Relapse of polymyalgia rheumatica following adjuvanted influenza vaccine: A case-based review

Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatological condition affecting individuals aged >50 years. There have been rare reports of PMR and other vasculitides developing within 3 months of influenza vaccination. Influenza is a major public health issue associated with seasonal increased mortality and intensified health care service use. Annual vaccination is the most effective intervention to prevent influenza, especially in elderly individuals. We report a severe “flare” of PMR in a 70-year-old patient after receiving the adjuvanted trivalent influenza vaccine, as recommended by the Joint Committee on Vaccination and Immunisations for this age group in the UK National Health Service in 2018-2019. The adverse event (AE) could be interpreted as the newly described autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome) as both PMR and ASIA display hyperactive immune responses. Caution is warranted in the use of vaccine adjuvants in patients with PMR with pre-existing imbalance of B and T cell homeostasis. Rare AEs are important to individuals, and personalized medicine means we should move away from “one size fits all” for vaccines, as well as for therapeutics

Identification of a residue in hepatitis C virus E2 glycoprotein that determines scavenger receptor BI and CD81 receptor dependency and sensitivity to neutralizing antibodies.

Hepatitis C virus (HCV) infection is dependent on at least three coreceptors: CD81, scavenger receptor BI (SR-BI), and claudin-1. The mechanism of how these molecules coordinate HCV entry is unknown. In this study we demonstrate that a cell culture-adapted JFH-1 mutant, with an amino acid change in E2 at position 451 (G451R), has a reduced dependency on SR-BI. This altered receptor dependency is accompanied by an increased sensitivity to neutralization by soluble CD81 and enhanced binding of recombinant E2 to cell surface-expressed and soluble CD81. Fractionation of HCV by density gradient centrifugation allows the analysis of particle-lipoprotein associations. The cell culture-adapted mutation alters the relationship between particle density and infectivity, with the peak infectivity occurring at higher density than the parental virus. No association was observed between particle density and SR-BI or CD81 coreceptor dependence. JFH-1 G451R is highly sensitive to neutralization by gp-specific antibodies, suggesting increased epitope exposure at the virion surface. Finally, an association was observed between JFH-1 particle density and sensitivity to neutralizing antibodies (NAbs), suggesting that lipoprotein association reduces the sensitivity of particles to NAbs. In summary, mutation of E2 at position 451 alters the relationship between particle density and infectivity, disrupts coreceptor dependence, and increases virion sensitivity to receptor mimics and NAbs. Our data suggest that a balanced interplay between HCV particles, lipoprotein components, and viral receptors allows the evasion of host immune responses

HCV and the hepatic lipid pathway as a potential treatment target

Atherosclerosis has been described as a liver disease of the heart. The liver is the central regulatory organ of lipid pathways but since dyslipidaemias are major contributors to cardiovascular disease and type 2 diabetes rather than liver disease, research in this area has not been a major focus for hepatologists. Virus-host interaction is a continuous co-evolutionary process involving the host immune system and viral escape mechanisms. One of the strategies HCV has adopted to escape immune clearance and establish persistent infection is to make use of hepatic lipid pathways. This review aims to: update the hepatologist on lipid metabolism; review the evidence that HCV exploits hepatic lipid pathways to its advantage; discuss approaches to targeting host lipid pathways as adjunctive therapy

Revisiting the Elusive Hepatitis C Vaccine

The impactful discovery and subsequent characterisation of hepatitis C virus (HCV), an RNA virus of the flavivirus family, led to the awarding of the 2020 Nobel Prize in Physiology or Medicine to Harvey J. Alter, Michael Houghton and Charles M. Rice [...

Infection with the hepatitis C virus causes viral genotype-specific differences in cholesterol metabolism and hepatic steatosis

Lipids play essential roles in the hepatitis C virus (HCV) life cycle and patients with chronic HCV infection display disordered lipid metabolism which resolves following successful anti-viral therapy. It has been proposed that HCV genotype 3 (HCV-G3) infection is an independent risk factor for hepatocellular carcinoma and evidence suggests lipogenic proteins are involved in hepatocarcinogenesis. We aimed to characterise variation in host lipid metabolism between participants chronically infected with HCV genotype 1 (HCV-G1) and HCV-G3 to identify likely genotype-specific differences in lipid metabolism. We combined several lipidomic approaches: analysis was performed between participants infected with HCV-G1 and HCV-G3, both in the fasting and non-fasting states, and after sustained virological response (SVR) to treatment. Sera were obtained from 112 fasting patients (25% with cirrhosis). Serum lipids were measured using standard enzymatic methods. Lathosterol and desmosterol were measured by gas-chromatography mass spectrometry (MS). For further metabolic insight on lipid metabolism, ultra-performance liquid chromatography MS was performed on all samples. A subgroup of 13 participants had whole body fat distribution determined using in vivo magnetic resonance imaging and spectroscopy. A second cohort of (non-fasting) sera were obtained from HCV Research UK for comparative analyses: 150 treatment naïve patients and 100 non-viraemic patients post-SVR. HCV-G3 patients had significantly decreased serum apoB, non-HDL cholesterol concentrations, and more hepatic steatosis than those with HCV-G1. HCV-G3 patients also had significantly decreased serum levels of lathosterol, without significant reductions in desmosterol. Lipidomic analysis showed lipid species associated with reverse cholesterol transport pathway in HCV-G3. We demonstrated that compared to HCV-G1, HCV-G3 infection is characterised by low LDL cholesterol levels, with preferential suppression of cholesterol synthesis via lathosterol, associated with increasing hepatic steatosis. The genotype-specific lipid disturbances may shed light on genotypic variations in liver disease progression and promotion of hepatocellular cancer in HCV-G3

A Collaborative Clearinghouse for Data Management Training and Education Resources

Objective: The main objectives of this breakout session are for the Data Management Training (DMT) Clearinghouse team to: 1) introduce the Clearinghouse and its current design and implementation, 2) solicit submissions to its learning resource inventory, and 3) collect feedback upon its web interface and future development. Features of the Clearinghouse that will be demonstrated include how to search and browse its inventory as well as submit a learning resource to the Clearinghouse using the LRMI (Learning Resource Metadata Initiative) metadata format. The team will also share the roadmap for the Clearinghouse’s upcoming features. In order to provide feedback regarding the Clearinghouse’s usability, the team will invite the session attendees to test the Clearinghouse’s services and will encourage comments to guide its future development. Setting/Participants/Resources: Since the DMT Clearinghouse is entirely accessible via the web, in order to demonstrate the Clearinghouse successfully, a reliable (and preferably free of charge) internet connection, and an overhead projecting capability will need to be available to the presenter. It would also be very useful for the attendees of the session to have access to the same internet connection, so that if they desire, the attendees can follow along with the steps of the demonstration, and contribute to the Clearinghouse inventory. The main presenter will plan to bring her own laptop with built-in standard HDMI and USB ports. As a result, it will be helpful if a HDMI or USB cable could also be provided for the presenter to connect her laptop to the projecting equipment. Method: Many research organizations, government agencies, and academic institutions have been developing excellent learning resources in order to support and meet the needs for data management training. However, these learning resources are often hosted on various websites and spread across various scientific domains. Consequently, these resources can be difficult to locate, especially by those who are not already familiar with the creators/authors. This is a barrier to the use and reuse of these resources, and can have significant impact on the promotion and propagation of best practices for data management. To address this need within the Earth sciences, the U.S. Geological Survey’s (USGS) Community for Data Integration (CDI), the Federation of Earth Science Information Partners (ESIP), and the Data Observation Network for Earth (DataONE) have collaborated to create a web-based Clearinghouse1 for collecting data management learning resources that are focused on the Earth sciences. The initial seed funding for the effort was provided by a grant received from the USGS CDI earlier in 2016, and ESIP’s Drupal site provided the hosting infrastructure for the Clearinghouse. Members from the USGS, DataONE, ESIP’s Data Stewardship Committee and its Data Management Training Working Group, Knowledge Motifs LLC, as well as Blue Dot Lab met regularly between April and October, 2016 in order to discuss, create, and implement the content structure and infrastructure components necessary to build the current revision of the Clearinghouse. 1. http://dmtclearinghouse.esipfed.org Results: As a registry of information about the educational resources on topics related to research data management (initially focused on Earth sciences), the Clearinghouse serves as a centralized location for searching or browsing an inventory of these learning resources. Currently, the Clearinghouse offers search and browse functionality that is open to all, and submission of information about educational resources by login with a free ESIP account. To assist with discoverability, the learning resources are described using Learning Resource Metadata Initiative (LRMI) schema. Additionally, the resources may be associated with the steps of data and research life cycles, such as the USGS CDI’s Science Support Framework2 and DataONE’s Data Life Cycle3. Leveraging the team’s collective experience in creating, presenting and distributing data management learning resources, the Clearinghouse included the learning resources from USGS, ESIP, and DataONE as its initial inventory, but is expanding to resources from NASA and others. Crowdsourcing is currently the main mechanism for sustaining the Clearinghouse. Going forward, in addition to the built-in workflow to allow anyone from the public to submit descriptive information about the data management learning resources that s/he wishes to share, future capabilities will be added to enable contributions to review, edit, and rank the submissions, as desired. 2. https://my.usgs.gov/confluence/display/cdi/CDI+Science+Support+Framework3. https://www.dataone.org/data-life-cycle Discussion/Conclusion: The DMT Clearinghouse team was successful in completing the initial development phase as scheduled for the first six months of its funding, including some informal usability testing of the interface. The team aims to continue to develop and enhance the Clearinghouse’s capabilities, including the evaluation of its usability, through collaboration with additional communities, and if feasible, adding the capability for bulk-loading of learning resources. Being able to present the Clearinghouse at the eScience Symposium would not only allow those who are involved with or would like to learn about data management to leverage the Clearinghouse’s resources, but also connect those who would like to contribute to the project with the Clearinghouse team. Ultimately, the Clearinghouse is designed so that the resources from its inventory could be used in a variety of data management training and education environments. By exposing the Clearinghouse to diverse users and communities, the Clearinghouse team can better assess how the Clearinghouse can be updated and what technological enhancements to pursue in the future in order to improve our support of research data management training needs

Characterization and epitope mapping of human monoclonal antibodies to PDC-E2, the immunodominant autoantigen of primary biliary cirrhosis

Further to define the epitopes of PDC-E2, the major autoantigen in primary biliary cirrhosis (PBC), we have developed and characterized five human monoclonal antibodies. These antibodies were derived by fusing a regional hepatic lymph node from a patient with PBC with the mouse human heterohybrid cell line F3B6. Previous studies of epitope mapping of PDC-E2 have relied on whole sera and have suggested that the immunodominant epitope lies within the inner lipoyl domain of the molecule. However, selective absorption studies using whole sera and a series of overlapping recombinant peptides of PDC-E2 have suggested that the epitope may also include a large conformational component. Moreover, several laboratories have suggested that autoantibodies against the 2-oxo acids dehydrogenase autoantigens are cross-reactive. The five monoclonal antibodies generated included three IgG2a and two IgM antibodies and were studied for antigen specificity using recombinant PDC-E2, recombinant BCKD-E2, histone, dsDNA, IgG (Fc), collagen and a recombinant irrelevant liver specific control, the F alloantigen. The antibodies were also used to probe blots of human, bovine, mouse and rat mitochondria. Finally, fine specificity was studied by selective ELISA and absorption against overlapping expressing fragments of PDC-E2. All five monoclonals, but none of the other mitochondrial autoantigens were specific for PDC-E2. In fact, although affinity purified antibodies to PDC-E2 from patients with PBC cross-reacted with protein X, the human monoclonals did not, suggesting that protein X contains an epitope distinct from that found on PDC-E2. Additionally, all three IgG2 monoclonals recognized distinct epitopes within the inner lipoyl domain of PDC-E2. © 1992