Murine serum glycoprotein gp70 behaves as an acute phase reactant.

Hara, Ikuo; Izui, Shozo; Dixon, Frank J.

doi:10.1084/jem.155.2.345

Cited by 47 publications

(48 citation statements)

References 38 publications

(46 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…Moreover, the Sgp3 locus was found to control the gp70 expression of a modified polytropic (mPT) provirus (ssRNA virus), and not of the xenotropic proviruses (NZB-X1 or NZB-X2) shown to accelerate anti-chromatin antibody production in NZB mice [28][29][30]. Interestingly, it has been previously reported that in vivo exposure to poly(I:C) potently increases serum gp70 levels in NZB mice, which suggested a potential role for gp70 as an acute phase reactant [31].Although autoreactive B cells play an integral role in disease pathogenesis and are required to initiate the cellular phenotypic abnormalities in B6.NZBc13 mice, both B6 and congenic B cells were abnormally activated in mixed chimeric mice. These findings suggest that cell extrinsic factors play an important role in augmentation and perpetuation of the autoimmune process.…”

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confidence: 99%

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An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

et al. 2010

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Introgression of a New Zealand Black (NZB) chromosome 13 interval onto a C57BL/6 (B6) background (B6.NZBc13) is sufficient to produce many hallmarks of lupus, including hightitre anti-chromatin antibody production, abnormal B-and T-cell activation, and renal disease. In this study we sought to characterize the immune defects leading to these abnormalities. By generating hematopoietic chimeras and BCR transgenic mice, we show that the congenic autoimmune phenotype can be transferred by BM cells and requires the presence of autoreactive B cells. Using the hen egg white lysozyme immunoglobulin transgenic mouse model, we demonstrate that B-cell anergy, deletion, and receptor editing are intact. Nevertheless, congenic B cells exhibit altered peripheral B-cell selection, as demonstrated by enhanced survival and activation of endogenous B cells with autoreactivity to chromatin and Sm/ribonucleoprotein. Given the autoantibody specificities to nuclear antigens, TLR signalling was assessed. B6.NZBc13 B cells were hyper-responsive to poly(I:C), a TLR3 ligand, demonstrating enhanced proliferation and survival as compared to B6 B cells. Our findings indicate the presence of an intrinsic B-cell defect on NZB chromosome 13 that results in hyper-responsiveness to a dsRNA analogue and implicates its potential supporting role in the generation of autoimmunity in B6.NZBc13 mice. Keywords: Autoimmunity . B cells . TLRs Supporting Information available online IntroductionSystemic lupus erythematosus is a chronic autoimmune disorder characterized by the production of antibodies directed against nuclear antigens (ANAs). Similar to human lupus, the New Zealand Black (NZB) mouse produces antibodies directed against nuclear antigens, develops Coomb's positive hemolytic anaemia, and exhibits a number of phenotypic and functional B-cell abnormalities (reviewed in [1]). Although glomerulonephritis is mild in these mice, severe nephritis develops when the NZB background is crossed onto a permissive MHC haplotype (H-2 bm12 ), indicating that this mouse possesses a full complement of non-MHC lupus susceptibility genes [2].Generation of congenic mice, by introgression of homozygous chromosomal intervals from the NZB mouse strain onto a normal mouse C57BL/6 (B6) background, has been a particularly useful technique for characterizing susceptibility loci and their role in disease genesis [3]. In our mapping study of (B6 Â NZB) F 2 mice, we identified a locus on NZB chromosome (c) 13 that was linked to increased B-cell activation and abnormal IgM production [4]. To further characterize this locus, we generated congenic mice with an NZB c13 interval (denoted B6.NZBc13). B6.NZBc13 mice spontaneously developed autoimmunity characterized by hightitre IgM and IgG anti-chromatin antibody production, increased 527T-cell activation, expansion of DCs, and the development of mild glomerulonephritis [5]. Moreover, as predicted from our mapping study, B6.NZBc13 mice closely recapitulated the abnormal polyclonal B-cell activation and B-cell subset distribution...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

et al. 2010

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“…If so, a stronger correlation of Ag levels with disease might have been observed if production was more completely reduced or eliminated by genetic breeding, knockout, or other gene suppression technologies. It is also possible that with the onset of disease and the corresponding systemic inflammation, genetically low levels of gp70 are subsequently boosted to levels that are adequate for optimal immune complex formation, since gp70 acts as an acute phase reactant (20,21,45,46). One may also have to consider the possible heterogeneity of serum gp70 proteins, most of which are closely related to gp70 on xenotropic virus isolated from NZB mice (5, 7).…”

Section: Discussionmentioning

confidence: 99%

“…The genes responsible for production of serum gp70 most likely represent past integrations of murine leukemia viruses, which have yielded nonfunctional (i.e., virus-free) sites of envelope expression. Studies suggest that most of the serum gp70 is produced by hepatic cells and levels can further increase as an acute phase reactant more than 10-fold in high-producing strains (20,21). It seems likely that higher circulating gp70 levels in the lupus-prone strains may affect the quantity and size of gp70 IC and the development of nephritis.…”

Section: Genetic Control Of Glycoprotein 70 Autoantigen Production Anmentioning

confidence: 99%

Genetic Control of Glycoprotein 70 Autoantigen Production and Its Influence on Immune Complex Levels and Nephritis in Murine Lupus

Tucker¹,

Vyse

Rozzo

et al. 2000

The Journal of Immunology

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The F1 hybrids of New Zealand Black (NZB) and New Zealand White (NZW) mice spontaneously develop an autoimmune disease that serves as a model for human systemic lupus erythematosus. Autoimmunity in (NZB × NZW)F1 mice includes the production of autoantibodies to the endogenous retroviral envelope glycoprotein, gp70, and gp70-anti-gp70 immune complexes (gp70 IC) have been implicated in the development of lupus nephritis in these animals. We used backcross and intercross combinations of C57BL/6 (B6; low gp70 levels) and NZB mice (high gp70 levels) to examine the contribution of serum gp70 Ag levels to the development of gp70 IC and nephritis. Analysis of (B6.H2z × NZB)F1 × NZB backcross mice and (NZB × B6)F2 mice showed a much stronger association of gp70 IC with kidney disease compared with IgG anti-chromatin autoantibodies in both populations of mice. Serum levels of gp70 correlated with production of gp70 IC in mice producing autoantibodies, although the overall effect on nephritis appeared to be small. Genetic mapping revealed three NZB-derived regions on chromosomes 2, 4, and 13 that were strongly linked with increased gp70 levels, and together, accounted for over 80% of the variance for this trait. However, additional linkage analyses of these crosses showed that loci controlling autoantibody production rather than gp70 levels were most important in the development of nephritogenic immune complexes. Together, these studies characterize a set of lupus-susceptibility loci distinct from those that control autoantibody production and provide new insight into the components involved in the strong association of gp70 IC with murine lupus nephritis.

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“…gp70 acts as an acute-phase reactant, with serum levels being enhanced by acute-phase reactant inducers such as bacterial LPS (2) and IL-6 (3). The major source of serum gp70 production is believed to be hepatic parenchymal cells (4). gp70 is detectable in the serum of nearly all inbred mouse strains (5).…”

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confidence: 99%

A Novel Locus Regulates Both Retroviral Glycoprotein 70 and Anti-Glycoprotein 70 Antibody Production in New Zealand Mice When Crossed with BALB/c

Rigby

Rozzo

Gill

et al. 2004

The Journal of Immunology

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Lupus-prone New Zealand Black and New Zealand White mice produce high serum levels of the endogenous retroviral envelope protein gp70 and develop an Ab response to this autoantigen as part of their autoimmune disease. Linkage analysis of two crosses involving New Zealand and BALB/c mice mapped these traits to a group of overlapping loci, including a novel locus on proximal chromosome 12. This locus was linked with serum gp70 and the autoimmune response against it. The linkage of serum gp70 levels to a previously described locus on distal chromosome 4 was also confirmed. Sequence analysis of a candidate gene on distal chromosome 4, Fv1, provided support that this gene may be associated with the control of serum gp70 levels in both New Zealand Black and New Zealand White mice. Linkage data and statistical analysis confirmed a close correlation between gp70 Ag and anti-gp70 Ab levels, and together gave support to the concept that a threshold level of gp70 is required for the production of anti-gp70 Abs. Serum levels of anti-gp70 Abs were closely correlated with the presence of renal disease, more so than anti-dsDNA Abs. Understanding the genetic basis of this complex autoantigen-autoantibody system will provide insight into the pathogenesis of lupus in mice, which may have implications for human disease.

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Murine serum glycoprotein gp70 behaves as an acute phase reactant.

Cited by 47 publications

References 38 publications

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

Genetic Control of Glycoprotein 70 Autoantigen Production and Its Influence on Immune Complex Levels and Nephritis in Murine Lupus

A Novel Locus Regulates Both Retroviral Glycoprotein 70 and Anti-Glycoprotein 70 Antibody Production in New Zealand Mice When Crossed with BALB/c

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