A Toll-like receptor 7 single nucleotide polymorphism protects from advanced inflammation and fibrosis in male patients with chronic HCV-infection

Schott, Eckart; Witt, Heiko; Neumann, Konrad; Taube, Stefan; Oh, Djin-Ye; Schreier, E.; Vierich, Sandra; Puhl, Gero; Bergk, A.; Halangk, Juliane; Weich, V.; Wiedenmann, Bertram; Berg, Thomas

doi:10.1016/j.jhep.2007.03.021

Cited by 86 publications

(65 citation statements)

References 48 publications

(49 reference statements)

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“…Incomplete X-inactivation of TLR7 may contribute to the effects of sex. Although previous studies found no evidence for incomplete or skewed X-inactivation this was recently challenged by Souyris and colleagues who reported that pDC express more TLR7 in females due to escape of X-inactivation (Schott et al, 2007a;Berghöfer et al, 2006;Souyris et al, 2018). Besides, TLR7 function may be enhanced by female hormones and/or enhanced expression of molecules downstream of TLR7 (Seillet et al, 2012(Seillet et al, , 2013Griesbeck et al, 2015).…”

Section: Discussionmentioning

confidence: 94%

“…Furthermore, in HIV, the variant allele associated with higher infection rates, viral load and disease progression (Oh et al, 2009;Said et al, 2014). In HCV, the variant was more prevalent among chronic patients as compared to healthy controls and related to a poor IFNα treatment response (Schott et al, 2007a;Askar et al, 2010). For HBV, the prevalence of the variant allele among chronic patients has not yet been explored.…”

Section: Introductionmentioning

confidence: 99%

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TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

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A B S T R A C TTLR7 agonists are of high interest for the treatment of cancer, auto-immunity and chronic viral infections. They are known to activate plasmacytoid dendritic cells (pDCs) to produce high amounts of Type I Interferon (IFN) and to facilitate T and B cell responses, the latter with the help of maturation markers such as CD40, CD80 and CD86. The TLR7 single nucleotide polymorphism (SNP) rs179008 (GLn11Leu), sex and chronic viral infection have all been reported to influence pDC IFN production. It is unknown, however, whether these factors also influence pDC phenotypic maturation and thereby IFN-independent pDC functions. Furthermore, it is unclear whether SNP rs179008 influences HBV susceptibility and/or clearance.Here we investigated whether the SNP rs179008, sex and HBV infection affected phenotypic maturation of pDCs from 38 healthy individuals and 28 chronic HBV patients. In addition, we assessed SNP prevalence in a large cohort of healthy individuals (n = 231) and chronic HBV patients (n = 1054).Consistent with previous reports, the rs179008 variant allele was largely absent in Asians and more prevalent in Caucasians. Among Caucasians, the SNP was equally prevalent in healthy and chronically infected males. The SNP was, however, significantly more prevalent in healthy females than in those with chronic HBV infection (42 versus 28%), suggesting that in females it may offer protection from chronic infection. Ex vivo experiments demonstrated that induction of the co-stimulatory molecules CD40 and CD86 by TLR7 ligands, but not TLR9 ligands, was augmented in pDCs from healthy SNP-carrying females. Furthermore, CD80 and CD86 upregulation was more pronounced in females independent of the SNP. Lastly, our data suggested that chronic HBV infection impairs pDC maturation. These findings provide insight into factors determining TLR7 responses, which is important for further clinical development of TLR7-based therapies.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

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“…Important variations in type I IFN response were observed between outbred sheep, but all of the tested LDL cells (20 sheep in total) displayed type I IFN response after in vitro stimulation with CpG ODN (data not shown). These intersheep variations in type I IFN response might be attributable to individual genetic characteristics, such as single nucleotide polymorphism in the TLR or in the signaling molecules of the TLR cascade (46). Interestingly, when a same sheep was cannulated for afferent and efferent lymph collection on contralateral sides, LDL cells collected from efferent lymph and cultured with CpG did not produce any detectable IFN, whereas LDL cells from afferent lymph produced 500 UI/ml type I IFN (Fig.…”

Section: In Vitro Induction Of Type I Ifn Synthesis In Sheep Lymph Cementioning

confidence: 98%

Plasmacytoid Dendritic Cells Migrate in Afferent Skin Lymph

Pascale

Contreras

Bonneau³

et al. 2008

The Journal of Immunology

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Conventional dendritic cells enter lymph nodes by migrating from peripheral tissues via the lymphatic route, whereas plasmacytoid dendritic cells (pDC), also called IFN-producing cells (IPC), are described to gain nodes from blood via the high endothelial venules. We demonstrate here that IPC/pDC migrate in the afferent lymph of two large mammals. In sheep, injection of type A CpG oligodinucleotide (ODN) induced lymph cells to produce type I IFN. Furthermore, low-density lymph cells collected at steady state produced type I IFN after stimulation with type A CpG ODN and enveloped viruses. Sheep lymph IPC were found within a minor BnegCD11cneg subset expressing CD45RB. They presented a plasmacytoid morphology, expressed high levels of TLR-7, TLR-9, and IFN regulatory factor 7 mRNA, induced IFN-γ production in allogeneic CD4pos T cells, and differentiated into dendritic cell-like cells under viral stimulation, thus fulfilling criteria of bona fide pDC. In mini-pig, a CD4posSIRPpos subset in afferent lymph cells, corresponding to pDC homologs, produced type I IFN after type A CpG-ODN triggering. Thus, pDC can link innate and acquired immunity by migrating from tissue to draining node via lymph, similarly to conventional dendritic cells.

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“…Likewise, polymorphisms in TLR7 and TLR8 have been linked to susceptibility to HCV infection in the Taiwanese population (Wang and others 2011). On the other hand, the c.1-120T > G TLR7 SNP was found to protect against advanced inflammation and fibrosis in male patients with chronic HCV infection (Schott 2007).…”

Section: Snps In Other Tlrsmentioning

confidence: 97%

Toll-Like Receptor Polymorphisms, Inflammatory and Infectious Diseases, Allergies, and Cancer

Medvedev

2013

Journal of Interferon & Cytokine Research

123

101

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Toll-like receptors (TLRs) are germ-line-encoded innate immune sensors that recognize conserved microbial structures and host alarmins and signal expression of MHC proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These processes activate immediate and early mechanisms of innate host defense, as well as initiate and orchestrate adaptive immune responses. Several single-nucleotide polymorphisms (SNPs) within the TLR genes have been associated with altered susceptibility to infectious, inflammatory, and allergic diseases, and have been found to play a role in tumorigenesis. Critical advances in our understanding of innate immune functions and genome-wide association studies (GWAS) have uncovered complex interactions of genetic polymorphisms within TLRs and environmental factors. However, conclusions obtained in the course of such analyses are restricted by limited power of many studies that is likely to explain controversial findings. Further, linkages to certain ethnic backgrounds, gender, and the presence of multigenic effects further complicate the interpretations of how the TLR SNPs affect immune responses. For many TLRs, the molecular mechanisms by which SNPs impact receptor functions remain unknown. In this review, I have summarized current knowledge about the TLR polymorphisms, their impact on TLR signaling, and associations with various inflammatory, infectious, allergic diseases and cancers, and discussed the directions of future scientific research.

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A Toll-like receptor 7 single nucleotide polymorphism protects from advanced inflammation and fibrosis in male patients with chronic HCV-infection

Cited by 86 publications

References 48 publications

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

Plasmacytoid Dendritic Cells Migrate in Afferent Skin Lymph

Toll-Like Receptor Polymorphisms, Inflammatory and Infectious Diseases, Allergies, and Cancer

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