Evaluation of the IRF-2 Gene as a Candidate for PSORS3

Foerster, John; Nolte, Ilja M.; Schweiger, Susann; Ehlert, Claudia; Bruinenberg, Marcel; Spaar, Katja; Steege, Gerrit van der; Mulder, Martijn; Kalscheuer, Vera M.; Moser, Bettina A.; Kijas, Zofia; Seeman, P.; Ständer, M; Sterry, Wolfram; Meerman, Gerard te

doi:10.1046/j.0022-202x.2003.22104.x

Cited by 31 publications

(20 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among several other susceptibility loci, the PSORS3 locus is unique as it contains genes for immunoregulatory molecules such as IFN regulatory factor-2 (IRF-2) 3 as well as IL-15, TLR2, and TLR3. IRF-2 was in fact reported as a candidate susceptible gene for psoriasis in Irish families (6), although examination in other families excluded variations in the IRF2 gene as a candidate of PSORS3 (7). These apparently contradicting observations may suggest that bias in concomitant variations of other genes might obscure the effect of IRF-2 polymorphism on susceptibility to psoriasis through epistasis.…”

mentioning

confidence: 69%

“…Those background genes, whatever they might be, seemed to constitute a fail-safe device for the homeostasis of the skin immune system, functioning to compensate for the absence of IRF-2. It is an intriguing possibility, of course yet to be proven, that possible human counterparts of these murine genes would negate the effect of, if any, IRF-2 malfunctions in the pathogenesis of human psoriasis (6,7).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Genetic Control Directed toward Spontaneous IFN-α/IFN-β Responses and Downstream IFN-γ Expression Influences the Pathogenesis of a Murine Psoriasis-Like Skin Disease

Arakura

Hida

Ichikawa

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

Psoriasis is an inflammatory skin disease, onset and severity of which are controlled by multiple genetic factors; aberrant expression of and responses to several cytokines including IFN-α/IFN-β and IFN-γ are associated with this “type 1” disease. However, it remains unclear whether genetic regulation influences these cytokine-related abnormalities. Mice deficient for IFN regulatory factor-2 (IRF-2) on the C57BL/6 background (IRF-2−/−BN mice) exhibited accelerated IFN-α/IFN-β responses leading to a psoriasis-like skin inflammation. In this study, we found that this skin phenotype disappeared in IRF-2−/− mice with the BALB/c or BALB/c × C57BL/6 F1 backgrounds. Genome-wide scan revealed two major quantitative trait loci controlled the skin disease severity. Interestingly, these loci were different from that for the defect in CD4+ dendritic cells, another IFN-α/IFN-β-dependent phenotype of the mice. Notably, IFN-γ expression as well as spontaneous IFN-α/IFN-β responses were up-regulated several fold spontaneously in the skin in IRF-2−/−BN mice but not in IRF-2−/− mice with “resistant” backgrounds. The absence of such IFN-γ up-regulation in IRF-2−/−BN mice lacking the IFN-α/IFN-β receptor or β2-microglobulin indicated that accelerated IFN-α/IFN-β signals augmented IFN-γ expression by CD8+ T cells in the skin. IFN-γ indeed played pathogenic roles as skin inflammation was delayed and was much more infrequent when IRF-2−/−BN mice lacked the IFN-γ receptor. Our current study thus revealed a novel genetic mechanism that kept the skin immune system under control and prevented skin inflammation through regulating the magnitude of IFN-α/IFN-β responses and downstream IFN-γ production, independently of CD4+ dendritic cells.

show abstract

mentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Genetic Control Directed toward Spontaneous IFN-α/IFN-β Responses and Downstream IFN-γ Expression Influences the Pathogenesis of a Murine Psoriasis-Like Skin Disease

Arakura

Hida

Ichikawa

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Ongoing efforts to map the psoriasis gene, PSOR3, in this region have shown association between variants of the interferon-regulatory factor 2 (IRF2) gene and this disorder. 104 Evidence for association of IRF2 has also been reported with atopic dermatitis.…”

Section: à3mentioning

confidence: 98%

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

et al. 2006

View full text Add to dashboard Cite

Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, antinRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P ¼ 1.9 Â 10 À6 ), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P ¼ 3.5 Â 10 À6 ), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P ¼ 3.4 Â 10 À4 ) and to antiIgM aPL Abs on chromosome 13q14 (adjusted P ¼ 2.3 Â 10 À4). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.

show abstract

“…Weak association of IRF-2 variants with psoriasis has been reported (PSORS3). 77 It is not clear if this is because the true variant has not been detected in this, or a nearby gene, or if the association is spurious. Abbreviations: IL, interleukin; mTOR, mammalian target of rapamycin; RAPTOR, regulatory associated protein of mTOR; SNP, singlenucleotide polymorphism; TNF, tumor necrosis factor; UTR, untranslated region.…”

Section: Psors9mentioning

confidence: 99%

Psoriasis: genetic associations and immune system changes

2006

View full text Add to dashboard Cite

Psoriasis is a common inflammatory skin disease characterized by infiltration of inflammatory cells into the epidermis and altered keratinocyte differentiation. Psoriasis is currently thought of as a T-cell mediated 'Type-1' autoimmune disease. Gene expression changes in psoriasis lesions have been well documented, and strongly support an important role for tumor necrosis factor and interferon gamma signal pathways in its pathogenesis. The strongest genetic determinant of psoriasis identified to date lies within the class I region of the multiple histocompatibility locus antigen cluster, although its low penetrance implicates a requirement for other genetic risk factors. Multiple genome-wide linkage and an increasing number of association studies have been carried out, leading to multiple linkage peaks, and the identification of potential low risk variants. A number of these variants lie within genes encoding components of the immune system. However, the functional relationships between predisposing genetic variation is unclear, and presumably involves genetic susceptibility factors affecting both immune cell activation and keratinocyte differentiation. The interaction of environmental trigger factors with genetic effects is also not understood, but provide further evidence for the complex basis of this disease.

show abstract

Evaluation of the IRF-2 Gene as a Candidate for PSORS3

Cited by 31 publications

References 23 publications

Genetic Control Directed toward Spontaneous IFN-α/IFN-β Responses and Downstream IFN-γ Expression Influences the Pathogenesis of a Murine Psoriasis-Like Skin Disease

Genetic Control Directed toward Spontaneous IFN-α/IFN-β Responses and Downstream IFN-γ Expression Influences the Pathogenesis of a Murine Psoriasis-Like Skin Disease

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

Psoriasis: genetic associations and immune system changes

Contact Info

Product

Resources

About