IFN Signature Genes Research Articles

Decreased Pattern Recognition Receptor Signaling, Interferon-Signature, and Bactericidal/Permeability-Increasing Protein Gene Expression in Cord Blood of Term Low Birth Weight Human Newborns

BackgroundMorbidity and mortality rates of low birth weight (LBW) newborns at term are higher than rates in normal birth weight (NBW) newborns. LBW newborns are at greater risk to acquire recurrent bacterial and viral infections during their first few weeks of life possibly as an outcome of compromised innate immune functions. As adaptive immunity is in a naive state, increased risk of infection of LBW as compared to NBW newborns may reflect impairments in innate immunity.MethodologyTo characterize the increased susceptibility to infections in LBW newborns we used microarray technology to identify differences in gene expression in LBW newborns (n = 8) compared to NBW newborns (n = 4) using cord blood. The results obtained from the microarray study were validated on a larger number of samples using real time RT-PCR (LBW = 22, NBW = 18) and western blotting (LBW = 12, NBW = 12). The Interferome database was used to identify interferon (IFN) signature genes and ingenuity pathway analysis identified canonical pathways and biological functions associated with the differentially expressed genes in LBW newborns. ELISAs for IFNs and bactericidal/permeability-increasing protein were performed in both LBW and NBW newborns and in adults (LBW = 18, NBW = 18, Adults = 8).Principal FindingsUpon microarray analysis, we identified 1,391 differentially expressed genes, of which, 1,065 genes were down-regulated and 326 genes were up-regulated in the LBW compared to NBW newborns. Of note, 70 IFN-signature genes were found to be significantly down-regulated in LBW compared to NBW newborns. Ingenuity pathway analysis revealed pattern recognition receptors signaling including Toll-Like Receptors (TLRs) -1, -5, and -8 genes and IFN signaling as the most significantly impacted pathways. Respiratory infectious diseases were the most significantly affected bio-functions in LBW newborns.Conclusion and SignificanceDiminished PRRs, IFN-signature, and BPI gene expression raises the possibility that impairments in these pathways contribute to the susceptibility of LBW term infants to infection.

Interferon signature gene expression is correlated with autoantibody profiles in patients with incomplete lupus syndromes

Interferon (IFN) signature genes have been shown to be expressed highly in peripheral blood of patients with systemic lupus erythematosus (SLE), especially in the presence of active disease. However, the expression of this gene signature in individuals with incomplete forms of lupus and the pathogenic relationship between IFN signature genes and autoantibody production have not been explored fully. In the present study, we examined the gene expression and autoantibody profiles of patients diagnosed with incomplete lupus erythematosus (ILE) to determine correlations of the gene expression signature with autoantibody production. Gene expression analysis was carried out on the 24K Illumina Human Refseq-8 arrays using blood samples from 84 subjects, including patients with SLE (n = 27) or ILE (n = 24), first-degree relatives (FDR) of these patients (n = 22) and non-autoimmune control (NC) individuals (n = 11). Autoantibody expression was measured using standard immunoassays and autoantigen proteomic arrays. Up-regulation of a set of 63 IFN signature genes was seen in 83% of SLE patients and 50% of ILE patients. High levels of IFN gene expression in ILE and SLE showed significant correlations with the expression of a subset of IgG autoantibodies, including chromatin, dsDNA, dsRNA, U1snRNP, Ro/SSA, La/SSB, topoisomerase I and Scl 70, while low IFN levels were correlated with immunoglobulin (Ig)M autoreactivity. These studies suggest that in patients with ILE the IFN gene expression signature may identify a subset of these individuals who are at risk for disease progression. Furthermore, high levels of alpha IFN may promote autoantibody class-switch from IgM to the more pathogenic IgG class.

O.189 Interferon regulatory factor-1 promoter polymorphism and the outcome of hepatitis C virus infection

IFNλ is important for epidermal defense against viruses. It is produced by, and acts on, keratinocytes, whereas fibroblasts were previously considered to be unresponsive to this type III IFN. Herein we report findings revealing cell type-specific differences in IFNλ signaling and function in skin resident cells. In dermal fibroblasts, IFNλ induced the expression of myxovirus protein A (MxA), a potent antiviral factor, but not other IFN signature genes as it does in primary keratinocytes. In contrast to its effect on keratinocytes, IFNλ did not phosphorylate signal transducer and activator of transcription 1 in fibroblasts, but instead activated mitogen activated protein kinases (MAPK). Accordingly, inhibition of MAPK activation (p38 and p42/44) blocked the expression of MxA protein in fibroblasts but not in keratinocytes. Functionally, IFNλ inhibited proliferation in keratinocytes but not in fibroblasts. Moreover, IFNλ upregulated the expression of Tumor growth factor beta 1 (TGFβ1)-induced collagens in fibroblasts. Taken together, our findings identify primary human dermal fibroblasts as responder cells to IFNλ. Our study shows cutaneous cell type-specific IFN signaling and suggests that IFNλ, although important for epidermal antiviral competence, may also have a regulatory role in the dermal compartment balancing type I IFN-induced inhibition of tissue repair processes.

O.190 Inhibition of hepatitis C virus replication by tumor suppressor p53: Novel prospects of p53 in antiviral defense

IFNλ is important for epidermal defense against viruses. It is produced by, and acts on, keratinocytes, whereas fibroblasts were previously considered to be unresponsive to this type III IFN. Herein we report findings revealing cell type-specific differences in IFNλ signaling and function in skin resident cells. In dermal fibroblasts, IFNλ induced the expression of myxovirus protein A (MxA), a potent antiviral factor, but not other IFN signature genes as it does in primary keratinocytes. In contrast to its effect on keratinocytes, IFNλ did not phosphorylate signal transducer and activator of transcription 1 in fibroblasts, but instead activated mitogen activated protein kinases (MAPK). Accordingly, inhibition of MAPK activation (p38 and p42/44) blocked the expression of MxA protein in fibroblasts but not in keratinocytes. Functionally, IFNλ inhibited proliferation in keratinocytes but not in fibroblasts. Moreover, IFNλ upregulated the expression of Tumor growth factor beta 1 (TGFβ1)-induced collagens in fibroblasts. Taken together, our findings identify primary human dermal fibroblasts as responder cells to IFNλ. Our study shows cutaneous cell type-specific IFN signaling and suggests that IFNλ, although important for epidermal antiviral competence, may also have a regulatory role in the dermal compartment balancing type I IFN-induced inhibition of tissue repair processes.