Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7–dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid–protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways.

Heme oxygenase-1 is a regulator of vascular function in hypertension via determining the phenotype of inflammatory circulating and infiltrating monocytes with possible implications for all-cause mortality.

Background Antiphospholipid antibodies (aPLs) contribute to the pathogenesis of the antiphospholipid syndrome (APS) by induction of an inflammatory and procoagulant state in different cell types, and several signaling pathways have been described. Objectives To investigate whether signaling depends on the epitope specificity of aPLs. Methods Cellular effects of three human monoclonal aPLs with distinctly different epitope specificities were analyzed in vitro. Expression of tumor necrosis factor-α mRNA by mouse and human monocytes was the major readout. Analysis included cells from genetically modified mice, and the use of specific inhibitors in human monocytes. Data were validated with IgG isolated from 20 APS patients. Results Cofactor-independent anticardiolipin aPLs activated monocytes by induction of endosomal NADPH oxidase. Activation could be blocked by hydroxychloroquine (HCQ). Anti-β -glycoprotein I aPL activated monocytes by interacting with LDL receptor-related protein 8 (LRP8). This could be blocked by rapamycin. Analysis of 20 APS patients' IgG showed that all IgG fractions activated the same two pathways as the monoclonal aPL, depending on their epitope patterns as determined by ELISA. Monocyte activation by APS IgG could be blocked completely by HCQ and/or rapamycin, suggesting that in most, if not all, APS patients there is no other relevant signaling pathway. Conclusions aPLs activate two major proinflammatory signal transduction pathways, depending on their epitope specificity. HCQ and rapamycin, either alone or in combination, completely suppress signaling by APS IgG. These observations may provide a rationale for specific treatment of APS patients according to their aPL profile.

Background: Severe plasma prekallikrein (PK) deficiency is an autosomal-recessive defect characterized by isolated activated partial thromboplastin time prolongation. To date, no comprehensive methodologically firm analysis has investigated the diagnostic, clinical, and genetic characteristics of PK deficiency, and its prevalence remains unknown.Patients/Methods: We described new families with PK deficiency, retrieved clinical and laboratory information of cases systematically searched in the (gray) literature, and collected blood of these cases for complementary analyses. The Genome Aggregation Database (gnomAD) and the population-based Gutenberg Health Study served to study the prevalence of mutations and relevant genetic variants. Results:We assembled a cohort of 111 cases from 89 families and performed new genetic analyses in eight families (three unpublished). We identified new KLKB1 mutations, excluded the pathogenicity of some of the previously described ones, and estimated a prevalence of severe PK deficiency of 1/155 668 overall and 1/4725 among Africans. One individual reported with PK deficiency had, in fact, congenital kininogen deficiency associated with decreased PK activity. One quarter of individuals had factor XII clotting activity below the reference range. Four major bleeding events were described in 96 individuals, of which 3 were provoked, for a prevalence of 4% and an annualized rate of 0.1%. The prevalence of cardiovascular events was 15% (6% <40 years; 21% 40-65 years; 33% >65 years) for an annualized rate of 0.4%. Conclusions:We characterized the genetic background of severe PK deficiency, critically appraised mutations, and provided prevalence estimates. Our data onThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. | 1599BARCO et Al.

We found a rate of 20% HEV infections in LT patients undergoing liver biopsy for elevated liver enzymes and suspected acute rejection. These data indicate the necessity for HEV testing in all LT patients with elevated liver enzymes and suspected acute rejection.