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      Reduction of Natural Killer but Not Effector CD8 T Lymphoyctes in Three Consecutive Cases of Severe/Lethal H1N1/09 Influenza A Virus Infection

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          Abstract

          Background

          The cause of severe disease in some patients infected with pandemic influenza A virus is unclear.

          Methodology/Principal Findings

          We present the cellular immunology profile in the blood, and detailed clinical (and post-mortem) findings of three patients with rapidly progressive infection, including a pregnant patient who died. The striking finding is of reduction in natural killer (NK) cells but preservation of activated effector CD8 T lymphocytes; with viraemia in the patient who had no NK cells. Comparison with control groups suggests that the reduction of NK cells is unique to these severely ill patients.

          Conclusion/Significance

          Our report shows markedly reduced NK cells in the three patients that we sampled and raises the hypothesis that NK may have a more significant role than T lymphocytes in controlling viral burden when the host is confronted with a new influenza A virus subtype.

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          Most cited references26

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          Phenotypic analysis of antigen-specific T lymphocytes.

          Identification and characterization of antigen-specific T lymphocytes during the course of an immune response is tedious and indirect. To address this problem, the peptide-major histocompatability complex (MHC) ligand for a given population of T cells was multimerized to make soluble peptide-MHC tetramers. Tetramers of human lymphocyte antigen A2 that were complexed with two different human immunodeficiency virus (HIV)-derived peptides or with a peptide derived from influenza A matrix protein bound to peptide-specific cytotoxic T cells in vitro and to T cells from the blood of HIV-infected individuals. In general, tetramer binding correlated well with cytotoxicity assays. This approach should be useful in the analysis of T cells specific for infectious agents, tumors, and autoantigens.
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            HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection.

            Natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection. This effect was observed in Caucasians and African Americans with expected low infectious doses of HCV but not in those with high-dose exposure, in whom the innate immune response is likely overwhelmed. The data strongly suggest that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against HCV.
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              Combinations of Maternal KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success

              Preeclampsia is a serious complication of pregnancy in which the fetus receives an inadequate supply of blood due to failure of trophoblast invasion. There is evidence that the condition has an immunological basis. The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. We tested the idea that recognition of these molecules by killer immunoglobulin receptors (KIRs) on maternal decidual NK cells is a key factor in the development of preeclampsia. Striking differences were observed when these polymorphic ligand: receptor pairs were considered in combination. Mothers lacking most or all activating KIR (AA genotype) when the fetus possessed HLA-C belonging to the HLA-C2 group were at a greatly increased risk of preeclampsia. This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative. Thus, this interaction between maternal KIR and trophoblast appears not to have an immune function, but instead plays a physiological role related to placental development. Different human populations have a reciprocal relationship between AA frequency and HLA-C2 frequency, suggesting selection against this combination. In light of our findings, reproductive success may have been a factor in the evolution and maintenance of human HLA-C and KIR polymorphisms.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                18 May 2010
                : 5
                : 5
                : e10675
                Affiliations
                [1 ]Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, United Kingdom
                [2 ]West of Scotland Specialist Virology Centre, Gartnavel General Hospital, Glasgow, United Kingdom
                [3 ]Pathology Department, John Radcliffe Hospital, Oxford, United Kingdom
                [4 ]Adult Intensive Care Unit, John Radcliffe Hospital, Oxford, United Kingdom
                [5 ]Intensive Care Unit, Royal Alexandra Hospital, Paisley, United Kingdom
                [6 ]Oxford Centre for Respiratory Medicine, Oxford Radcliffe NHS Trust, Oxford, United Kingdom
                Karolinska Institutet, Sweden
                Author notes

                Conceived and designed the experiments: DY AJM LPH. Performed the experiments: LD CA CKFL CC. Analyzed the data: CC LPH. Contributed reagents/materials/analysis tools: CA CKFL EWD WLK CC KR TD WFC. Wrote the paper: LPH.

                Article
                10-PONE-RA-17311R1
                10.1371/journal.pone.0010675
                2872666
                20502691
                0311775e-653b-4726-9286-1b40a8c4c606
                Denney et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 22 March 2010
                : 26 April 2010
                Page count
                Pages: 9
                Categories
                Research Article
                Immunology/Immune Response
                Immunology/Immunity to Infections
                Infectious Diseases/Viral Infections

                Uncategorized
                Uncategorized

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