Autoantigen Glycoprotein 70 Expression Is Regulated by a Single Locus, Which Acts as a Checkpoint for Pathogenic Anti-Glycoprotein 70 Autoantibody Production and Hence for the Corresponding Development of Severe Nephritis, in Lupus-Prone BXSB Mice1

Haywood, M; Vyse, Timothy J.; McDermott, Aileen; Thompson, E. M.; Ida, Akinori; Walport, Mark J.; Izui, Shozo; Morley, Bernard J

doi:10.4049/jimmunol.167.3.1728

Cited by 36 publications

(39 citation statements)

References 31 publications

(35 reference statements)

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“…However, as described above, it is apparent that other genetic factors also contribute to the loss of tolerance to gp70. There seems to be a threshold level of serum gp70, ϳ1.1 g/ml, under which minimal gp70IC is produced, a phenomenon shown previously by Haywood et al (11) in BXSB ϫ C57BL/10 crosses. The presence of individuals that have high serum gp70 levels and low gp70IC levels indicate there are other genetic factors that drive the production of gp70IC, and that it is not solely reliant on high levels of serum gp70 Ag.…”

Section: Relationship Between Gp70 Ag and Anti-gp70icsmentioning

confidence: 60%

“…NZB and NZW share the Fv1 nr allele (28), which encodes a protein that is polymorphic, truncated, and functionally different compared with the product of the Fv1 b allele (28). A previous study in which linkage to gp70 was examined in a BXSB ϫ C57BL/10 cross demonstrated no linkage to the distal region of chromosome 4 (11). Based on genotype (Table V), we confirm that NZB and NZW were identical in sequence and polymorphic features, and carry the Fv1 nr allele.…”

Section: Proposed Mechanism Of Chromosome 4 Locusmentioning

confidence: 99%

“…Thus, Fv1 is a good candidate gene to explain the linkage data in NZ mice. In a study of genetic associations with gp70 and gp70IC in BXSB mice crossed with C57BL/10, no linkage to distal chromosome 4 was observed (11). Therefore, we investigated the polymorphisms in Fv1, comparing NZB, NZW, BXSB, C56BL/10, and BALB/c strains.…”

Section: Investigation Of Fv1 As a Candidate Gene For The Chromosome mentioning

confidence: 99%

“…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%

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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: Relationship Between Gp70 Ag and Anti-gp70icsmentioning

confidence: 60%

Section: Proposed Mechanism Of Chromosome 4 Locusmentioning

confidence: 99%

Section: Investigation Of Fv1 As a Candidate Gene For The Chromosome 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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“…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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Association between nuclear antigens and endogenous retrovirus in the generation of autoantibody responses in murine lupus

Tucker¹,

Roark²,

Santiago-Raber³

et al. 2004

Arthritis & Rheumatism

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Objective. (NZB ؋ NZW)F 1 (NZB/NZW) mice and other strains of mice with experimental lupus frequently produce autoantibodies to both chromatin constituents and murine leukemia virus envelope gp70. These autoantibody responses are involved in the glomerulonephritis that develops in these mice. This study was undertaken to explore possible connections between these 2 antigen systems.Methods. We used monoclonal antibodies (mAb) derived from unmanipulated NZB/NZW mice to investigate the specificity of anti-gp70 and antichromatin autoantibodies for chromatin constituents, recombinant gp70, NZB retroviruses, and retrovirally infected cells. NZB mice were also immunized with retroviral particles and followed up for study of autoantibody responses.Results. Spontaneous autoantibody production in NZB/NZW mice reflects high-level autoimmune responses to nuclear antigens and gp70 that do not cross-react with the other antigen. However, both types of autoantibodies have the capability to bind to the endogenous xenotropic virions NZB-X1 or NZB-X2. The mAbs to recombinant gp70 cross-reacted only with the NZB-X2 virus, whereas the antichromatin mAb frequently bound to both retroviruses. The binding of antichromatin autoantibodies was mediated by nuclear material complexed to the retrovirus, and studies showed that this material can be acquired through the budding process. Immunization with NZB-X1 or NZB-X2 virions induced strong responses to gp70 and was much more effective than chromatin at inducing autoantibody responses to chromatin and doublestranded DNA in NZB mice.Conclusion. These studies suggest that retroviral virions may harbor nuclear antigens and may link together the autoimmune responses to the disparate antigens, chromatin and gp70.The F 1 hybrid of NZB and NZW mice spontaneously develops an autoimmune disease characterized by production of IgG autoantibodies and development of a severe immune complex (IC)-mediated glomerulonephritis (1). These (NZB ϫ NZW)F 1 (NZB/NZW) mice are considered to be an excellent model of human systemic lupus erythematosus. The major known targets of autoantibodies in this model are chromatin and its major constituents (DNA and histones) and the murine leukemia virus (MuLV)-derived serum glycoprotein gp70 (1-5). Both antichromatin and anti-gp70 autoantibodies, the latter measured as gp70-anti-gp70 ICs (gp70 ICs), have been implicated in the development of the progressive lupus nephritis in these mice (1-10). Interestingly, in other murine models of lupus nephritis, such as MRL-Fas lpr and BXSB mice, the mice also produce high levels of autoantibodies to both nuclear antigens and gp70 (1,(11)(12)(13)(14)(15).Although serum gp70 may be critical for the formation of pathogenic gp70 ICs, it is not the only gp70 produced in these mice. Numerous functional and nonfunctional copies of MuLV are inherited in mouse

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Autoantigen Glycoprotein 70 Expression Is Regulated by a Single Locus, Which Acts as a Checkpoint for Pathogenic Anti-Glycoprotein 70 Autoantibody Production and Hence for the Corresponding Development of Severe Nephritis, in Lupus-Prone BXSB Mice1

Cited by 36 publications

References 31 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

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

Association between nuclear antigens and endogenous retrovirus in the generation of autoantibody responses in murine lupus

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