Abstract
Antiviral defenses are inappropriately activated in systemic lupus erythematosus (SLE) and association between SLE and the antiviral helicase gene, IFIH1, is well established. We sought to extend the previously reported association of pathogenic soluble mediators and autoantibodies with mouse Mda5 to its human ortholog, IFIH1. To better understand the role this gene plays in human lupus, we assessed association of IFIH1 variants with soluble mediators and autoantibodies in 357 European-American SLE patients, first-degree relatives, and unrelated, unaffected healthy controls. Association between each of 135 genotyped SNPs in IFIH1 and four lupus-associated plasma mediators, IL-6, TNF-α, IFN-β, and IP-10, were investigated via linear regression. No significant associations were found to SNPs orthologous to those identified in exon 13 of the mouse. However, outside of this region there were significant associations between IL-6 and rs76162067 (p = 0.008), as well as IP-10 and rs79711023 (p = 0.003), located in a region of IFIH1 previously shown to directly influence MDA-5 mediated IP-10 and IL-6 secretion. SLE patients and FDRs carrying the minor allele for rs79711023 demonstrated lower levels of IP-10, while only FDRs carrying the minor allele for rs76162067 demonstrated an increased level of IL-6. This would suggest that the change in IP-10 is genotypically driven, while the change in IL-6 may be reflective of SLE transition status. These data suggest that IFIH1 may contribute to SLE pathogenesis via altered inflammatory mechanisms.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease marked by immune dysregulation and chronic inflammation resulting from reduced immunologic tolerance to nuclear selfantigens
We sought to determine if the soluble mediators that significantly associated with mutant melanoma-differentiation-associated gene 5 (Mda5) [2], associated with the human ortholog, Interferon induced with helicase C domain 1 (IFIH1)
When we expanded our analyses, to include 135 SNPs across IFIH1 we found two promising effects associated with IL-6 and IP-10
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease marked by immune dysregulation and chronic inflammation resulting from reduced immunologic tolerance to nuclear selfantigens. Melanoma-differentiation-associated gene 5 (Mda5), the mouse ortholog to IFIH1, was shown to be associated with IFN-β, IL-6, CXCL10 (IP-10), ISg56, TNF-α, antinuclear antibodies (ANA), and anti-dsDNA antibodies [2]. The findings of Funabiki et al link Mda with dysregulated immune function resulting in lupus-like disease [2]. As these associations have yet to be investigated in human SLE, we sought to determine if IFIH1, the human ortholog of Mda, is associated with altered soluble mediators and autoantibodies in SLE patients compared to unaffected first-degree relatives of SLE patients (FDRs) and unrelated, unaffected controls with no family history of SLE. We have recently demonstrated immunologic differences between FDRs who remained unaffected during a follow-up period of over six years vs. those who have transitioned to classified SLE and unrelated, unaffected healthy individuals [6]
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