest serological correlate for lupus nephritis is antibody to double-stranded DNA although the mechanism by which anti-DNA antibodies initiate lupus nephritis is unresolved. Most recent reports indicate that anti-DNA must bind chromatin in the glomerular basement membrane or mesangial matrix to form glomerular deposits. Here we determined whether direct binding of anti-DNA antibody to glomerular basement membrane is critical to initiate glomerular binding of anti-DNA in experimental lupus nephritis. Mice were co-injected with IgG monoclonal antibodies or hybridomas with similar specificity for DNA and chromatin but different IgG subclass and different relative affinity for basement membrane. Only anti-DNA antibodies that bound basement membrane bound to glomeruli, activated complement, and induced proteinuria whether injected alone or co-injected with a non-basement membrane-binding anti-DNA antibody. Basement membrane-binding anti-DNA antibodies co-localized with heparan sulfate proteoglycan in glomerular basement membrane and mesangial matrix but not with chromatin. Thus, direct binding of anti-DNA antibody to antigens in the glomerular basement membrane or mesangial matrix may be critical to initiate glomerular inflammation. This may accelerate and exacerbate glomerular immune complex formation in human and murine lupus nephritis.

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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

Cited by 15 publications

References 51 publications

Understanding B-cell tolerance through the use of immunoglobulin transgenic models

Understanding B-cell tolerance through the use of immunoglobulin transgenic models

TheYaaLocus and IFN-α Fine-Tune Germinal Center B Cell Selection in Murine Systemic Lupus Erythematosus

Anti-DNA autoantibodies initiate experimental lupus nephritis by binding directly to the glomerular basement membrane in mice

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