The COVID-19 pandemic caused by SARS-CoV-2 is a continuous challenge worldwide, and there is an urgent need to map the landscape of immunogenic and immunodominant epitopes recognized by CD8+ T cells. Here, we analyze samples from 31 patients with COVID-19 for CD8+ T cell recognition of 500 peptide-HLA class I complexes, restricted by 10 common HLA alleles. We identify 18 CD8+ T cell recognized SARS-CoV-2 epitopes, including an epitope with immunodominant features derived from ORF1ab and restricted by HLA-A*01:01. In-depth characterization of SARS-CoV-2-specific CD8+ T cell responses of patients with acute critical and severe disease reveals high expression of NKG2A, lack of cytokine production and a gene expression profile inhibiting T cell re-activation and migration while sustaining survival. SARS-CoV-2-specific CD8+ T cell responses are detectable up to 5 months after recovery from critical and severe disease, and these responses convert from dysfunctional effector to functional memory CD8+ T cells during convalescence.
ETP fits with the concept that reversal assessment of NOAC anticoagulation by PCC should be based on measurements on the clotting potential or thrombin generating potential of the plasma or whole blood patient sample. Low sensitivity of ETP for NOACs and its correlation with bleeding are issues that remain to be resolved.
The lectin pathway (LP) of complement has a protective function against invading pathogens. Recent studies have also shown that the LP plays an important role in ischemia/reperfusion (I/R)-injury. MBL-associated serine protease (MASP)-2 appears to be crucial in this process. The serpin C1-inhibitor is the major inhibitor of MASP-2. In addition, aprotinin, a Kunitz-type inhibitor, was shown to inhibit MASP-2 activity in vitro.In this study we investigated whether the Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI) is also able to inhibit MASP-2. Ex vivo LP was induced and detected by C4-deposition on mannan-coated plates. The MASP-2 activity was measured in a fluid-phase chromogenic assay. rTFPI in the absence or presence of specific monoclonal antibodies was used to investigate which TFPI-domains contribute to MASP-2 inhibition. Here, we identify TFPI as a novel selective inhibitor of MASP-2, without affecting MASP-1 or the classical pathway proteases C1s and C1r. Kunitz-2 domain of TFPI is required for the inhibition of MASP-2. Considering the role of MASP-2 in complement-mediated I/R-injury, the inhibition of this protease by TFPI could be an interesting therapeutic approach to limit the tissue damage in conditions such as cerebral stroke, myocardial infarction or solid organ transplantation.Keywords: Complement-coagulation crosstalk r Complement inhibition r MASP-2 r TFPI Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe complement system comprises over 30 different plasma proteins. The complement system consists of three activation pathways, each differing in their recognition mechanism while Correspondence: Mischa P. Keizer e-mail: m.keizer@sanquin.nl converging in a common terminal pathway at the level of complement component 3 (C3). The antibody-dependent classical pathway (CP) initiates the complement system via the binding of C1q to antibodies. Binding to specific sugar motifs by mannan-binding lectins (MBLs) or one of the ficolins activates the lectin pathway (LP) by subsequent activation of the MBL-associated serine proteases (MASPs). The alternative pathway activates spontaneously on surfaces that lack complement regulatory proteins and acts as amplification route for the other two pathways.www.eji-journal.eu Eur. J. Immunol. 2015. 45: 544-550 Innate immunity 545Besides the LP role as first line of defense against invading pathogens, by opsonization and induction of an inflammatory response, recent studies have shown that the LP also plays a prominent role in ischemia/reperfusion (I/R) injury. MBL-deficiency appears to be protective in human myocardial infarction [1], gastrointestinal I/R injury [1], and stroke [2]. This detrimental role of the LP in I/R injury has been confirmed in mice by selectively targeting MASP-2. MASP-2 knockout mice were protected from both gastrointestinal and myocardial I/R injury [3]. Together, these data indicate an important role for MASP-2 in aggravating cell damage in ischemi...
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