The innate immune response plays an essential role in the prevention of early viral dissemination. We used the lymphocytic choriomeningitis virus model system to analyze the role of tissue macrophages/Kupffer cells in this process. Our findings demonstrated that Kupffer cells are essential for the efficient capture of infectious virus and for preventing viral replication. The latter process involved activation of Kupffer cells by interferon (IFN)-I and prevented viral spread to neighboring hepatocytes. In the absence of Kupffer cells, hepatocytes were not able to suppress virus replication, even in the presence of IFN-I, leading to prolonged viral replication and severe T cell-dependent immunopathology. Conclusion: Tissue-resident macrophages play a crucial role in early viral capture and represent the major liver cell type exhibiting responsiveness to IFN-I and providing control of viral replication. (HEPATOLOGY 2010;52:25-32) P ersistent infection with hepatitis B or hepatitis C virus is one of the leading causes of lethal liver disease resulting from the development of liver cirrhosis and/or hepatocellular cancer.1 Because both viruses are poorly cytopathic, most of the ensuing liver destruction results from CD8 þ T cell responses directed against virus-infected hepatocytes. These cells prevent rapid dissemination of the virus and control viral replication by secreting interferon (IFN)-c and perforin. However, in the event of viral persistence, exaggerated and prolonged T cell activation results in severe liver pathology which can eventually be fatal. 2,3Thus CD8 þ T cells play a crucial role in both virus control and immunopathology. [4][5][6][7][8] Macrophages are resident in every organ of the body.9-11 With their potent phagocytic capacity, theyAbbreviations: ALT, alanine aminotransferase; IFN, interferon; IFNAR, IFN-a receptor; LCMV, lymphocytic choriomeningitis virus; LCMV-NP, lymphocytic choriomeningitis virus nucleoprotein.From the

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The pathological hallmark of neurodegenerative diseases is the formation of toxic oligomers by proteins such as alpha-synuclein (aSyn) or microtubule-associated protein tau (Tau). Consequently, such oligomers are promising biomarker candidates for diagnostics as well as drug development. However, measuring oligomers and other aggregates in human biofluids is still challenging as extreme sensitivity and specificity are required. We previously developed surface-based fluorescence intensity distribution analysis (sFIDA) featuring single-particle sensitivity and absolute specificity for aggregates. In this work, we measured aSyn and Tau aggregate concentrations of 237 cerebrospinal fluid (CSF) samples from five cohorts: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and a neurologically-normal control group. aSyn aggregate concentration discriminates PD and DLB patients from normal controls (sensitivity 73%, specificity 65%, area under the receiver operating curve (AUC) 0.68). Tau aggregates were significantly elevated in PSP patients compared to all other groups (sensitivity 87%, specificity 70%, AUC 0.76). Further, we found a tight correlation between aSyn and Tau aggregate titers among all patient cohorts (Pearson coefficient of correlation r = 0.81). Our results demonstrate that aSyn and Tau aggregate concentrations measured by sFIDA differentiate neurodegenerative disease diagnostic groups. Moreover, sFIDA-based Tau aggregate measurements might be particularly useful in distinguishing PSP from other parkinsonisms. Finally, our findings suggest that sFIDA can improve pre-clinical and clinical studies by identifying those individuals that will most likely respond to compounds designed to eliminate specific oligomers or to prevent their formation.