CRP Enhances the Innate Killing Mechanisms Phagocytosis and ROS Formation in a Conformation and Complement-Dependent Manner

Phagocytosis and the formation of reactive oxygen species (ROS) in phagocytic leukocytes are an effective killing mechanism of the innate host defense. These cellular processes of innate immunity function in a complex interplay with humoral factors. C-reactive protein (CRP) in its activated, monomeric isoform (mCRP) has been shown to activate immune cells via the classical complement pathway. We investigated the complement-dependent effects of monomeric CRP (mCRP) on neutrophils and monocyte subtypes using complement-specific inhibitors by both flow cytometry and confocal fluorescence microscopy. We demonstrate that CRP-induced ROS generation is a conformation-specific and complement-dependent process in leukocyte subsets with classical monocytes as the primary source of ROS amongst human monocyte subsets. Elucidation of this complex interplay of CRP and complement in inflammation pathophysiology might help to improve anti-inflammatory therapeutic strategies

Dissociation of C-Reactive Protein Localizes and Amplifies Inflammation: Evidence for a Direct Biological Role of C-Reactive Protein and Its Conformational Changes

C-reactive protein (CRP) is a member of the pentraxin superfamily that is widely recognized as a marker of inflammatory reactions and cardiovascular risk in humans. Recently, a growing body of data is emerging, which demonstrates that CRP is not only a marker of inflammation but also acts as a direct mediator of inflammatory reactions and the innate immune response. Here, we critically review the various lines of evidence supporting the concept of a pro-inflammatory "CRP system." The CRP system consists of a functionally inert circulating pentameric form (pCRP), which is transformed to its highly pro-inflammatory structural isoforms, pCRP* and ultimately to monomeric CRP (mCRP). While retaining an overall pentameric structure, pCRP* is structurally more relaxed than pCRP, thus exposing neoepitopes important for immune activation and complement fixation. Thereby, pCRP* shares its pro-inflammatory properties with the fully dissociated structural isoform mCRP. The dissociation of pCRP into its pro-inflammatory structural isoforms and thus activation of the CRP system occur on necrotic, apoptotic, and ischemic cells, regular β-sheet structures such as β-amyloid, the membranes of activated cells (e.g., platelets, monocytes, and endothelial cells), and/or the surface of microparticles, the latter by binding to phosphocholine. Both pCRP* and mCRP can cause activation of platelets, leukocytes, endothelial cells, and complement. The localization and deposition of these pro-inflammatory structural isoforms of CRP in inflamed tissue appear to be important mediators for a range of clinical conditions, including ischemia/reperfusion (I/R) injury of various organs, cardiovascular disease, transplant rejection, Alzheimer's disease, and age-related macular degeneration. These findings provide the impetus to tackle the vexing problem of innate immunity response by targeting CRP. Understanding the "activation process" of CRP will also likely allow the development of novel anti-inflammatory drugs, thereby providing potential new immunomodulatory therapeutics in a broad range of inflammatory diseases

Dissociation of C-Reactive Protein Localizes and Amplifies Inflammation: Evidence for a Direct Biological Role of C-Reactive Protein and Its Conformational Changes

C-reactive protein (CRP) is a member of the pentraxin superfamily that is widely recognized as a marker of inflammatory reactions and cardiovascular risk in humans. Recently, a growing body of data is emerging, which demonstrates that CRP is not only a marker of inflammation but also acts as a direct mediator of inflammatory reactions and the innate immune response. Here, we critically review the various lines of evidence supporting the concept of a pro-inflammatory “CRP system.” The CRP system consists of a functionally inert circulating pentameric form (pCRP), which is transformed to its highly pro-inflammatory structural isoforms, pCRP* and ultimately to monomeric CRP (mCRP). While retaining an overall pentameric structure, pCRP* is structurally more relaxed than pCRP, thus exposing neoepitopes important for immune activation and complement fixation. Thereby, pCRP* shares its pro-inflammatory properties with the fully dissociated structural isoform mCRP. The dissociation of pCRP into its pro-inflammatory structural isoforms and thus activation of the CRP system occur on necrotic, apoptotic, and ischemic cells, regular β-sheet structures such as β-amyloid, the membranes of activated cells (e.g., platelets, monocytes, and endothelial cells), and/or the surface of microparticles, the latter by binding to phosphocholine. Both pCRP* and mCRP can cause activation of platelets, leukocytes, endothelial cells, and complement. The localization and deposition of these pro-inflammatory structural isoforms of CRP in inflamed tissue appear to be important mediators for a range of clinical conditions, including ischemia/reperfusion (I/R) injury of various organs, cardiovascular disease, transplant rejection, Alzheimer’s disease, and age-related macular degeneration. These findings provide the impetus to tackle the vexing problem of innate immunity response by targeting CRP. Understanding the “activation process” of CRP will also likely allow the development of novel anti-inflammatory drugs, thereby providing potential new immunomodulatory therapeutics in a broad range of inflammatory diseases

Active galactic nuclei: what’s in a name?

Active Galactic Nuclei (AGN) are energetic astrophysical sources powered by accretion onto supermassive black holes in galaxies, and present unique observational signatures that cover the full electromagnetic spectrum over more than twenty orders of magnitude in frequency. The rich phenomenology of AGN has resulted in a large number of different "flavours" in the literature that now comprise a complex and confusing AGN "zoo". It is increasingly clear that these classifications are only partially related to intrinsic differences between AGN, and primarily reflect variations in a relatively small number of astrophysical parameters as well the method by which each class of AGN is selected. Taken together, observations in different electromagnetic bands as well as variations over time provide complementary windows on the physics of different sub-structures in the AGN. In this review, we present an overview of AGN multi-wavelength properties with the aim of painting their "big picture" through observations in each electromagnetic band from radio to gamma-rays as well as AGN variability. We address what we can learn from each observational method, the impact of selection effects, the physics behind the emission at each wavelength, and the potential for future studies. To conclude we use these observations to piece together the basic architecture of AGN, discuss our current understanding of unification models, and highlight some open questions that present opportunities for future observational and theoretical progress.Comment: Accepted for publication in Astronomy & Astrophysics Review, 56 pages, 25 figure

Observation of the Λb0→χc1(3872)pK−\Lambda_b^0\rightarrow \chi_{c1}(3872)pK^- decay

International audienceUsing proton-proton collision data, collected with the LHCb detector and corresponding to 1.0, 2.0 and 1.9 fb$^{−1}$ of integrated luminosity at the centre-of-mass energies of 7, 8, and 13 TeV, respectively, the decay {\Lambda}_{\mathrm{b}}^0\to {\upchi}_{\mathrm{c}1} (3872)pK$^{−}$ with χ$_{c1}$(3872) → J/ψ π$^{+}$π$^{−}$ is observed for the first time. The significance of the observed signal is in excess of seven standard deviations. It is found that (58 ± 15)% of the decays proceed via the two-body intermediate state χ$_{c1}$(3872)Λ(1520). The branching fraction with respect to that of the ${\Lambda}_{\mathrm{b}}^0$ → ψ(2S)pK$^{−}$ decay mode, where the ψ(2S) meson is reconstructed in the J/ψ π$^{+}$π$^{−}$ final state, is measured to be: $ \frac{\beta \left({\Lambda}_{\mathrm{b}}^0\to {\upchi}_{\mathrm{c}1}(3872){\mathrm{pK}}^{-}\right)}{\beta \left({\Lambda}_{\mathrm{b}}^0\to \uppsi \left(2\mathrm{S}\right){\mathrm{pK}}^{-}\right)}\times \frac{\beta \left({\upchi}_{\mathrm{c}1}(3872)\to \mathrm{J}/\uppsi {\uppi}^{+}{\uppi}^{-}\right)}{\beta \left(\uppsi \left(2\mathrm{S}\right)\to \mathrm{J}/\uppsi {\uppi}^{+}{\uppi}^{-}\right)}=\left(5.4\pm 1.1\pm 0.2\right)\times {10}^{-2},

Search for Lepton-Flavor Violating Decays B+→K+μ±e∓B^+ \to K^+ {\mu}^{\pm} e^{\mp}

International audienceA search for the lepton-flavor violating decays B+→K+μ±e∓ is performed using a sample of proton-proton collision data, collected with the LHCb experiment at center-of-mass energies of 7 and 8 TeV and corresponding to an integrated luminosity of 3  fb-1. No significant signal is observed, and upper limits on the branching fractions are set as B(B+→K+μ-e+)<7.0(9.5)×10-9 and B(B+→K+μ+e-)<6.4(8.8)×10-9 at 90% (95)% confidence level. The results improve the current best limits on these decays by more than one order of magnitude

Updated measurement of time-dependent CP-violating observables in Bs0→J/ψK+K−B^{0}_{s}\to J/\psi K^+ K^- decays

International audienceThe decay-time-dependent $CP$ asymmetry in ${{B} ^0_{s}} \rightarrow J/\psi {{K} ^+} {{K} ^-}$ decays is measured using proton–proton collision data, corresponding to an integrated luminosity of $1.9\,\mathrm{fb}^{-1}$ , collected with the LHCb detector at a centre-of-mass energy of $13\,\mathrm {TeV}$ in 2015 and 2016. Using a sample of approximately 117 000 signal decays with an invariant ${{K} ^+} {{K} ^-}$ mass in the vicinity of the $\phi (1020)$ resonance, the $CP$ -violating phase $\phi _s$ is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the ${{B} ^0_{s}}$ - ${{\overline{B}{}} {}^0_{s}}$ system, $\Delta \Gamma _s$ . The difference of the average ${{B} ^0_{s}}$ and ${{B} ^0}$ meson decay widths, $\Gamma _s-\Gamma _d$ , is determined using in addition a sample of ${{B} ^0} \rightarrow J/\psi {{K} ^+} {{\pi } ^-}$ decays. The values obtained are $\phi _s = -0.083\pm 0.041\pm 0.006\mathrm { \,rad}$ , $\Delta \Gamma _s = 0.077 \pm 0.008 \pm 0.003 {\mathrm { \,ps^{-1}}}$ and $\Gamma _s-\Gamma _d = -0.0041 \pm 0.0024 \pm 0.0015{\mathrm { \,ps^{-1}}}$ , where the first uncertainty is statistical and the second systematic. These are the most precise single measurements of these quantities to date and are consistent with expectations based on the Standard Model and with a previous LHCb analysis of this decay using data recorded at centre-of-mass energies 7 and 8 TeV. Finally, the results are combined with recent results from ${{B} ^0_{s}} \rightarrow J/\psi {{\pi } ^+} {{\pi } ^-}$ decays obtained using the same dataset as this analysis, and with previous independent LHCb results