Hepatitis B virus (HBV)-associated acute liver failure (ALF) is a dramatic clinical syndrome leading to death or liver transplantation in 80% of cases. Due to the extremely rapid clinical course, the difficulties in obtaining liver specimens, and the lack of an animal model, the pathogenesis of ALF remains largely unknown. Here, we performed a comprehensive genetic and functional characterization of the virus and the host in liver tissue from HBV-associated ALF and compared the results with those of classic acute hepatitis B in chimpanzees. In contrast with acute hepatitis B, HBV strains detected in ALF livers displayed highly mutated HBV core antigen (HBcAg), associated with increased HBcAg expression ex vivo, which was independent of viral replication levels. Combined gene and miRNA expression profiling revealed a dominant B cell disease signature, with extensive intrahepatic production of IgM and IgG in germline configuration exclusively targeting HBcAg with subnanomolar affinities, and complement deposition. Thus, HBV ALF appears to be an anomalous T cell-independent, HBV core-driven B cell disease, which results from the rare and unfortunate encounter between a host with an unusual B cell response and an infecting virus with a highly mutated core antigen.

RI provides unique insights into disease pathogenesis. For molecular and cellular MRI, several contrast agents, each with different ability to enhance water proton relaxivity, have been exploited, including gadolinium chelates, iron oxide particles, and a family of chemical shift saturation transfer contrast agents (1-3). More recently, interest in fluorine 19 ( 19 F) emulsions has grown because fluorine MR signal from soft tissues is absent, and emulsions of fluorocarbon are biocompatible agents (4). Therefore, 19 F MRI is being explored for several applications, including cell tracking (4-8), molecular sensing (9,10) and for imaging inflammation in various diseased models (11)(12)(13)(14)(15)(16). Furthermore, since the 19 F MRI signal is directly related to the number of fluorine atoms, labeled cells can be quantified and monitored for a long time. Importantly, 19 F signal from fluorocarbons does not disturb standard proton ( 1 H) MRI and does not need precontrast data acquisition.Multicolor 19 F MRI has been previously attempted (8,17,18) with the use of fluorocarbons with multiresonance frequencies from nonequivalent fluorine nuclei that induce image artifacts and considerably limit the sensitivity and specificity of fluorine signal (19).We propose the use of two fluorocarbons with two clearly distinct resonance frequencies and a high number of chemically equivalent fluorine nuclei suitable for multispectral 19 F MRI. In particular, both 19 F nanoparticles were used to differentiate the normal and enhanced activity of phagocytosis after temporary inhibition of the colony stimulating factor 1 receptor (CSF1R), a key regulator of mononuclear cell production, differentiation, migration, and activation (20). CSF1R inhibition has been reported to be effective for depleting macrophages and microglial cells, which are rapidly regenerated within a few days after treatment interruption (21) and with an increase of phagocytic activity (20). In our study, we aimed to follow this