Correlates of immune-mediated protection to most viral and cancer vaccines are still unknown. This impedes the development of novel vaccines to incurable diseases such as HIV and cancer. In this study, we have used functional genomics and polychromatic flow cytometry to define the signature of the immune response to the yellow fever (YF) vaccine 17D (YF17D) in a cohort of 40 volunteers followed for up to 1 yr after vaccination. We show that immunization with YF17D leads to an integrated immune response that includes several effector arms of innate immunity, including complement, the inflammasome, and interferons, as well as adaptive immunity as shown by an early T cell response followed by a brisk and variable B cell response. Development of these responses is preceded, as demonstrated in three independent vaccination trials and in a novel in vitro system of primary immune responses (modular immune in vitro construct [MIMIC] system), by the coordinated up-regulation of transcripts for specific transcription factors, including STAT1, IRF7, and ETS2, which are upstream of the different effector arms of the immune response. These results clearly show that the immune response to a strong vaccine is preceded by coordinated induction of master transcription factors that lead to the development of a broad, polyfunctional, and persistent immune response that integrates all effector cells of the immune system.
It is not understood how immune inflammation influences the pathogenesis of severe acute respiratory syndrome (SARS). One area of strong controversy is the role of interferon (IFN) responses in the natural history of SARS.The fact that the majority of SARS patients recover after relatively moderate illness suggests that the prevailing notion of deficient type I IFN-mediated immunity, with hypercytokinemia driving a poor clinical course, is oversimplified. We used proteomic and genomic technology to systematically analyze host innate and adaptive immune responses of 40 clinically well-described patients with SARS during discrete phases of illness from the onset of symptoms to discharge or a fatal outcome. A novel signature of high IFN-␣, IFN-␥, and IFN-stimulated chemokine levels, plus robust antiviral IFN-stimulated gene (ISG) expression, accompanied early SARS sequelae. As acute illness progressed, SARS patients entered a crisis phase linked to oxygen saturation profiles. The majority of SARS patients resolved IFN responses at crisis and expressed adaptive immune genes. In contrast, patients with poor outcomes showed deviated ISG and immunoglobulin gene expression levels, persistent chemokine levels, and deficient anti-SARS spike antibody production. We contend that unregulated IFN responses during acute-phase SARS may culminate in a malfunction of the switch from innate immunity to adaptive immunity. The potential for the use of the gene signatures we describe in this study to better assess the immunopathology and clinical management of severe viral infections, such as SARS and avian influenza (H5N1), is therefore worth careful examination.Severe acute respiratory syndrome coronavirus (SARS CoV) causes a spectrum of disease ranging from flu-like symptoms and viral pneumonia to acute respiratory distress syndrome and fatal outcomes (14,16,23,31,41). The mechanisms by which SARS CoV causes severe illness in humans are largely unknown. SARS CoV takes hold in the airways and other organs via its main putative receptor, angiotensin-converting enzyme 2 (ACE2), expressed on many cell types, including pneumocytes, enterocytes, and endothelial cells (19,25,32). SARS CoV appears to evade innate immunity during the first 10 days of infection during a period of widespread inflammation and steadily increasing viral load (39, 52). The consequent immune inflammation and hypercytokinemia, or "cytokine storm," during the course of SARS has been illustrated (22,27,33,37,51), but the molecular and cellular basis of how SARS CoV impacts host defense, resulting in a poor prognosis, is not understood. One particular area of controversy is the role of interferon (IFN) responses in human host immune responses against SARS CoV.Type I IFNs, such as IFN-␣ and -, are critical to innate immune responses against viral and other microbial infections and act in concert with IFN-␥ in the activation of antiviral IFN-stimulated genes (ISGs) and the immunomodulation of innate and adaptive immunity (3,36,42,48). It has been proposed that deficie...
A fundamental tenet of scientific research is that published results are open to independent validation and refutation. Minimum data standards aid data providers, users, and publishers by providing a specification of what is required to unambiguously interpret experimental findings. Here, we present the Minimum Information about a Flow Cytometry Experiment (MIFlowCyt) standard, stating the minimum information required to report flow cytometry (FCM) experiments. We brought together a crossdisciplinary international collaborative group of bioinformaticians, computational statisticians, software developers, instrument manufacturers, and clinical and basic research scientists to develop the standard. The standard was subsequently vetted by the International Society for Advancement of Cytometry (ISAC) Data Standards Task Force, Standards Committee, membership, and Council. The MIFlowCyt standard includes recommendations about descriptions of the specimens and reagents included in the FCM experiment, the configuration of the instrument used to perform the assays, and the data processing approaches used to interpret the primary output data. MIFlowCyt has been adopted as a standard by ISAC, representing the FCM scientific community including scientists as well as software and hardware manufacturers. Adoption of MIFlowCyt by the scientific and publishing communities will facilitate third-party understanding and reuse of FCM data. ' 2008 International Society for Advancement of Cytometry Key termsimmunology; fluorescence-activated cell sorting; knowledge representation FLOW cytometry (FCM) systems have been available to investigators for over 30 years, and the field continues to advance at a rapid rate. FCM has been responsible for major progress in basic and clinical research by enabling the phenotypic and functional characterization of individual cells in a high-throughput manner. Advances in the technology now allow for automated, multiparametric analyses of thousands of samples per day (1). Each data set can consist of multidimensional descriptions of millions of individual cells, producing data similar in size and complexity to gene expression microarrays. Like the microarray field, the ability to collect FCM data is outpacing the computational means for data handling and analysis. Furthermore, the lack of reporting standardization limits collaboration, independent validation/refutation, and meta-analysis, and thus minimizes the value of the wealth
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