ID: 231. Issue 1 (November 2015)

• Record Type: Journal Article
• Authors: Nooruzzaman, Mohammed; Grabski, Elena; Hartmann, Rune; Pietschmann, Thomas; Kalinke, Ulrich
• Is Part Of: Cytokine. Volume 76:Issue 1(2015)
• Page Start: 107
• Publication Date: 2015-11
• Subjects: Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2015.08.234
• Languages: English
• ISSNs: 1043-4666

Abstract

<abstract xml:lang="en" abstract-type="author" id="ab005"> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p id="sp005">Host genetic variability, as manifested in single nucleotide (SNP) variations found within distinct alleles of genes that are relevant for the immune system, may have dramatic consequences on infection susceptibility and disease outcome. A recently identified SNP (rs12979860, minor TT allele) within the promoter region of IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7p9s" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e120" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">λ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>3 (IL28B) turned out to be associated with reduced spontaneous clearance of hepatitis C virus (HCV) as well as impaired sustained viral response in chronically HCV infected patients. rs12979860 shows high linkage disequilibrium with the ss469415590 (<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7rr0" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e125" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>G/<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7rr0" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e130" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>G, minor allele) that results in frameshift and reconstitution of the IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7p9s" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e135" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">λ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>4 gene. Although IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7p9s" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e140" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">λ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>4 positive individuals cleared HCV less efficiently than IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7p9s" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e146" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">λ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>4 negative ones, recombinant IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7p9s" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e151" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">λ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>4 exhibits anti-HCV activity <italic>in vitro</italic>. To test whether the minor allele is associated with compromised immune cell functions, we stimulated human peripheral blood mononuclear cells (PBMC) carrying either the minor or the major allele with synthetic TLR ligands. Interestingly, under such conditions all PBMC mounted similar IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7m63" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si8.gif" display="inline" overflow="scroll" id="d13e159" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">α</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> response. Furthermore, primary human plasmacytoid dendritic cells (pDC) stimulated with the HCV variant Jc1 responded similarly, irrespective of whether they carried the major or the minor allele. On the contrary, pDC carrying the minor allele mounted reduced IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7m63" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si8.gif" display="inline" overflow="scroll" id="d13e164" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">α</mml:mi></mml:mrow></mml:math></alternatives></inline-formula> responses upon stimulation with Jc1 infected hepatoma cells. In conclusion, this observation correlated with impaired responses to IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7m63" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si8.gif" display="inline" overflow="scroll" id="d13e169" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">α</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>2/ribavirin therapy and reduced spontaneous virus clearance of chronically HCV infected <inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7rr0" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e175" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>G/<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7rr0" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si2.gif" display="inline" overflow="scroll" id="d13e180" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>G patients, highlighting the option to now in depth analyse the functional role of IFN-<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7p9s" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e185" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi mathvariant="normal">λ</mml:mi></mml:mrow></mml:math></alternatives></inline-formula>4.</p> </sec> </abstract>