Cytokine Profiles in Sepsis Have Limited Relevance for Stratifying Patients in the Emergency Department: A Prospective Observational Study

INTRODUCTION: Morbidity, mortality and social cost of sepsis are high. Previous studies have suggested that individual cytokines levels could be used as sepsis markers. Therefore, we assessed whether the multiplex technology could identify useful cytokine profiles in Emergency Department (ED) patients. METHODS: ED patients were included in a single tertiary-care center prospective study. Eligible patients were >18 years and met at least one of the following criteria: fever, suspected systemic infection, ≥ 2 systemic inflammatory response syndrome (SIRS) criteria, hypotension or shock. Multiplex cytokine measurements were performed on serum samples collected at inclusion. Associations between cytokine levels and sepsis were assessed using univariate and multivariate logistic regressions, principal component analysis (PCA) and agglomerative hierarchical clustering (AHC). RESULTS: Among the 126 patients (71 men, 55 women; median age: 54 years [19-96 years]) included, 102 had SIRS (81%), 55 (44%) had severe sepsis and 10 (8%) had septic shock. Univariate analysis revealed weak associations between cytokine levels and sepsis. Multivariate analysis revealed independent association between sIL-2R (p = 0.01) and severe sepsis, as well as between sIL-2R (p = 0.04), IL-1β (p = 0.046), IL-8 (p = 0.02) and septic shock. However, neither PCA nor AHC distinguished profiles characteristic of sepsis. CONCLUSIONS: Previous non-multiparametric studies might have reached inappropriate conclusions. Indeed, well-defined clinical conditions do not translate into particular cytokine profiles. Additional and larger trials are now required to validate the limited interest of expensive multiplex cytokine profiling for staging septic patients

Pre-Existing T- and B-Cell Defects in One Progressive Multifocal Leukoencephalopathy Patient

Progressive multifocal leukoencephalopathy (PML) usually occurs in patients with severe immunosuppression, hematological malignancies, chronic inflammatory conditions or receiving organ transplant. Recently, PML has also been observed in patients treated with monoclonal antibodies. By taking advantage of the availability of samples from a multiple sclerosis (MS) patient treated with natalizumab, the antibody anti-α4 integrin, who developed PML and was monitored starting before therapy initiation, we investigated the fate of T and B lymphocytes in the onset of PML. Real-time PCR was used to measure new T- and B-cell production by means of T-cell receptor excision circle (TREC) and K-deleting recombination excision circle (KREC) analysis and to quantify transcripts for CD34, terminal-deoxynucleotidyltransferase, and V pre-B lymphocyte gene 1. T- and B-cell subsets and T-cell heterogeneity were measured by flow cytometry and spectratyping. The data were compared to those of untreated and natalizumab-treated MS patients and healthy donors. Before therapy, a patient who developed PML had a low TREC and KREC number; TRECs remained low, while KRECs and pre-B lymphocyte gene 1 transcripts peaked at 6 months of therapy and then decreased at PML diagnosis. Flow cytometry confirmed the deficient number of newly produced T lymphocytes, counterbalanced by an increase in TEMRA cells. The percentage of naive B cells increased by approximately 70% after 6 months of therapy, but B lymphocyte number remained low for the entire treatment period. T-cell heterogeneity and immunoglobulins were reduced

Exhausted Cytotoxic Control of Epstein-Barr Virus in Human Lupus

Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanism remains elusive. Here, we investigate whether frequent peaks of EBV viral load in SLE patients are a consequence of dysfunctional anti-EBV CD8+ T cell responses. Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8+ T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8+ T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients

Diagnostic techniques for inflammatory eye disease: past, present and future: a review

Investigations used to aid diagnosis and prognosticate outcomes in ocular inflammatory disorders are based on techniques that have evolved over the last two centuries have dramatically evolved with the advances in molecular biological and imaging technology. Our improved understanding of basic biological processes of infective drives of innate immunity bridging the engagement of adaptive immunity have formed techniques to tailor and develop assays, and deliver targeted treatment options. Diagnostic techniques are paramount to distinguish infective from non-infective intraocular inflammatory disease, particularly in atypical cases. The advances have enabled our ability to multiplex assay small amount of specimen quantities of intraocular samples including aqueous, vitreous or small tissue samples. Nevertheless to achieve diagnosis, techniques often require a range of assays from traditional hypersensitivity reactions and microbe specific immunoglobulin analysis to modern molecular techniques and cytokine analysis. Such approaches capitalise on the advantages of each technique, thereby improving the sensitivity and specificity of diagnoses. This review article highlights the development of laboratory diagnostic techniques for intraocular inflammatory disorders now readily available to assist in accurate identification of infective agents and appropriation of appropriate therapies as well as formulating patient stratification alongside clinical diagnoses into disease groups for clinical trials

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Étude par diffraction des neutrons de la structure magnétique de l'antiferromagnétique LaCrSe3

The magnetic structure of orthorhombic LaCrSe3 is determined and is found to belong to the magnetic space group Pnam'. The observed magnetic structure indicates the presence of two types of magnetic interactions : first, antiferromagnetic super-superexchange interactions through Cr—Se—Se—Cr paths and secondly, ferromagnetic interactions due to the polarization of the ligands in the case of Cr—Se—Cr paths with an angle of about π/2, the strength of interaction being strongly distance dependent.On détermine par diffraction des neutrons la structure magnétique du composé orthorhombique LaCrSe3. Le groupe magnétique est Pnam'. La structure magnétique observée met en évidence l'existence de deux types d'interactions magnétiques : d'une part, des interactions antiferromagnétiques de super-superéchange s'effectuant par l'intermédiaire de liaisons Cr—Se—Se—Cr ; d'autre part des interactions ferromagnétiques liées à la polarisation des ligandes dans le cas de liaisons Cr—Se—Cr pour lesquelles l'angle est voisin de π/2, l'intensité de ces interactions décroissant notablement avec la distance entre cations

TRANSPORT AND MAGNETIC PROPERTIES OF Ni1-xCrxS with x ≤ 2 %

Les propriétés électriques (résistivité et effet Hall), la susceptibilité magnétique et l'analyse thermique différentielle ont été mesurées pour les monocristaux et les poudres de NiS substitué par du chrome (de 0 à 2 %). Ce composé présente une susceptibilité magnétique qui suit une loi de Curie-Weiss et confirme la présence de Cr sous la forme trivalente. La transition métal-non métal de NiS est observée dans les phases substituées. La température de transition ne varie pas. La phase non métallique de type p dans le cas de NiS devient n dans les cristaux dopés pour x > 1 %. Ces propriétés sont interprétées en terme de compensation du semiconducteur par un remplissage de la bande 3d (egα) de NiS.Electrical transport (ρ and RH), magnetic susceptibility and DTA experiments have been done on single crystals and powders with a composition range from 0 to 2 % Cr substituted in NiS. The materials exhibit Curie-Weiss behaviour indicating a Cr3+ state. The netal-non metal transition of NiS is still observed in Cr substituted NiS, the temperature of the transition is invariable with Cr content but the type of conduction in the non metallic phase changes from p to n when x > 1 %. The physical properties are discussed in terms of compensating the semiconductor by filling the 3d (egα) subband

PRÉPARATION ET PROPRIÉTÉS DE MONOCRISTAUX DE COMPOSÉS DE TYPE A4BX6 (A = Cd, Hg ; B = Ge, Si ; X = S, Se)

Les composés de type A4BX6 (A = Cd, Hg ; B = Ge, Si et X = S, Se) sont isostructuraux. Des monocristaux de ces matériaux ont été préparés par la méthode de transport chimique en phase gazeuse en utilisant l'iode, le chlore et le brome comme agents de transport. Ils sont caractérisés par leurs propriétés électriques et optiques.The compounds of A4BX6 type (A = Cd, Hg ; B = Ge, Si and X = S, Se) are isostructural. They have been prepared by the chemical vapor transport method using iodine, chlorine and bromine as transporting agents. They are characterized by their electrical and optical properties