Activation of CD4 T cells by B cells has been extensively studied, but B cell-regulated priming, proliferation, and survival of CD8 T cells remains controversial. B cells express high levels of MHC ...class I molecules and can potentially act as antigen-presenting cells (APCs) for CD8 T cells. Several
studies in mice and humans demonstrate the role of B cells as modulators of CD8 T cell function in the context of viral infections, autoimmune diseases, cancer and allograft rejection. In addition, B-cell depletion therapies can lead to impaired CD8 T-cell responses. In this review, we attempt to answer 2 important questions: 1. the role of B cell antigen presentation and cytokine production in the regulation of CD8 T cell survival and cell fate determination, and 2. The role of B cells in the formation and maintenance of CD8 T cell memory.
Coagulopathy in COVID-19 is a burning issue and strategies to prevent thromboembolic events are debated and highly heterogeneous. The objective was to determine incidence and risk factors of venous ...thromboembolism (VTE) in COVID-19 inpatients receiving thromboprophylaxis. In this retrospective French cohort study, patients hospitalized in medical wards non-ICU with confirmed COVID-19 and adequate thromboprophylaxis were included. A systematic low limb venous duplex ultrasonography was performed at hospital discharge or earlier if deep venous thrombosis (DVT) was clinically suspected. Chest angio-CT scan was performed when pulmonary embolism (PE) was suspected. Of 71 patients, 16 developed VTE (22.5%) and 7 PE (10%) despite adequate thromboprophylaxis. D-dimers at baseline were significantly higher in patients with DVT (p < 0.001). Demographics, comorbidities, disease manifestations, severity score, and other biological parameters, including inflammatory markers, were similar in patients with and without VTE. The negative predictive value of a baseline D-dimer level < 1.0 µg/ml was 90% for VTE and 98% for PE. The positive predictive value for VTE was 44% and 67% for D-dimer level ≥ 1.0 µg/ml and ≥ 3 µg/ml, respectively. The association between D-dimer level and VTE risk increased by taking into account the latest available D-dimer level prior to venous duplex ultrasonography for the patients with monitoring of D-dimer. Despite thromboprophylaxis, the risk of VTE is high in COVID-19 non-ICU inpatients. Increased D-dimer concentrations of more than 1.0 μg/ml predict the risk of venous thromboembolism. D-dimer level-guided aggressive thromboprophylaxis regimens using higher doses of heparin should be evaluated in prospective studies.
Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are rare histiocytic disorders induced by somatic mutation of MAPK pathway genes. BRAFV600E mutation is the most common mutation ...in both conditions and also occurs in the hematopoietic neoplasm hairy cell leukemia (HCL). It is not known if adult LCH or ECD arises from hematopoietic stem cells (HSCs), nor which potential blood borne precursors lead to the formation of histiocytic lesions. In this study, BRAFV600E allele–specific polymerase chain reaction was used to map the neoplastic clone in 20 adults with LCH, ECD, and HCL. BRAFV600E was tracked to classical monocytes, nonclassical monocytes, and CD1c+ myeloid dendritic cells (DCs) in the blood, and mutations were observed in HSCs and myeloid progenitors in the bone marrow of 4 patients. The pattern of involvement of peripheral blood myeloid cells was indistinguishable between LCH and ECD, although the histiocytic disorders were distinct to HCL. As reported in children, detection of BRAFV600E in peripheral blood of adults was a marker of active multisystem LCH. The healthy counterparts of myeloid cells affected by BRAF mutation had a range of differentiation potentials depending on exogenous signals. CD1c+ DCs acquired high langerin and CD1a with granulocyte-macrophage colony-stimulating factor and transforming growth factor β alone, whereas CD14+ classical monocytes required additional notch ligation. Both classical and nonclassical monocytes, but not CD1c+ DCs, made foamy macrophages easily in vitro with macrophage colony-stimulating factor and human serum. These studies are consistent with a hematopoietic origin and >1 immediate cellular precursor in both LCH and ECD.
•Bone marrow progenitors, monocytes, and myeloid DCs contain BRAFV600E alleles in adults with LCH and ECD.•Mutant allele distribution is not disease specific, but precursors have distinct LCH-like and macrophage differentiation capacities.
Abstract
Objectives
This study aimed to examine the sensitivity of muscle biopsy (MB) in ANCA-associated vasculitis (AAV), identify factors predicting MB positivity and assess the prognostic value of ...a positive MB.
Methods
We conducted a single-centre retrospective study of AAV with an MB performed at diagnosis. AAV classification granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA) followed the European Medicines Agency algorithm. A logistic regression model was used to identify the factors associated with MB positivity. Survival curves were generated using the Kaplan–Meier method.
Results
Among 276 AAV patients (1995–2018), 101 had an MB. Seventy-eight patients were included: 33 with GPA, 25 with MPA and 20 with EGPA. MB samples were positive in 45 cases (58%): 17 GPA, 16 MPA and 12 EGPA. Univariate analysis focussed on GPA and MPA, revealed that the MB yield was higher in females 22/31 (71%) vs 11/27 (41%); P = 0.02 and in anti-MPO patients 25/37 (68%) vs 6/19 (32%) for anti-PR3; P = 0.01. By multivariate analysis, three factors predicted MB positivity: anti-MPO ANCA odds ratio (OR) 10.67 (CI 2.09, 81.68), female sex OR 5.3 (CI 1.16, 32.35) and neutrophil count OR 1.33 (CI 1.07, 1.8). MB positivity had no impact on relapse, death or end-stage renal disease–free survival.
Conclusions
MB is a safe and efficient diagnostic tool for AAV. Predictors of MB yield include ANCA type, sex and neutrophil count. MB cannot substitute for kidney biopsy when indicated, but should be considered in other cases.
TLR repertoire and in vitro responsiveness of blood classical DC subsets.
Human blood DCs encompass pDCs and two subsets of mDCs: CD1c+ mDCs and CD141+ mDCs. The rare CD141+ DC population is thought ...to be the equivalent of mouse CD8α+ cDCs that play a significant role in antigen cross‐presentation. Here, we analyzed by Q‐PCR TLR1–10 expression in blood DC subsets. Whereas CD1c+ DCs express all TLR except TLR9, CD141+ DCs present a more restricted pattern with high expression of TLR3 and ‐10, expression of TLR1,‐2, ‐6, and ‐8, and lack of TLR4, ‐5, ‐7, and ‐9. The in vitro analysis of isolated mDC subset reponsiveness to an extensive panel of TLR ligands confirmed these results, with CD141+ DCs responding only to TLR1/2, ‐3, and ‐7/8. The cytokine/chemokine production profile of isolated CD141+ DCs was also more restricted, as they produced mainly proinflammatory cytokines but no IL‐12 and to a lower level, in comparison with CD1c+ DCs, except for CXCL10, CCL5, and IFN‐β. In contrast, with the use of a whole blood assay, we found that CD141+ DCs produce IL‐12 in response to TLR1/2, ‐3, and more surprisingly, ‐9. Finally, both mDC subsets are potent inducers of Th1 response, particularly after TLR3 triggering. Taken together, these data confirmed functional differences between blood mDC subsets. The major response of CD141+ mDCs to TLR3 ligand and their cytokine production pattern suggest a role for these cells in antiviral immunity.
Biannual rituximab infusions over 18 months effectively maintain remission after a "standard" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis ...(AAV).
To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen.
Randomized controlled trial. (ClinicalTrials.gov: NCT02433522).
39 clinical centers in France.
68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy.
Rituximab or placebo infusion every 6 months for 18 months (4 infusions).
The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0.
From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) (
= 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) (
= 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients 12%) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients 9%). No deaths occurred in either group.
Potential selection bias based on previous rituximab response and tolerance.
Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy.
French Ministry of Health and Hoffmann-La Roche.
Eosinophilic-related clinical manifestations are protean and the underlying conditions underpinning eosinophilia are highly diverse. The etiological workup of unexplained ...eosinophilia/hypereosinophilia can be challenging, and can lead sometimes to extensive, inappropriate, costly and/or invasive investigations. To date, guidelines for the etiological workup and management of eosinophilia are mainly issued by hematologists, and thus mostly cover the scope of clonal hypereosinophilic syndromes (HES). Here, thanks to an extensive literature review, and thanks to the joint work of a large panel of experts involving physicians from both adult and pediatric medicine and from various subspecialties (as well as a representative of a patients' association representative), we provide recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophilic disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Lastly, this set of recommendations also includes a summary intended for general practitioners, as well as an overview of the therapeutic patient education program set up by the French reference center for HES. Further updates will be mandatory as new validated information emerges.
Adult-onset Still disease (AOSD) is a rare systemic inflammatory disorder. A few patients develop organ complications that can be life-threatening. Our objectives were to describe the disease course ...and phenotype of life-threatening AOSD, including response to therapy and long-term outcome.
A multicenter case series of intensive care medicine (ICU) patients with life-threatening AOSD and a systematic literature review.
Twenty patients were included. ICU admission mostly occurred at disease onset (90%). Disease manifestations included fever (100%), sore throat (65%), skin rash (65%), and arthromyalgia (55%). Serum ferritin was markedly high (median: 29,110 ng/mL). Acute respiratory failure, shock and multiple organ failure occurred in 15 (75%), 10 (50%), and 7 (35%) cases, respectively. Hemophagocytosis was demonstrated in eight cases. Two patients died. Treatment delay was significant. All patients received corticosteroids. Response rate was 50%. As second-line, intravenous immunoglobulins were ineffective. Anakinra was highly effective. After ICU discharge, most patients required additional treatment. Literature analysis included 79 cases of AOSD with organ manifestations, which mainly included reactive hemophagocytic syndrome (42%), acute respiratory failure (34%), and cardiac complications (23%). Response rate to corticosteroids was 68%. Response rates to IVIgs, cyclosporin, and anakinra were 50%, 80%, and 100%, respectively.
AOSD should be recognized as a rare cause of sepsis mimic in patients with fever of unknown origin admitted to the ICU. The diagnosis relies on a few simple clinical clues. Early intensive treatment may be discussed. IVIgs should be abandoned. Long-term prognosis is favorable.
The critical role of neutrophils in pathological inflammation, notably in various autoimmune disorders, is currently the focus of renewed interest. Here, we demonstrate for the first time that ...activation of neutrophils with various inflammatory stimuli induces the release of extracellular vesicles (EVs) that are internalized by endothelial cells (ECs), thus leading to the transfer of miR-223, miR-142–3p and miR-451 and subsequent endothelial damage. Indeed, while miR-223 has little effect on EC responses, we show that the induced expression of miR-142–3p and miR-451 in ECs results in profound cell damage, especially in inflammatory conditions, characterized by a dramatic increase in cell apoptosis, impaired angiogenic repair responses, and the induction of IL-6, IL-8, CXCL10 and CXCL11 expression. We show that the strong deleterious effect of miR-142–3p may be due in part to its ability to block the activation of ERK1/2 and eNOS-mediated signals in ECs. miR-142–3p also inhibits the expression of RAC1, ROCK2 and CLIC4, three genes that are critical for EC migration and angiogenic responses. Importantly, miR-223, miR-142–3p and miR-451 are markedly increased in kidney biopsies from patients with active ANCA-associated vasculitis, a severe autoimmune disease that is prototypical of a neutrophil-induced microvascular damage. Taken together, our results suggest that miR-142–3p and miR-451 released in EVs by activated neutrophils can target EC to trigger an inflammatory cascade and induce direct vascular damage, and that therapeutic strategies based on the inhibition of these miRNAs in ECs will have implications for neutrophil-mediated inflammatory diseases.
•Neutrophil-derived extracellular vesicles (EVs) damage endothelium during inflammation.•miRNAs released within neutrophil EVs are internalized by endothelial cells.•miR-142–3p and miR-451 induce endothelial cell inflammation and damage.•miR-223, -142–3p and −451 are increased in kidneys with ANCA-associated vasculitis.•miR-142–3p/451: new therapeutic targets for neutrophil-mediated diseases.
Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and ...efficacy of a short course of intravenous ATO in patients with active SLE.
This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS).
Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P < 0.01). In the long term, 6 patients attained LLDAS at W52, which continued at last follow-up (median LLDAS duration 3 years, range 2-4).
A short course of ATO has an acceptable safety profile in SLE patients and encouraging efficacy.
ClinicalTrials.gov, NCT01738360 registered 30 November 2012.
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