Dataset Information

Interferon gamma inducible protein 16 (IFI16) expression is reduced in mantle cell lymphoma.

ABSTRACT: IFI16, member of the IFN-inducible PYHIN-200 gene family, modulates proliferation, survival and differentiation of different cell lineages. In particular, IFI16 expression, which is regulated during the differentiation of B cells, was recently studied in B-CLL as well. Here, we compared IFI16 expression in several lymphomas including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma and mantle cell lymphoma with respect to normal cell counterparts. We observed that IFI16 expression was significantly deregulated only in mantle cell lymphoma (p < 0.05). Notably, IFI16 was associated with the expression of genes involved in interferon response, cell cycle, cell death and proliferation and, interestingly, lipid and glucose metabolism, suggesting that IFI16 deregulation might be associated with relevant changes in cell biology. In our group of mantle cell lymphoma samples a correlation between patient survival and IFI16 expression was not detected even though mantle cell lymphoma prognosis is known to be associated with cell proliferation. Altogether, these results suggest a complex relationship between IFI16 expression and MCL which needs to be analyzed in further studies.

SUBMITTER: Piccaluga PP

PROVIDER: S-EPMC6893061 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Interferon gamma inducible protein 16 (IFI16) expression is reduced in mantle cell lymphoma.

Piccaluga Pier Paolo PP Navari Mohsen M Visani Axel A Rigotti Flavia F Agostinelli Claudio C Righi Simona S Diani Erica E Ligozzi Marco M Carelli Maria M Ponti Cristina C Bon Isabella I Zipeto Donato D Landolfo Santo S Gibellini Davide D

Heliyon 20191114 11

IFI16, member of the IFN-inducible PYHIN-200 gene family, modulates proliferation, survival and differentiation of different cell lineages. In particular, IFI16 expression, which is regulated during the differentiation of B cells, was recently studied in B-CLL as well. Here, we compared IFI16 expression in several lymphomas including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma and mantle cell lymphoma with respect to normal cell counterparts. We o ...[more]

PMID: 31840115

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Project description:We determined the transcription profile of adeno-associated virus type 2 (AAV2)-infected primary human fibroblasts. Subsequent analysis revealed that cells respond to AAV infection through changes in several significantly affected pathways, including cell cycle regulation, chromatin modulation, and innate immune responses. Various assays were performed to validate selected differentially expressed genes and to confirm not only the quality but also the robustness of the raw data. One of the genes upregulated in AAV2-infected cells was interferon-γ inducible factor 16 (IFI16). IFI16 is known as a multifunctional cytosolic and nuclear innate immune sensor for double-stranded as well as single-stranded DNA, exerting its effects through various mechanisms, such as interferon response, epigenetic modifications, or transcriptional regulation. IFI16 thereby constitutes a restriction factor for many different viruses among them, as shown here, AAV2 and thereof derived vectors. Indeed, the post-transcriptional silencing of IFI16 significantly increased AAV2 transduction efficiency, independent of the structure of the virus/vector genome. We also show that IFI16 exerts its inhibitory effect on AAV2 transduction in an immune-modulatory independent way by interfering with Sp1-dependent transactivation of wild-type AAV2 and AAV2 vector promoters.ImportanceAdeno-associated virus (AAV) vectors are among the most frequently used viral vectors for gene therapy. The lack of pathogenicity of the parental virus, the long-term persistence as episomes in non-proliferating cells, and the availability of a variety of AAV serotypes differing in their cellular tropism are advantageous features of this biological nanoparticle. To deepen our understanding of virus-host interactions, especially in terms of antiviral responses, we present here the first transcriptome analysis of AAV serotype 2 (AAV2)-infected human primary fibroblasts. Our findings indicate that interferon-γ inducible factor 16 acts as an antiviral factor in AAV2 infection and AAV2 vector-mediated cell transduction in an immune-modulatory independent way by interrupting the Sp1-dependent gene expression from viral or vector genomes.

Project description:Human endogenous retroviruses (HERVs) are under genomic and epigenetic control but can be expressed in normal tissues, producing RNA transcripts some of which are translated. While it has not been demonstrated experimentally in modern humans, cDNA copies from HERV RNA (namely HERV-K HML-2 or HK2) were produced after the human-chimp split and until at least 250,000 years ago. We were interested in determining if such cDNA could be a ligand for pattern recognition receptors (PRRs) of the innate immune response. The AIM-2-like receptors for DNA, interferon-γ-inducible protein 16 (IFI16) and Cyclic GMP-AMP synthase (cGAS) were candidate PRRs. IFI16 can detect cDNA produced during HIV-1 replication, causing increased T cell death. While HIV-1 has emerged relatively recently as a human pathogen, the cDNA functionality of IFI16 could have been selected for during the course of human evolution. Here we present a novel hypothesis that the products of reverse transcription of HK2, which has been proliferating in the genome of human ancestors for 30 million years, could interact with IFI16. In support of our hypothesis, we provide preliminary data showing that IFI16 (but not cGAS) interacts with synthetic single-stranded HK2 oligos corresponding to the first product of reverse transcription. Further, we show that ssDNA detection by IFI16 has variability with respect to sequence features but is not dependent on strong secondary structures mimicking dsDNA. Among the HK2 oligos, IFI16 interacts more intensely with those derived from LTRs, suggesting these oligos have undetermined structural features that allow IFI16 to bind with greater affinity. Further, cells with stem cell features that naturally allow HK2 expression were found to express many components of the innate immune system including cGAS but not IFI16. Based on the presented preliminary data we further postulate another hypothesis: that the IFI16 functionality in human cells has been acting as "second-line" defense to control abnormal HK2 replication in somatic tissues. The absence of this protein in stem cells and a stem cell line could permit these cells to express HERVs which contribute to stem cell identity. Finally, we also comment on potential studies that could support or refute our hypothesis.

Project description:ObjectiveTo examine the association between anti-interferon-inducible protein 16 (anti-IFI-16) antibodies and clinical features of scleroderma.MethodsSera from a discovery sample of 94 patients with scleroderma and 47 healthy controls were assayed for anti-IFI-16 antibodies by enzyme-linked immunosorbent assay, and associations were examined using regression analyses. Since anti-IFI-16 autoantibodies were found to be strongly associated with digital gangrene in the discovery sample, a subsequent case-control study (with subjects matched 1:1 on disease duration) was designed for further exploration. Cases were patients with scleroderma and digital gangrene, while controls were patients with scleroderma and Raynaud's phenomenon alone (n = 39 matched pairs). Nonparametric, unadjusted matched pairs analysis as well as univariate and multivariable conditional logistic regression analyses were performed.ResultsIn the discovery sample, anti-IFI-16 antibodies were more prevalent in patients with scleroderma than in healthy controls (18% versus 2%; P = 0.01). Patients with anti-IFI-16 antibodies, compared to anti-IFI-16 antibody-negative patients, were more likely to have limited scleroderma (77% versus 46%; P = 0.03), a longer disease duration (median 15.2 years [interquartile range 10.6-18.3] versus 6.0 years [interquartile range 3.4-13.8]; P < 0.01), digital gangrene (24% versus 4%; P = 0.02), and a low diffusing capacity for carbon monoxide (DLco) (P < 0.01). In the case-control study, 35 (45%) of 78 patients were anti-IFI-16 antibody positive. Anti-IFI-16 antibody levels were significantly higher in cases with digital gangrene than in matched controls (P = 0.02). In analyses adjusted for age, cutaneous scleroderma subtype, smoking, and DLco, high anti-IFI-16 antibody levels were associated with the presence of digital gangrene (adjusted odds ratio 2.3, 95% confidence interval 1.0-5.6, P = 0.05). The odds of having digital gangrene increased with higher anti-IFI-16 antibody titers, in a dose-dependent manner.ConclusionAnti-IFI-16 antibodies are associated with digital gangrene in patients with scleroderma. Longitudinal prospective studies exploring anti-IFI-16 antibodies as a disease biomarker, and biologic studies investigating the pathogenicity of these antibodies, are warranted.

Dataset Information

Interferon gamma inducible protein 16 (IFI16) expression is reduced in mantle cell lymphoma.

Publications

Interferon gamma inducible protein 16 (IFI16) expression is reduced in mantle cell lymphoma.

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