Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus

Heidari, Yasin; Bygrave, Anne E.; Rigby, Robert J.; Rose, Kirsten L.; Walport, Mark J.; Cook, H. Terence; Vyse, Timothy J.; Botto, Marina

doi:10.1038/sj.gene.6364335

Cited by 37 publications

(45 citation statements)

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“…There is no evidence from crosses involving the 129 and B6 strains that chromosome 10 contains a locus that impacts lupus susceptibility. [32][33][34] Thus, the genetic background of this strain is more than 98% B6 and does not carry 129 alleles in any of the regions of the To generate the (NZB Â NZW)F 1 mice of the desired ERa genotypes, we produced two congenic mouse strains, one in which this ERa knockout (ERaKO) was carried on the NZB/BlNJ (NZB) genetic background and the other in which the ERa knockout was carried on the NZW/LacJ (NZW) genetic background. NZB.ERaKO and NZW.ERaKO congenic lines were produced using a modification of the marker-assisted selection method we have described previously.…”

Section: Methodsmentioning

confidence: 99%

“…Because the 129 strain, on which the original knockout was generated, carries alleles that impact lupus susceptibility, [32][33][34] it was important to identify any regions of residual 129-derived genome in the B6.129-Esr1 tm1Ksk strain, even though this congenic line was already extensively backcrossed. Therefore, we genotyped our original founder B6.129-Esr1 tm1Ksk animals using 61 markers spanning the 19 autosomes and the X chromosome (Table 1).…”

Section: Methodsmentioning

confidence: 99%

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Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice

et al. 2008

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Estrogens promote lupus in humans and some mouse models of this disease. Nonetheless, little is known about the role of estrogen receptors in lupus pathogenesis. Here, we report that in females on the lupus-prone (NZB Â NZW)F 1 background, disruption of estrogen receptor-a (ERa or Esr1) attenuated glomerulonephritis and increased survival. ERa deficiency also retarded development of anti-histone/DNA antibodies, suggesting that ERa promotes loss of immunologic tolerance. Furthermore, ERa deficiency in (NZB Â NZW)F 1 females attenuated the subsequent development of anti-double-stranded DNA (dsDNA) IgG antibodies, which are associated with glomerulonephritis in this model. We provide evidence that ERa may promote lupus, at least in part, by inducing interferon-g, an estrogen-regulated cytokine that impacts this disease. ERa deficiency in (NZB Â NZW)F 1 males increased survival and reduced anti-dsDNA antibodies, suggesting that ERa also modulates lupus in males. These studies demonstrate that ERa, rather than ERb, plays a major role in regulating autoimmunity in (NZB Â NZW)F 1 mice. Furthermore, our results suggest for the first time that ERa promotes lupus, at least in part, by impacting the initial loss of tolerance. These data suggest that targeted therapy disrupting ERa, most likely within the immune system, may be effective in the prevention and/or treatment of lupus.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice

et al. 2008

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“…The SLAM/CD2 (Sle1b) cluster on chromosome 1 was characterized to cause autoimmunity when present in a mixed background containing B6 and another genetic background such as BALB/c or 129 (29). Another study showed that this region on chromosome 1 and regions on chromosomes 3, 7, and 13 are linked to lupus-like disease in mice when present on a mixed 129/B6 background (35). Therefore, the genetic background of the B6-backcrossed Siglec-G 2/2 mice was carefully analyzed with 69 SNP markers covering all chromosomes.…”

Section: Discussionmentioning

confidence: 99%

“…These B6-backcrossed mice (N 6 generation) were tested with 69 SNP markers to be ∼95% homozygous for the B6 background. In particular, chromosomes 1, 3, and 13, which contain loci that can contribute to autoimmunity in mixed mouse background strains (29,35), were determined to be 100% B6 in all tested B6-backcrossed mice (not shown). In these B6-backcrossed mice, parameters for B cell hyperreactivity, such as spontaneous plasma cell and germinal center formation or Ig serum levels, were analyzed.…”

Section: Resultsmentioning

confidence: 99%

Siglec-G Deficiency Leads to Autoimmunity in Aging C57BL/6 Mice

Müller

Lunz

Schwab

et al. 2015

The Journal of Immunology

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Siglec-G, a member of the sialic acid–binding Ig-like lectin (Siglec) family, is expressed on B cell and dendritic cell surfaces. It acts as an inhibitory coreceptor and modulates B cell activation, especially on B1 cells, as Siglec-G–deficient mice show mainly a B1 cell–restricted phenotype resulting in increased B1 cell numbers. Although higher B1 cell numbers are discussed to be associated with autoimmunity, loss of Siglec-G does not result in autoimmune disease in BALB/c mice. However, there is evidence from Siglec-G × CD22 double-deficient mice and Siglec-G−/− mice on an autoimmune-prone MRL/lpr background that Siglec-G is important to maintain tolerance in B cells. In this study, we analyzed the role of Siglec-G in induction and maintenance of B cell tolerance on C57BL/6 background and in the FcγRIIb-deficient background. We find that aging Siglec-G–deficient and Siglec-G × FcγRIIb double-deficient mice develop an autoimmune phenotype with elevated autoantibody levels and mild glomerulonephritis. Aging Siglec-G–deficient mice have elevated numbers of plasma cells and germinal center B cells, as well as a higher number of activated CD4 T cells, which likely all contribute to autoantibody production. Additional loss of the inhibitory receptor FcγRIIb in Siglec-G−/− mice does not result in exacerbation of disease. These results indicate that Siglec-G is important to maintain tolerance in B cells and prevent autoimmunity.

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“…There are a number of examples of gene-targeted mice in which autoimmune phenotypes, originally attributed to targeted mutations, arise from accompanying neighbouring ES cell-derived DNA [45,46]. Furthermore, a number of unmanipulated 129/Sv-derived genomic regions have been identified that are sufficient to promote autoimmunity in mixed 129/Sv × C57Bl/6 strains [47,48]. Genetic background is indeed relevant to the CD22-deficient strains utilised in this study; the Cd22 tm1Msn strain develops autoantibodies with age while the Cd22 tm1Lam strain does not [10,13,49,50].…”

Section: Discussionmentioning

confidence: 99%

Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1^c: A model for hereditary haemolytic anaemia

et al. 2012

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CD22, an inhibitory co-receptor of the BCR, has been identified as a potential candidate gene for the development of autoimmune haemolytic anaemia in mice. In this study, we have examined Cd22 tm1Msn CD22-deficient mice and identified an increase in RBC turnover and stress erythropoiesis, which might be consistent with haemolysis. We then, however, eliminated CD22 deficiency as the cause of accelerated RBC turnover and established that enhanced RBC turnover occurs independently of B cells and anti-RBC autoantibodies. Accelerated RBC turnover in this particular strain of CD22-deficient mice is red cell intrinsic and appears to be the consequence of a defective allele of glucose phosphate isomerase, Gpi1 c . This form of Gpi1 was originally derived from wild mice and results in a substantial reduction in enzyme activity. We have identified the polymorphism that causes impaired catalytic activity in the Gpi1 c allele, and biochemically confirmed an approximate 75% reduction of GPI1 activity in Cd22 −/− RBCs. The Cd22 −/− .Gpi1 c congenic mouse provides a novel animal model of GPI1-deficiency, which is one of the most common causes of chronic non-spherocytic haemolytic anaemia in humans.Keywords: Anaemia r CD22 r Erythrocytes r Glucose-6-phosphate isomerase r Polymorphism Supporting Information available online IntroductionClearance of RBCs by anti-RBC auto-Ab gives rise to the condition known as autoimmune haemolytic anaemia (AIHA). The pathoCorrespondence: Dr. Kenneth G.C. Smith e-mail: kgcs2@cam.ac.uk logical mechanisms underlying the generation of anti-RBC autoantibodies are incompletely understood, but are likely to involve defects in both T-and B-cell tolerance [1,2]. New Zealand Black (NZB) mice spontaneously develop AIHA at around 6 months of age [3], which is characterised by a progressive anaemia of varying severity, accompanied by reticulocytosis and splenomegaly, the results of on-going stress erythropoiesis. There is a clear genetic contribution to AIHA in NZB mice, and a number of quantitative C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 3212-3222 Cellular immune response 3213 trait loci (QTLs) that either promote or protect from disease have been identified [4][5][6][7]. One such anaemia-promoting QTL, designated Aia3 (autoimmune anemia 3), is present on NZB proximal chromosome 7 and peaks in the vicinity of the Cd22 gene, around 9 cM from the centromere [7]. Of the many genes present within this interval, Cd22 is an attractive candidate for promoting Coombs auto-Ab production and AIHA [7]. As discussed below, NZB mice express a defective form of this receptor, and loss of CD22 function is associated with auto-Ab generation in some mouse models [8][9][10]. Other potential candidates include Cd79a, which encodes a component of the BCR signalling complex, and Fcgbp, which encodes an IgG-binding protein.CD22 is an inhibitory co-receptor of the BCR and, like other co-receptors, modulates the Ag receptor signal in response to cues from the local microen...

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Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus

Cited by 37 publications

References 31 publications

Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice

Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice

Siglec-G Deficiency Leads to Autoimmunity in Aging C57BL/6 Mice

Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1^c: A model for hereditary haemolytic anaemia

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Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus

Cited by 37 publications

References 31 publications

Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice

Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice

Siglec-G Deficiency Leads to Autoimmunity in Aging C57BL/6 Mice

Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1c: A model for hereditary haemolytic anaemia

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Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1^c: A model for hereditary haemolytic anaemia