The lupus-prone BXSB strain: the Yaa gene model of systemic lupus erythematosus

Merino, Ramón; Fossati, Liliane; Izui, Shozo

doi:10.1007/bf00195291

Cited by 24 publications

(12 citation statements)

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“…7 Furthermore, we recently reported that not only male BXSB/MpJ-Yaa mice, but also female BXSB/MpJ mice, clearly exhibit symptoms of age-related autoimmune disease onset, such as increased spleen weights, elevated serum autoantibodies and glomerulonephritis, without the contribution of the Yaa mutation. 44,45 For the BXSB/MpJ strain, age-related autoimmune disease onset was attributed to the expression of immune-associated genes in the telomeric regions of chromosome 1. 45 Therefore, gene mutations as well as genetic backgrounds associated with the immune response may also be important in the development of MFALCs and lung cellular infiltration in murine autoimmune disease models.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of mediastinal fat‐associated lymphoid cluster development and lung cellular infiltration in murine autoimmune disease models and the corresponding normal control strains

2015

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SummaryWe previously discovered mediastinal fat-associated lymphoid clusters (MFALCs) as novel lymphoid clusters associated with mediastinal fat tissue in healthy mice. However, no data about their morphology in immune-associated disease conditions, and their relationship with lung infiltration, is available to date. In the present study, we compared the morphological features of MFALCs in 4-month-old male murine autoimmune disease models (MRL/MpJ-lpr mice and BXSB/MpJ-Yaa mice) with those of the corresponding control strains (MRL/MpJ and BXSB/MpJ, respectively). In addition, we analysed their correlation with lung infiltration. Furthermore, immunohistochemistry for CD3, B220, Iba1, Gr1 and BrdU was performed to detect T cells and B cells, macrophages, granulocytes and proliferating cells, respectively. The spleen weight to body weight ratios and anti-double-stranded DNA autoantibody titres were found to be significantly higher in the autoimmune models than in the control strains. Furthermore, the autoimmune model presented prominent MFALCs, with a significantly greater ratio of lymphoid cluster area to total mediastinal fat tissue area, and more apparent diffused cellular infiltration into the lung lobes than the other studied strains. Higher numbers of T and B cells, macrophages and proliferating cells, but fewer granulocytes, were observed in the autoimmune models than in the control strains. Interestingly, a significant positive Pearson's correlation between the size of the MFALCs and the density of CD3-, B220-and Iba1-positive cells in the lung was observed. Therefore, our data suggest a potentially important role for MFALCs in the progression of lung disease. However, further investigation is required to clarify the pathological role of MFALCs in lung disease, especially in inflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Comparative analysis of mediastinal fat‐associated lymphoid cluster development and lung cellular infiltration in murine autoimmune disease models and the corresponding normal control strains

2015

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“…The mouse strains ((NZB Â NZW)F1, MRL/lpr, BXSB) spontaneously develop anti-dsDNA antibodies and an SLE-like disease, which evokes some of the symptoms of human SLE like proteinuria and glomerulonephritis [29][30][31][32][33][34]. However, these animal models do not reproduce the severe complicated clinical manifestation found in humans [35][36][37][38].…”

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confidence: 99%

“…To circumvent this problem, we employed a dsDNA-mimicking decapeptide DWEYSVWLSN, which is recognized by the pathogenic antidsDNA antibodies and may be used instead of native DNA [27]. A protein chimeric molecule containing copies of the DNAmimotope peptide bound to anti-human CD35 mAb was constructed, able to cross-link cell surface BCR with the inhibitory CR1 on self-reactive DNA-specific B cells from SLE patients [28].The mouse strains ((NZB Â NZW)F1, MRL/lpr, BXSB) spontaneously develop anti-dsDNA antibodies and an SLE-like disease, which evokes some of the symptoms of human SLE like proteinuria and glomerulonephritis [29][30][31][32][33][34]. However, these animal models do not reproduce the severe complicated clinical manifestation found in humans [35][36][37][38].…”

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confidence: 99%

Elimination of autoreactive B cells in humanized SCID mouse model of SLE

Kerekov¹,

Mihaylova²,

Grozdev³

et al. 2011

Eur J Immunol

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Although the exact etiology of systemic lupus erythematosus (SLE) remains elusive, B-cell hyperactivity and production of autoantibodies directed to components of the cell nucleus are a well-established pathogenetic mechanism of the disease. Therefore, the targeted inhibition of DNA-specific B cells is a logical therapeutic approach. The complement receptor type 1 (CR1, CD35) has been shown to suppress human B-cell activation and proliferation after co-cross-linking with the BCR, and may serve as a mediator for negative signal delivery. In order to evaluate this therapeutic approach in a human-like system, we used immune-restricted SCID mice transferred with PBMCs from SLE patients. The tolerance of these humanized SCID mice to native DNA was re-established after administration of a chimeric molecule consisting of a CR1-specific mAb coupled to the decapeptide DWEYSVWLSN that mimics dsDNA. The generated protein-engineered chimera was able to co-cross-link selectively native DNA-specific BCR with the B-cell inhibitory receptor CR1, thus delivering a strong inhibitory signal.Key words: Chimeric molecules . Inhibitory B-cell receptors . SCID models of SLE IntroductionThe pathogenesis of systemic lupus erythematosus (SLE) is characterized by the formation of autoantibodies against a wide range of self-antigens. Development of this multi-system autoimmune syndrome in many severe cases leads to mortality. SLE patients develop high-titered anti-nuclear antibodies (ANA), the majority of them against double-stranded (ds) DNA. Multiple organs can be involved in human SLE (skin, lung, heart, arteries, nervous system), but kidneys being most severely affected. The pathological changes are provoked by deposition of immune complexes into renal glomeruli, followed by kidney structure damages and development of nephritis and proteinuria [1]. 3301The pathogenetic role of self-specific B cells has been attributed not only to the generation of autoreactive antibodies, but also to their antigen-presenting functions [2,3]. A number of studies have clearly documented the strong correlation between the level of these B cells and disease severity. The efficacy of B-cell depletion therapy further supports the key role of B cells in the pathology of SLE. Activity of any self-specific B cells is regulated by the interplay of multiple factors controlling B-cell proliferation and differentiation. BCR-mediated activation may be counteracted by a number of inhibitory receptors: CD32 (FcgRIIb), CD22, CD5, CD72, CD66a, ILT2, PIR-B, CD279 (PD-1), LAIR-1, as well as the complement receptor type 1 (CR1, CD35). While a reduced expression of these receptors can result in uncontrolled B-cell activation [4,5] and autoimmunity, their cross-linking inhibits B-cell activation and proliferation and may serve for targeted suppressive signal delivery [6,7].Non-specific immunosuppressive drugs are by now the most frequent therapy for autoimmune diseases, including SLE. Their effects are purely symptomatic while most of them are associated with severe side ef...

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“…One particularly important animal model at the forefront of these observations has been the BXSB mouse. This model was derived from a cross between C57BL/6 and SB/Le inbred strains, which resulted in male mice expressing an accelerated, lupus-like autoimmune disease phenotype characterized by production of ANAs and circulating immune complexes causing severe glomerulonephritis [48, 49]. Several subsequent studies have shown that the reason for the male bias in these mice was due to an X-to-Y chromosomal translocation of a gene cluster known as Y autoimmune accelerator ( Yaa ) and that the primary contributor to this accelerated autoimmunity is TLR 7 overexpression [16, 17].…”

Section: Tlrs In Autoimmunitymentioning

confidence: 99%

Targeting Toll-Like Receptors for Treatment of SLE

Horton

Pan

Farris

2010

Mediators of Inflammation

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Toll-like receptors (TLRs) are important innate immune receptors for the identification and clearance of invading pathogens. Twelve TLRs that recognize various conserved components of microorganisms are currently known. Among these, the endosomal TLRs 3, 7/8, and 9 recognize dsRNA, ssRNA, and CpG DNA, respectively. Nucleic acid-sensing TLRs, TLR 7 in particular, have been implicated in systemic lupus erythematosus (SLE) and are thought to exacerbate disease pathology. Activation of these TLRs results in the production of inflammatory cytokines and type I interferon. Genome-wide association studies, single nucleotide polymorphism analyses as well as experimental mouse models have provided evidence of TLR signaling involvement in SLE and other autoimmune diseases. Since activation of these receptor pathways promotes autoimmune phenotypes, inhibitory drugs that target these pathways constitute important new therapeutic strategies for the treatment of systemic autoimmunity.

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The lupus-prone BXSB strain: the Yaa gene model of systemic lupus erythematosus

Cited by 24 publications

References 64 publications

Comparative analysis of mediastinal fat‐associated lymphoid cluster development and lung cellular infiltration in murine autoimmune disease models and the corresponding normal control strains

Comparative analysis of mediastinal fat‐associated lymphoid cluster development and lung cellular infiltration in murine autoimmune disease models and the corresponding normal control strains

Elimination of autoreactive B cells in humanized SCID mouse model of SLE

Targeting Toll-Like Receptors for Treatment of SLE

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