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

Tucker, Rebecca M.; Vyse, Timothy J.; Rozzo, Stephen J.; Roark, Christina L.; Izui, Shozo; Kotzin, Brian L.

doi:10.4049/jimmunol.165.3.1665

Cited by 41 publications

(36 citation statements)

References 50 publications

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“…This proximal chromosome 12 region has not been previously linked or associated with serum gp70 and gp70IC levels, and therefore represents a novel locus, specific to NZ mice and observed only in crosses with BALB/c mice. gp70ICs have been implicated in the pathogenesis of murine lupus nephritis (7)(8)(9)(10). This study provides further support for this conclusion, because mice in the B-F 2 cohort with serum gp70IC levels equal to or above the 75th percentile of the entire cohort had a significantly higher degree of renal disease than mice with gp70IC levels equal to or below the 25th percentile ( p ϭ 0.0053).…”

Section: Genetic Linkage Of Serum Gp70 Ag Levelssupporting

confidence: 74%

“…A region on chromosome 13, between 30 and 50 cM from the centromere, was linked to gp70 and gp70IC levels in NZB, NZW, and BXSB mice on a C57BL/10 or C57BL/6 background (9,11,12). A region on distal chromosome 4 was linked to serum gp70 levels in NZB mice on a C57BL/6 background (9), and linkage with serum gp70 and/or serum gp70IC levels has also been demonstrated on chromosome 7 in NZW and 129 mice on a C57BL/6 background (12,13).…”

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confidence: 99%

“…3 Immune complexes (ICs) formed between gp70 and anti-gp70 Abs (gp70IC) have been shown to be present in the glomeruli of diseased New Zealand (NZ) mice (6), and serum gp70IC levels closely correlate with the development of lupus nephritis (7)(8)(9)(10). gp70 provides a unique system to examine autoantibody production in lupus-prone mice, because, unlike antinuclear Abs, the Ag availability can be quantified and potentially manipulated.…”

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confidence: 99%

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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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Section: Genetic Linkage Of Serum Gp70 Ag Levelssupporting

confidence: 74%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Loci in the region of Sle3 on Chr 7 confer susceptibility to lymphadenopathy and antidouble-strand DNA [22] and linkage to glomerulonephritis [23]. On Chr 11, Tucker has identified D11Mit207 (29 cm) as a weak marker associated with serum gp70 [24]. Using BXD RI lines of mice, T-cell proliferative unresponsiveness in NOD mice was mapped to a region on Chr 11 (49 cm) [25].…”

Section: Quantitative Trait Loci (Qtls) Affecting the Haematopoietic mentioning

confidence: 99%

Genetic Dissection of Age‐Related Changes of Immune Function in Mice

et al. 2001

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Understanding of the genetic basis of normal and abnormal development of the immune response is an enormous undertaking. The immune response, at the most minimal level, involves interactions of antigen presenting cells (APCs), T and B cells. Each of these cells produce cell surface and soluble factors (cytokines) that affect both autocrine and paracrine functions. A second level of complexity needs to consider the development of the macrophage/monocyte lineage as well as the production of the common lymphoid precursor which undergoes distinct maturation steps in the thymus and periphery to form mature T cells as well as in BM (BM) and lymphoid organs to form mature B cells. A third level of complexity involves the immune response to infectious agents including viruses and also the response to tumour antigens. In addition, there are imbalances that predispose to decreased responses (immunodeficiencies) or increased responses (autoimmunity). A fourth level of complexity involves attempts to understand the differences in the immune response that occurs at a very young age, in adults, and at a very old age. This review will focus on the use of C57BL/6 J X DBA/2 J (BXD) recombinant inbred (RI) strains of mice to map genetic loci associated with the production of lymphoid precursors in the BM, development of T cells in the thymus, and T-cell responses to stimulation in the peripheral lymphoid organs in adult and in aged mice. Strategies to improve the power and precision in which complex traits such as the age-related immune response can be mapped is limited with the current set of 35 strains of BXD mice. Strategies to increase these strains by generating recombinant intercross (RIX) strains of mice are being developed to enable this large set of lines to detect quantitative trait loci (QTLs) with a much higher consistency and statistical power. More importantly, the resolution with which these QTLs can be mapped would be greatly improved and, in many cases, adequate to carry out direct identification of candidate genes. It is likely that, given the complexity of the immune system development, the number of cells involved in an immune response, and especially the changes in the immune system with ageing, mapping hundreds of genes will be required to fully understand age-related changes in the immune response. This review outlines ongoing and future strategies that will enable the mapping and identification of these genes.

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“…However, several normal strains have equally high levels of serum gp70, indicating that the gp70 autoantigen is not nephritogenic by itself. By studying the progeny of crosses of lupus-prone NZB, NZW and BXSB with B6 or B10 strains, we (5) and others (10,11) mapped a quantitative trait locus (QTL) on chromosome 13 at ϳ37 centiMorgans (cM) from the centromere that was strongly linked with basal levels of serum gp70. This locus mapped to a chromosomal location different from that of previously identified loci, Sgp1 linked to the H2 locus on chromosome 17 (12), and Sgp2 located at the telomeric end of chromosome 7 (13).…”

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confidence: 99%

The Sgp3 Locus on Mouse Chromosome 13 Regulates Nephritogenic gp70 Autoantigen Expression and Predisposes to Autoimmunity

Laporte

Ballester

Mary

et al. 2003

The Journal of Immunology

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By interval mapping of a backcross progeny between New Zealand White (NZW) and C57BL/6 (B6) mice bearing the Y chromosome-linked autoimmune acceleration gene Yaa, we previously identified a genetic locus on mid-chromosome 13, here designated as Sgp3, showing a major effect on the expression of a nephritogenic autoantigen, gp70. In this study, the NZW-derived Sgp3 region was transferred by backcross procedure and marker-assisted selection on the B6 background to produce three independent congenic strains B6.NZW-Sgp3/1, -Sgp3/2, and -Sgp3/3. We show that NZW homozygosity at a single 3 centiMorgans (∼12 megabases (Mb)) interval between markers D13Mit142 and D13Mit254 mediates increased basal serum levels of gp70 in B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice and with a higher degree in males (∼15 μg/ml) than in females (∼9 μg/ml) as compared with B6 (∼2 μg/ml), revealing a gender effect. However, their gp70 levels are still lower than that of NZW mice (∼60 μg/ml). In addition, B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice showed a moderate 2- to 3-fold increase in serum gp70 in response to LPS, which contrasted with over a 10-fold increase in NZW mice. Although both B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice failed to produce significant amounts of gp70 anti-gp70 immune complexes, unexpectedly, aged B6.NZW-Sgp3/2 congenic males bearing the Yaa gene developed increased titers of IgG autoantibodies to DNA and chromatin. Our data indicate that Sgp3 is involved in a complex process of gp70 production under polygenic control and may provide a significant contribution to lupus susceptibility not only through up-regulation of gp70 autoantigen production but also predisposition to autoimmunity.

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

Cited by 41 publications

References 50 publications

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

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

Genetic Dissection of Age‐Related Changes of Immune Function in Mice

The Sgp3 Locus on Mouse Chromosome 13 Regulates Nephritogenic gp70 Autoantigen Expression and Predisposes to Autoimmunity

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