Abstract
TLR7 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.
Highlights
Toll Like Receptor 7 (TLR7) is of interest as a therapeutic target for chronic viral infections, including those with Human Immunodeficiency virus (HIV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV), and for other non-infectious diseases such as cancer, asthma and autoimmunity (Savva and Roger, 2013; Funk et al, 2014; Boonstra et al, 2011)
We assessed single nucleotide polymorphism (SNP) prevalence between cohorts for the various ethnicities separately to exclude that the ethnical composition of the cohorts would influence SNP prevalence
Our results demonstrate that rs179008 may reduce the risk of heterozygous Caucasian females to develop chronic HBV (CHB), and that the heterozygous SNP genotype and female sex together positively influence plasmacytoid dendritic cells (pDCs) phenotypic maturation, while CHB impairs pDC maturation
Summary
Toll Like Receptor 7 (TLR7) is of interest as a therapeutic target for chronic viral infections, including those with Human Immunodeficiency virus (HIV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV), and for other non-infectious diseases such as cancer, asthma and autoimmunity (Savva and Roger, 2013; Funk et al, 2014; Boonstra et al, 2011). TLR ligation induces pDC phenotypic maturation, characterized by upregulation of co-stimulatory molecules such as CD40, CD80 and CD86 and by the secretion of pro-inflammatory cytokines (Gibson et al, 2002; Krug et al, 2001). Via these and other receptors and cytokines, pDCs communicate with other immune cells and exert IFN-independent immune functions, such as antigen presentation to T cells or facilitating B cell differentiation (Mathan et al, 2013). Both the induction of IFNα and adaptive immunity by pDCs are considered important for TRL7
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