MRL-<i>lpr/lpr</i> Mice Exhibit a Defect in Maintaining Developmental Arrest and Follicular Exclusion of Anti–double-stranded DNA B Cells

Mandik-Nayak, Laura; Seo, Su-jean; Sokol, Caroline L.; Potts, Kathryn M.; Bui, Anh; Erikson, Jan

doi:10.1084/jem.189.11.1799

Cited by 126 publications

(162 citation statements)

References 87 publications

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“…The majority (average Ͼ95%) of Ig ϩ B cells in VH3H9 BALB-lpr/lpr and BALB-gld/gld mice were Ig 1 ϩ (data not shown), as was demonstrated previously for VH3H9 BALB/c and MRLlpr/lpr mice by flow cytometry (17,18). Therefore, we used pan-anti-Ig as well as anti-Ig 1 reagents to identify anti-dsDNA B cells in VH3H9 mice.…”

Section: Identification Of Anti-dsdna B Cellsmentioning

confidence: 90%

“…2A), a phenotype that we and others have attributed to continual Ag encounter (17,18,30,(35)(36)(37)(38)(39)(40)(41)(42). At all ages examined, anti-dsDNA B cells from VH3H9 BALB-lpr/lpr mice had increased levels of B220, as compared with Fas-sufficient VH3H9 BALB/c mice (Fig.…”

Section: Altered Localization and Cell Surface Phenotype Of Anti-dsdnmentioning

confidence: 99%

“…The pairing of the VH3H9 IgH with the V 1 L chain generates an anti-dsDNA Ab (27,28). This facilitates tracking of anti-dsDNA B cells in vivo in a diverse repertoire by the use of anti-Ig reagents (17)(18)(19).…”

Section: Altered Localization and Cell Surface Phenotype Of Anti-dsdnmentioning

confidence: 99%

“…The presence of ANAs and anti-dsDNA Abs in the serum was detected using the ANA and C. luciliae assays, respectively, as previously described (18,30). Binding was detected using either anti-IgM ϩ IgG FITC (together, to detect total Ig) or anti-Ig FITC (all from Southern Biotechnology Associates, Birmingham, AL).…”

Section: Anti-nuclear Ab (Ana) and Crithidia Luciliae Assaysmentioning

confidence: 99%

“…Spleens from experimental mice were prepared and stained as previously described (18,31). The following Abs were used: Cy34.1 FITC or biotin (anti-CD22), RA3-6B2 biotin (anti-B220), GK1.5 FITC or biotin (anti-CD4), HC3 FITC (anti-CD11c), M1/70 FITC (anti-CD11b, Mac-1) (PharMingen), and/or anti-Ig alkaline phosphatase (AP; Southern Biotechnology Associates).…”

Section: Tissue Immunohistochemistrymentioning

confidence: 99%

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Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells

Fields

Sokol

Eaton-Bassiri

et al. 2001

The Journal of Immunology

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Autoantibodies directed against dsDNA are found in patients with systemic lupus erythematosus as well as in mice functionally deficient in either Fas or Fas ligand (FasL) (lpr/lpr or gld/gld mice). Previously, an IgH chain transgene has been used to track anti-dsDNA B cells in both nonautoimmune BALB/c mice, in which autoreactive B cells are held in check, and MRL-lpr/lpr mice, in which autoantibodies are produced. In this study, we have isolated the Fas/FasL mutations away from the autoimmune-prone MRL background, and we show that anti-dsDNA B cells in Fas/FasL-deficient BALB/c mice are no longer follicularly excluded, and they produce autoantibodies. Strikingly, this is accompanied by alterations in the frequency and localization of dendritic cells as well as a global increase in CD4 T cell activation. Notably, as opposed to MRL-lpr/lpr mice, BALB-lpr/lpr mice show no appreciable kidney pathology. Thus, while some aspects of autoimmune pathology (e.g., nephritis) rely on the interaction of the MRL background with the lpr mutation, mutations in Fas/FasL alone are sufficient to alter the fate of anti-dsDNA B cells, dendritic cells, and T cells.

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Section: Identification Of Anti-dsdna B Cellsmentioning

confidence: 90%

Section: Altered Localization and Cell Surface Phenotype Of Anti-dsdnmentioning

confidence: 99%

Section: Altered Localization and Cell Surface Phenotype Of Anti-dsdnmentioning

confidence: 99%

Section: Anti-nuclear Ab (Ana) and Crithidia Luciliae Assaysmentioning

confidence: 99%

Section: Tissue Immunohistochemistrymentioning

confidence: 99%

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Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells

Fields

Sokol

Eaton-Bassiri

et al. 2001

The Journal of Immunology

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Activation‐induced deaminase–deficient MRL/lpr mice secrete high levels of protective antibodies against lupus nephritis

Jiang¹,

Zhao²,

Scearce³

et al. 2011

Arthritis & Rheumatism

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Objective. We previously generated MRL/lpr mice deficient in activation-induced deaminase (AID) that lack isotype switching and immunoglobulin hypermutation. These mice have high levels of unmutated (germline) autoreactive IgM, yet they experienced an increase in survival and an improvement in lupus nephritis that exceeded that of MRL/lpr mice lacking IgG. The purpose of the present study was to test the hypothesis that high levels of germline autoreactive IgM in these mice confer protection against lupus nephritis.Methods. Autoreactive IgM antibodies of various specificities, including antibodies against doublestranded DNA (dsDNA), from AID-deficient MRL/lpr mice were given to asymptomatic MRL/lpr mice, and the levels of cytokines, proteinuria, immune complex deposition in the kidneys, and glomerulonephritis were examined. Novel AID-deficient MRL/lpr mice that lack any antibodies were generated for comparison to AIDdeficient MRL/lpr mice that secrete only IgM.Results. Treatment with IgM anti-dsDNA resulted in a dramatic improvement in lupus nephritis. Other autoreactive IgM antibodies, such as antiphospholipid and anti-Sm, did not alter the pathologic changes. Secretion of proinflammatory cytokines by macrophages and the levels of inflammatory cells and apoptotic debris in the kidneys were lower in mice receiving IgM anti-dsDNA. Protective IgM derived from AID-deficient MRL/lpr mice displayed a distinct B cell repertoire, with a bias toward members of the V H 7183 family. Conclusion. IgM anti-dsDNA protected MRL/lpr mice from lupus nephritis, likely by stopping the inflammatory cascade leading to kidney damage. A distinct repertoire of V H usage in IgM anti-dsDNA hybridomas from AID-deficient mice suggests that there is enrichment of a dedicated B cell population that secretes unmutated protective IgM in these mice.Autoreactive B cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE) (1-5). SLE is characterized by the circulation of autoantibodies and the deposition of immune complexes in various tissues, particularly the kidneys, leading to glomerulonephritis (6). Hallmark SLE autoantibodies include antibodies against double-stranded DNA (antidsDNA) and ribonucleoproteins (7). These pathogenic autoantibodies form immune complexes that trigger inflammatory responses, leading to organ damage. Factors that have been implicated in SLE and in lupus-like syndromes in mice include defective apoptosis, Toll receptor signaling, defects in B and T cell tolerance, complement activation, cytokine regulation, and defects in endothelial cell function (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).Strong evidence suggests an antibodyindependent contribution of B cells to autoimmunity (20). Lupus-prone mice with B cells unable to secrete antibodies were found to develop a milder form of lupus nephritis, while mice without B cells did not. The evidence suggests that B cells contribute to autoimmunity by activating autoreactive T cells, likely as antigenpresenting cells (20).MRL-Fas lpr/lpr (MRL/lp...

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Anti‐chromatin antibodies drive in vivo antigen‐specific activation and somatic hypermutation of rheumatoid factor B cells at extrafollicular sites

et al. 2007

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A dominant type of spontaneous autoreactive B cell activation in murine lupus is the extrafollicular generation of plasmablasts. The factors governing such activation have been difficult to identify due to the stochastic onset and chronic nature of the response. Thus, the ability to induce a similar autoreactive B cell response with a known autoantigen in vivo would be a powerful tool in deciphering how autoimmune responses are initiated. We report here the establishment and characterization of a system to initiate autoreactive extrafollicular B cell responses, using IgG anti-chromatin antibodies, that closely mirrors the spontaneous response. We demonstrate that exogenously administered anti-chromatin antibody, presumably by forming immune complexes with released nuclear material, drives activation of rheumatoid factor B cells in AM14 Tg mice. Anti-chromatin elicits autoreactive B cell activation and development into antibody-forming cells at the T zone/red pulp border. Plasmablast generation occurs equally in BALB/c, MRL/+ and MRL/lpr mice, indicating that an autoimmuneprone genetic background is not required for the induced response. Importantly, infused IgG anti-chromatin induces somatic hypermutation in the absence of a GC response, thus proving the extrafollicular somatic hypermutation pathway. This system provides a window on the initiation of an autoantibody response and reveals authentic initiators of it.See accompanying commentary: http://dx

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MRL-lpr/lpr Mice Exhibit a Defect in Maintaining Developmental Arrest and Follicular Exclusion of Anti–double-stranded DNA B Cells

Cited by 126 publications

References 87 publications

Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells

Fas/Fas Ligand Deficiency Results in Altered Localization of Anti-Double-Stranded DNA B Cells and Dendritic Cells

Activation‐induced deaminase–deficient MRL/lpr mice secrete high levels of protective antibodies against lupus nephritis

Anti‐chromatin antibodies drive in vivo antigen‐specific activation and somatic hypermutation of rheumatoid factor B cells at extrafollicular sites

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