A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature

Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
Nature (Impact Factor: 41.46). 09/2010; 467(7314):460-4. DOI: 10.1038/nature09386
Source: PubMed


Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-a macrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85 × 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 × 10(-10); odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.

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Available from: L. Bottolo, Dec 28, 2013
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    • "The helicase enzyme IFIH1 (also known as MDA5 or melanoma differentiation-associated protein-5) triggers the secretion of interferons in response to viral infection. The interferon-regulating factor 7-(IRF7-) driven inflammatory network (IDIN) genes also contribute to the risk of T1D [69]. Different non-MHC candidate gene products related to T1D involving the cytokine pathways are IL "
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    ABSTRACT: We review type 1 diabetes and host genetic components, as well as epigenetics and viruses associated with type 1 diabetes, with added emphasis on the enteroviruses, which are often associated with triggering the disease. Genus Enterovirus is classified into twelve species of which seven (Enterovirus A, Enterovirus B, Enterovirus C, and Enterovirus D and Rhinovirus A, Rhinovirus B, and Rhinovirus C) are human pathogens. These viruses are transmitted mainly by the fecal-oral route; they may also spread via the nasopharyngeal route. Enterovirus infections are highly prevalent, but these infections are usually subclinical or cause a mild flu-like illness. However, infections caused by enteroviruses can sometimes be serious, with manifestations of meningoencephalitis, paralysis, myocarditis, and in neonates a fulminant sepsis-like syndrome. These viruses are often implicated in chronic (inflammatory) diseases as chronic myocarditis, chronic pancreatitis, and type 1 diabetes. In this review we discuss the currently suggested mechanisms involved in the viral induction of type 1 diabetes. We recapitulate current basic knowledge and definitions.
    12/2014; 2014. DOI:10.1155/2014/738512
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    • "In addition to IFIH1 other innate immune system genes in the IRF7 - driven network may also be associated with the risk of diabetes [ Heinig et al . , 2010 ] . There was no ethical permission to carry out genetic analyses in these blood donors , and further studies in bigger study series are needed to find out if the IFIH1 / IRF7 polymorphisms regulate immune responses to CBV1 strains . In any case , CBV1 up - regulated genes in this IRF7 - driven inflam - matory network in different indiv"
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    ABSTRACT: Enterovirus infections are usually mild but can also cause severe illnesses and play a role in chronic diseases, such as cardiomyopathies and type 1 diabetes. Host response to the invading virus can markedly modulate the course of the infection, and this response varies between individuals due to the polymorphism of immune response genes. However, it is currently not known if virus strains also differ in their ability to stimulate the host immune system. Coxsackievirus B1 (CBV1) causes severe epidemics in young infants and it has recently been connected with type 1 diabetes in seroepidemiological studies. This study evaluated the ability of different field isolates of CBV1 to induce innate immune responses in PBMCs. CBV1 strains differed markedly in their capacity to induce innate immune responses. Out of the 18 tested CBV1 strains two induced exceptionally strong alpha interferon (IFN-α) response in PBMC cultures. The responding cell type was found to be the plasmacytoid dendritic cell. Such a strong innate immune response was accompanied by an up-regulation of several other immune response genes and secretion of cytokines, which modulate inflammation, and adaptive immune responses. These results suggest that enterovirus-induced immune activation depends on the virus strain. It is possible that the immunotype of the virus modulates the course of the infection and plays a role in the pathogenesis of chronic immune-mediated enterovirus diseases. J. Med. Virol. © 2014 Wiley Periodicals, Inc.
    Journal of Medical Virology 08/2014; 86(8). DOI:10.1002/jmv.23903 · 2.35 Impact Factor
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    • "Moreover, IFN-α-producing pDCs co-infiltrate and directly interact with B-1a cells and neutrophils in the pancreas of young NOD mice; this cross-talk is essential to the initiation of the diabetogenic T cell response and T1D development [98]. Interestingly, an integrated genome-wide analysis of human T1D revealed an IRF7-driven inflammatory network mimicking an antiviral response that may contribute to the risk of T1D [99]. Whether human pDCs are involved in such inflammation remains to be shown. "
    Wei Cao ·
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) were initially identified as the prominent natural type I interferon-producing cells during viral infection. Over the past decade, the aberrant production of interferon α/β by pDCs in response to self-derived molecular entities has been critically implicated in the pathogenesis of systemic lupus erythematosus and recognized as a general feature underlying other autoimmune diseases. On top of imperative studies on human pDCs, the functional involvement and mechanism by which the pDC-interferon α/β pathway facilitates the progression of autoimmunity have been unraveled recently from investigations with several experimental lupus models. This article reviews correlating information obtained from human in vitro characterization and murine in vivo studies and highlights the fundamental and multifaceted contribution of pDCs to the pathogenesis of systemic autoimmune manifestation.
    04/2014; 5(2):212. DOI:10.4172/2155-9899.1000212
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