TLR2 and TLR7/8 activation predict post partum HBV flares.

Abstract

Aim: To examine innate immune function in chronically infected HBV pregnant women (on/off antiviral medications to prevent vertical transmission) during and after pregnancy and correlate it with post-partum hepatic flares. Background(s): Maternal tolerance to fetal antigens reverses post partum, and causes immune reconstitution in HBV infection which can result in hepatic flares which can be life threatening to the mother. The characteristics of these immune changes and their impact on and association with a variety of innate immunological and virological parameters is not well established. Method(s): Plasma and PBMCs were collected from patients at two sites at 5 different time points: first half of pregnancy, 3rd Trimester, 6 weeks post partum, 3 months post partum and 1 year post partum. TLR expression was measured on monocytes, NK cells and NK T cells by flow cytometry. PBMCs were also stimulated with TLR ligands LPS(TLR4), Pam3Cys(TLR2), CpG2006(TLR9), PolyI:C(TLR3), R848(TLR7/8) and assayed for cytokines by ELISA. NK cells (CD56 bright and 107A expresssion) were also examined to see if they are activated and able to kill hepatocytes using a TRAIL mediated mechanism. HBV viral load, quantitative HBeAg and HBsAg were also done at each timepoint. Result(s): 126 women were recruited up to Aug 2011: 23% were HBeAg positive and 36% had a hepatitis flare. Our results demonstrate elevated TLR2 expression in both monocytes(p < 0.02) and NK cells (p < 0.01) with increased specific TLR2 (P < 0.02) and TLR7/8 (p < 0.04) cytokine production, occurred in the third trimester in patients who developed post partum flares, with and without an increase in viral load. Activated NK cells overexpressed TRAIL and in ex vivo models caused caspase associated apoptosis of primary hepatocytes. Conclusion(s): These results demonstrate the importance of innate immune responses in relation to pregnancy-associated HBV flares. Cytokines may be driven by various TLRs and in turn activate TRAIL-mediated mechanisms of apoptosis of hepatocytes. More broadly, the findings elucidate the general mechanisms underlying dynamic alterations in ALT elevations and liver inflammation of HBV-associated flares.