Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

Miyazaki, Tatsuhiko; Ono, M.; Qu, Wei Min; Zhang, Mingcai; Mori, Shiro; Nakatsuru, Shuichi; Nakamura, Yusuke; Sawasaki, Tatsuya; Endo, Yaeta; Nose, Masato

doi:10.1002/eji.200425672

Cited by 68 publications

(57 citation statements)

References 42 publications

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“…Marc4 and Marc7 overlap well with some of these loci associated with SpM [32,33], GN [34][35][36][37][38], vasculitis [39], anti-dsDNA [32,36,37], or mortality [33]. Sex-related preponderance was not examined for these loci.…”

Section: Discussionmentioning

confidence: 99%

Autosomal loci associated with a sex‐related difference in the development of autoimmune phenotypes in a lupus model

et al. 2007

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Sex-related differences (SrD) are a general characteristic of human autoimmune diseases. There is an increasing body of evidence that suggests a link between sexrelated hormones and autoimmune onsets. Here, through a genetic approach using a lupus mouse model, we attempted to show the involvement of genetic factors in the development of SrD in autoimmune diseases. Using MRL/lpr Â (MRL/lpr Â C57BL/ 6.Fas lpr )F1 (MBN2) mice, the whole genome was searched to identify linkage loci to autoimmune phenotypes inherited from a lupus MRL/Mp.Fas lpr (MRL/lpr) strain of mice, which exhibits glomerulonephritis, splenomegaly and antinuclear autoantibody. The genome-wide association study confirmed four linkage loci on chromosomes 4, 7, 13, and 17. Furthermore, differential analyses performed using male and female groups of MBN2 mice revealed that two loci located on chromosomes 4 (41-72 cM, MRL/lpr allele) and 7 (4-21 cM, B6/lpr allele) were male specific and suppressed autoimmune phenotypes. Notably, the sum effect of the two loci adequately explained a range of SrD developed in the MBN2 mice. Our present findings suggest the presence of a malepredominant mechanism underlying the development of SrD in autoimmunity, depending on the effects of autosomal loci under an undefined male-specific condition.

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Section: Discussionmentioning

confidence: 99%

Autosomal loci associated with a sex‐related difference in the development of autoimmune phenotypes in a lupus model

et al. 2007

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“…Interestingly, MRL and AKR, both of which develop autoimmune disease in the presence of Fas lpr , carry CD72 c , whereas most of the other strains of mice, including BALB/c and C57BL/6 (B6), carry either CD72 a or CD72 b (18,19). Moreover, studies using microsatellite markers revealed association of the loci containing Cd72 to development of glomerulonephritis in MRL/lpr mice (20)(21)(22) …”

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Cd72c Is a Modifier Gene that Regulates Faslpr-Induced Autoimmune Disease

Hou

Sato-Hayashizaki

et al. 2013

The Journal of Immunology

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Although modifier genes are extensively studied in various diseases, little is known about modifier genes that regulate autoimmune diseases. Autoimmune disease caused by the Faslpr mutation depends on the genetic background of mouse strains, suggesting a crucial role of modifier genes. MRL/MpJ-Faslpr (MRL/lpr) and AKR/lpr mice develop severe and mild lupus-like autoimmune disease, respectively, whereas this mutation does not cause disease on C57BL/6 (B6) or C3H background. Both MRL and AKR carry the same haplotype of the Cd72 gene encoding an inhibitory BCR coreceptor (CD72c), and CD72c contains several amino acid substitutions and a deletion in the extracellular region compared with CD72a and CD72b. To address the role of Cd72c locus in the regulation of Faslpr-induced autoimmune disease, we generated B6.CD72c/lpr and MRL.CD72b/lpr congenic mice. Introduction of the chromosomal interval containing Cd72c did not cause disease in B6 mice by itself, but caused development of lupus-like disease in the presence of Faslpr on B6 background, clearly demonstrating that this interval contains the modifier gene that regulates Faslpr-induced autoimmune disease. Conversely, MRL.CD72b/lpr congenic mice showed milder disease compared with MRL/lpr mice. We further demonstrated that Cd72c is a hypofunctional allele in BCR signal inhibition and that CD72 deficiency induces severe autoimmune disease in the presence of Faslpr. These results strongly suggest that the Cd72c is a crucial modifier gene that regulates Faslpr-induced autoimmune disease due to its reduced activity of B cell signal regulation.

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“…Dysregulated expression of Opn, in contrast, has been associated with autoimmune disease in mouse models 14 and in several types of human autoimmune disorders, including lupus nephritis, multiple sclerosis and rheumatoid arthritis [17][18][19][20][21][22] . Although most studies have focused on the activity of secreted Opn as a cytokine or chemokine 14,15,23 , a portion of newly synthesized Opn is retained as intracellular Opn (Opn-i) in the cytoplasm and distinct from secretory vesicles [24][25][26] . Given the early and decisive effect of Opn on type 1 immunity and evidence of its expression in activated DCs 27,28 , we investigated its possible involvement in mediating the specialized activation of DC subsets.…”

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Osteopontin expression is essential for interferon-α production by plasmacytoid dendritic cells

et al. 2006

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The observation that the T-bet transcription factor allows tissue-specific upregulation of intracellular osteopontin (Opn-i) in plasmacytoid dendritic cells (pDCs) suggests that Opn might contribute to the expression of interferon-α (IFN-α) in those cells. Here we show that Opn deficiency substantially reduced Toll-like receptor 9 (TLR9)-dependent IFN-α responses but spared expression of transcription factor NF-κB-dependent proinflammatory cytokines. Shortly after TLR9 engagement, colocalization of Opn-i and the adaptor molecule MyD88 was associated with induction of transcription factor IRF7-dependent IFN-α gene expression, whereas deficient expression of Opn-i was associated with defective nuclear translocation of IRF7 in pDCs. The importance of the Opn-IFN-α pathway was emphasized by its essential involvement in crosspresentation in vitro and in anti-herpes simplex virus 1 IFN-α response in vivo. The finding that Opn-i selectively coupled TLR9 signaling to expression of IFN-α but not to that of other proinflammatory cytokines provides new molecular insight into the biology of pDCs.Increasing evidence that innate immune responses can determine both the type and intensity of adaptive immune responses has stimulated great interest in the underlying regulatory mechanisms. The recognition phase of innate responses depends on a series of patternrecognition receptors, including Toll-like receptors (TLRs) expressed by dendritic cells (DCs), which detect a wide range of pathogen-associated molecules carried by bacteria and viruses 1 . Engagement of the TLR9 family of endosomal receptors by microbe-derived DNA triggers the production of large amounts of interferons α and β (IFN-αβ) 2 , key mediators that regulate the development of both innate and adaptive immunity [3][4][5][6] . However, the pathway initiated by TLR9 engagement that culminates in IFN-αβ production is not fully understood.

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Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

Cited by 68 publications

References 42 publications

Autosomal loci associated with a sex‐related difference in the development of autoimmune phenotypes in a lupus model

Autosomal loci associated with a sex‐related difference in the development of autoimmune phenotypes in a lupus model

Cd72c Is a Modifier Gene that Regulates Faslpr-Induced Autoimmune Disease

Osteopontin expression is essential for interferon-α production by plasmacytoid dendritic cells

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