The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

Yh, Cheung; Landolt-Marticorena, Carolina; Lajoie, Ginette; Wither, Joan E.

doi:10.1038/gene.2010.71

Cited by 9 publications

(26 citation statements)

References 36 publications

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“…As epistatic interactions between multiple susceptibility loci have been shown to additively augment lupus autoimmunity, we postulated that the NZB chromosome 4 genetic locus might require the presence of additional susceptibility genes to affect disease expression (17). Because we have previously shown that congenic mice with an NZB chromosome 1 (70-100 cM) interval (denoted as B6.NZBc1) develop high-titer antinuclear Ab production, glomerulonephritis (GN), and early mortality (18), bicongenic mice with both NZB chromosome 1 and 4 intervals (denoted B6.NZBc1c4) were generated to address this question.…”

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confidence: 99%

Epistatic Suppression of Fatal Autoimmunity in New Zealand Black Bicongenic Mice

Loh

Pau

Lajoie

et al. 2011

The Journal of Immunology

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Numerous mapping studies have implicated genetic intervals from lupus-prone New Zealand Black (NZB) chromosomes 1 and 4 as contributing to lupus pathogenesis. By introgressing NZB chromosomal intervals onto a non–lupus-prone B6 background, we determined that: NZB chromosome 1 congenic mice (denoted B6.NZBc1) developed fatal autoimmune-mediated kidney disease, and NZB chromosome 4 congenic mice (denoted B6.NZBc4) exhibited a marked expansion of B1a and NKT cells in the surprising absence of autoimmunity. In this study, we sought to examine whether epistatic interactions between these two loci would affect lupus autoimmunity by generating bicongenic mice that carry both NZB chromosomal intervals. Compared with B6.NZBc1 mice, bicongenic mice demonstrated significantly decreased mortality, kidney disease, Th1-biased IgG autoantibody isotypes, and differentiation of IFN-γ–producing T cells. Furthermore, a subset of bicongenic mice exhibited a paucity of CD21+CD1d+ B cells and an altered NKT cell activation profile that correlated with greater disease inhibition. Thus, NZBc4 contains suppressive epistatic modifiers that appear to inhibit the development of fatal NZBc1 autoimmunity by promoting a shift away from a proinflammatory cytokine profile, which in some mice may involve NKT cells.

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confidence: 99%

Epistatic Suppression of Fatal Autoimmunity in New Zealand Black Bicongenic Mice

Loh

Pau

Lajoie

et al. 2011

The Journal of Immunology

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“…We showed previously that full expression of the autoimmune phenotype in NZB c1 congenic mice results from the interaction among at least three genetic loci (6). Although a breach of tolerance to nuclear Ags was seen in mice with the NZB c1(96-100) interval, pathogenic autoimmunity required the presence of additional defects localized to the NZB 70-96 cM interval that were associated with marked expansion of proinflammatory T cell subsets, including Th1, Th17, and Tfh cells in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…To identify the immune mechanisms leading to disease in these mice, we produced and characterized a series of C57BL/6 (B6) congenic mouse strains with homozygous intervals containing susceptibility loci derived from this mouse strain. In previous work, we showed that mice with an NZB interval extending from 70 cM (125.6 Mb) to 100 cM (179.8 Mb) on chromosome 1 (c1) [c1(70-100)] developed a severe lupus phenotype, with fatal glomerulonephritis developing in 40% of animals by 8 mo of age (6). By examining subcongenic mice with shorter overlapping intervals, we found that at least three genetic loci were required to produce this phenotype (6).…”

Section: Studies In the Wither Laboratory Have Focused On The Newmentioning

confidence: 99%

“…In previous work, we showed that mice with an NZB interval extending from 70 cM (125.6 Mb) to 100 cM (179.8 Mb) on chromosome 1 (c1) [c1(70-100)] developed a severe lupus phenotype, with fatal glomerulonephritis developing in 40% of animals by 8 mo of age (6). By examining subcongenic mice with shorter overlapping intervals, we found that at least three genetic loci were required to produce this phenotype (6). Congenic mice with the shortest NZB interval, extending from 96 to 100 cM on c1 [170.…”

Section: Studies In the Wither Laboratory Have Focused On The Newmentioning

confidence: 99%

“…Congenic mouse strains with homozygous NZB c1 intervals of various length (Supplemental Fig. 1) were generated as previously described (6). OT-II TCR-Tg congenic mice were produced by polymorphic marker-assisted backcrossing.…”

Section: Micementioning

confidence: 99%

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Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling

Talaei

Tao

Manion

et al. 2015

The Journal of Immunology

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We showed previously that C57BL/6 congenic mice with an introgressed homozygous 70 cM (125.6 Mb) to 100 cM (179.8 Mb) interval on c1 from the lupus-prone New Zealand Black (NZB) mouse develop high titers of antinuclear Abs and severe glomerulonephritis. Using subcongenic mice, we found that a genetic locus in the 88–96 cM region was associated with altered dendritic cell (DC) function and synergized with T cell functional defects to promote expansion of pathogenic proinflammatory T cell subsets. In this article, we show that the promoter region of the NZB gene encoding the SLAM signaling pathway adapter molecule EWS-activated transcript 2 (EAT-2) is polymorphic, which results in an ∼70% reduction in EAT-2 in DC. Silencing of the EAT-2 gene in DC that lacked this polymorphism led to increased production of IL-12 and enhanced differentiation of T cells to a Th1 phenotype in T cell–DC cocultures, reproducing the phenotype observed for DC from congenic mice with the NZB c1 70–100 cM interval. SLAM signaling was shown to inhibit production of IL-12 by CD40L-activated DCs. Consistent with a role for EAT-2 in this inhibition, knockdown of EAT-2 resulted in increased production of IL-12 by CD40-stimulated DC. Assessment of downstream signaling following CD40 cross-linking in the presence or absence of SLAM cross-linking revealed that SLAM coengagement blocked activation of p38 MAPK and JNK signaling pathways in DC, which was reversed in DC with the NZB EAT-2 allele. We conclude that EAT-2 negatively regulates cytokine production in DC downstream of SLAM engagement and that a genetic polymorphism that disturbs this process promotes the development of lupus.

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T Cell and Dendritic Cell Abnormalities Synergize to Expand Pro-Inflammatory T Cell Subsets Leading to Fatal Autoimmunity in B6.NZBc1 Lupus-Prone Mice

et al. 2013

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We have previously shown that B6 congenic mice with a New Zealand Black chromosome 1 (c1) 96-100 cM interval produce anti-nuclear Abs and that at least two additional genetic loci are required to convert this subclinical disease to fatal glomerulonephritis in mice with a c1 70-100 cM interval (c1(70-100)). Here we show that the number of T follicular helper and IL-21-, IFN-γ-, and IL-17-secreting CD4+ T cells parallels disease severity and the number of susceptibility loci in these mice. Immunization of pre-autoimmune mice with OVA recapitulated these differences. Differentiation of naïve T cells in-vitro under polarizing conditions and in-vivo following adoptive transfer of OVA-specific TCR transgenic cells into c1(70-100) or B6 recipient mice, revealed T cell functional defects leading to increased differentiation of IFN-γ- and IL-17-producing cells in the 96-100 cM and 88-96 cM intervals, respectively. However, in-vivo enhanced differentiation of pro-inflammatory T cell subsets was predominantly restricted to c1(70-100) recipient mice, which demonstrated altered dendritic cell function, with increased production of IL-6 and IL-12. The data provide support for the role of pro-inflammatory T cells in the conversion of subclinical disease to fatal autoimmunity and highlight the importance of synergistic interactions between individual susceptibility loci in this process.

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The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

Cited by 9 publications

References 36 publications

Epistatic Suppression of Fatal Autoimmunity in New Zealand Black Bicongenic Mice

Epistatic Suppression of Fatal Autoimmunity in New Zealand Black Bicongenic Mice

Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling

T Cell and Dendritic Cell Abnormalities Synergize to Expand Pro-Inflammatory T Cell Subsets Leading to Fatal Autoimmunity in B6.NZBc1 Lupus-Prone Mice

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