scholarly journals A functionally distinct neutrophil landscape in severe COVID-19 reveals opportunities for adjunctive therapies

2021 ◽  
Author(s):  
Rachita Panda ◽  
Fernanda Vargas E Silva Castanheira ◽  
Jared Schlechte ◽  
Bas GJ Surewaard ◽  
Hanjoo Brian Shim ◽  
...  
Keyword(s):  
Single Cell Analysis ◽  
Ex Vivo ◽  
Diffuse Alveolar Damage ◽  
Neutrophil Activation ◽  
Effector Functions ◽  
Immune Mediated ◽  
Promising Target ◽  
Life Threatening ◽  
Outstanding Question ◽  
Neutrophil Response

Acute respiratory distress syndrome (ARDS) is a life-threatening syndrome of respiratory failure and diffuse alveolar damage that results from dysregulated local and systemic immune activation, causing pulmonary vascular, parenchymal and alveolar damage. SARS-CoV-2 infection has become the dominant cause of ARDS worldwide, and emerging evidence implicates neutrophils and their cytotoxic arsenal of effector functions as central drivers of immune-mediated lung injury in COVID-19 ARDS. However, a key outstanding question is whether COVID-19 drives a unique program of neutrophil activation or effector functions that contributes to the severe pathogenesis of this pandemic illness, and whether this unique neutrophil response can be targeted to attenuate disease. Using a combination of high-dimensional single cell analysis and ex vivo functional assays of neutrophils from patients with COVID-19 ARDS compared to non-COVID ARDS (caused by bacterial pneumonia), we identified a functionally distinct landscape of neutrophil activation in COVID-19 ARDS that was intrinsically programmed during SARS-CoV-2 infection. Furthermore, neutrophils in COVID-19 ARDS were functionally primed to produce high amounts of neutrophil extracellular traps (NETs). Surprisingly, this unique pathological program of neutrophil priming escaped conventional therapy with dexamethasone, thereby revealing a promising target for adjunctive immunotherapy in severe COVID-19.

scholarly journals Autoimmune Hemolytic Anemia as a Complication of Congenital Anemias. A Case Series and Review of the Literature

2021 ◽  
Vol 10 (15) ◽  
pp. 3439
Author(s):  
Irene Motta ◽  
Juri Giannotta ◽  
Marta Ferraresi ◽  
Kordelia Barbullushi ◽  
Nicoletta Revelli ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Case Series ◽  
Intravenous Immunoglobulins ◽  
Point Of View ◽  
First Line ◽  
Human Erythropoietin ◽  
Immune Mediated ◽  
Hemolytic Crisis ◽  
Life Threatening

Congenital anemias may be complicated by immune-mediated hemolytic crisis. Alloantibodies are usually seen in chronically transfused patients, and autoantibodies have also been described, although they are rarely associated with overt autoimmune hemolytic anemia (AIHA), a serious and potentially life-threatening complication. Given the lack of data on the AIHA diagnosis and management in congenital anemias, we retrospectively evaluated all clinically relevant AIHA cases occurring at a referral center for AIHA, hemoglobinopathies, and chronic hemolytic anemias, focusing on clinical management and outcome. In our cohort, AIHA had a prevalence of 1% (14/1410 patients). The majority were warm AIHA. Possible triggers were recent transfusion, infection, pregnancy, and surgery. All the patients received steroid therapy as the first line, and about 25% required further treatment, including rituximab, azathioprine, intravenous immunoglobulins, and cyclophosphamide. Transfusion support was required in 57% of the patients with non-transfusion-dependent anemia, and recombinant human erythropoietin was safely administered in one third of the patients. AIHA in congenital anemias may be challenging both from a diagnostic and a therapeutic point of view. A proper evaluation of hemolytic markers, bone marrow compensation, and assessment of the direct antiglobulin test is mandatory.

scholarly journals Localization and Bioreactivity of Cysteine-Rich Secretions in the Marine Gastropod Nucella lapillus

Marine Drugs ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. 276
Author(s):  
Mariaelena D’Ambrosio ◽  
Cátia Gonçalves ◽  
Mariana Calmão ◽  
Maria Rodrigues ◽  
Pedro M. Costa
Keyword(s):  
Salivary Glands ◽  
Digestive Gland ◽  
Crude Protein ◽  
Ex Vivo ◽  
Gill Tissue ◽  
Marine Biodiversity ◽  
Nucella Lapillus ◽  
Promising Target ◽  
Toxin Secretion ◽  
Molecular Damage

Marine biodiversity has been yielding promising novel bioproducts from venomous animals. Despite the auspices of conotoxins, which originated the paradigmatic painkiller Prialt, the biotechnological potential of gastropod venoms remains to be explored. Marine bioprospecting is expanding towards temperate species like the dogwhelk Nucella lapillus, which is suspected to secrete immobilizing agents through its salivary glands with a relaxing effect on the musculature of its preferential prey, Mytilus sp. This work focused on detecting, localizing, and testing the bioreactivity of cysteine-rich proteins and peptides, whose presence is a signature of animal venoms and poisons. The highest content of thiols was found in crude protein extracts from the digestive gland, which is associated with digestion, followed by the peribuccal mass, where the salivary glands are located. Conversely, the foot and siphon (which the gastropod uses for feeding) are not the main organs involved in toxin secretion. Ex vivo bioassays with Mytilus gill tissue disclosed the differential bioreactivity of crude protein extracts. Secretions from the digestive gland and peribuccal mass caused the most significant molecular damage, with evidence for the induction of apoptosis. These early findings indicate that salivary glands are a promising target for the extraction and characterization of bioactive cysteine-rich proteinaceous toxins from the species.

IMMU-29. B-CELL-BASED VACCINE PRODUCES GLIOBLASTOMA-REACTIVE ANTIBODIES THAT CONTRIBUTE TO TUMOR CLEARANCE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi98-vi98
Author(s):  
Brandyn Castro ◽  
Mark Dapash ◽  
David Hou ◽  
Aida Rashidi ◽  
Deepak Kanojia ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Humoral Immunity ◽  
Ex Vivo ◽  
Murine Models ◽  
Effector Functions ◽  
Tumor Bearing ◽  
Tumor Clearance ◽  
Cellular And Humoral Immunity

Abstract Glioblastomas (GBM) are characterized by a strong immunosuppressive environment, contributing to their poor prognosis and limited therapeutic response to immunotherapies. B-cells represent a unique opportunity to promote immunotherapy due to their potential to kill tumors by both cellular and humoral immunity. To generate our B-cell-based vaccine (BVax) platform, we activated 41BBL+ B cells from tumor bearing mice or GBM patient blood with BAFF, CD40, and IFNg. We have previously demonstrated that BVax potentiates radiation therapy, temozolomide and checkpoint blockade in murine models of GBM via enhancement of CD8+ T-cell based immunity. The aim of this current study is to evaluate the humoral effector functions of BVax. We examined the antibody (Ab) repertoire in vivo from serum of tumor-bearing B-cell knockout mice treated with BVax or by ex vivo stimulation of patient-derived BVax. Upon systemic administration, BVax infiltrates the tumor where it differentiates into plasmablasts. Murine BVax- and BNaive-derived serum immunoglobulin generated in vivo showed that the majority of murine BVax-derived Ab were IgG isotype, while BNaive mainly produced IgM isotype. Transfer of IgG from BVax treated mice directly into tumors of recipient animals significantly prolonged their survival, demonstrating anti-tumor cytotoxicity directly through humoral immunity. Patient-derived BVax activated ex vivo showed a plasmablast phenotype and the Ab repertoire supports the previous findings seen in our murine model. Our work suggests BVax-derived IgGs role in antibody-dependent cellular cytotoxicity and improved survival in murine models. This function, in addition to its role in cellular immunity against GBM, renders BVax a potentially effective alternative immunotherapeutic option for GBM patients.

scholarly journals Resveratrol displays anti-inflammatory properties in an ex vivo model of immune mediated inflammatory arthritis

2018 ◽  
Vol 2 (1) ◽  
Author(s):  
S. Lomholt ◽  
A. Mellemkjaer ◽  
M. B. Iversen ◽  
S. B. Pedersen ◽  
T. W. Kragstrup
Keyword(s):  
Inflammatory Arthritis ◽  
Ex Vivo ◽  
Ex Vivo Model ◽  
Immune Mediated ◽  
Anti Inflammatory

scholarly journals Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense against MurineLegionella pneumophilaPneumonia

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Yuta Nanjo ◽  
Michael W. Newstead ◽  
Tetsuji Aoyagi ◽  
Xianying Zeng ◽  
Kazuhisa Takahashi ◽  
...  
Keyword(s):  
Host Defense ◽  
Legionella Pneumophila ◽  
Ex Vivo ◽  
Inflammatory Cells ◽  
Bacterial Clearance ◽  
Content Type ◽  
Cytokines And Chemokines ◽  
M1 Polarization ◽  
Life Threatening ◽  
Deficient Mice

ABSTRACTLegionella pneumophilacauses life-threatening pneumonia culminating in acute lung injury. Innate and adaptive cytokines play an important role in host defense againstL. pneumophilainfection. Interleukin-36 (IL-36) cytokines are recently described members of the larger IL-1 cytokine family known to exert potent inflammatory effects. In this study, we elucidated the role for IL-36 cytokines in experimental pneumonia caused byL. pneumophila. Intratracheal (i.t.) administration ofL. pneumophilainduced the upregulation of both IL-36α and IL-36γ mRNA and protein production in the lung. Compared to the findings forL. pneumophila-infected wild-type (WT) mice, the i.t. administration ofL. pneumophilato IL-36 receptor-deficient (IL-36R−/−) mice resulted in increased mortality, a delay in lung bacterial clearance, increasedL. pneumophiladissemination to extrapulmonary organs, and impaired glucose homeostasis. Impaired lung bacterial clearance in IL-36R−/−mice was associated with a significantly reduced accumulation of inflammatory cells and the decreased production of proinflammatory cytokines and chemokines.Ex vivo, reduced expression of costimulatory molecules and impaired M1 polarization were observed in alveolar macrophages isolated from infected IL-36R−/−mice compared to macrophages from WT mice. WhileL. pneumophila-induced mortality in IL-36α- or IL-36γ-deficient mice was not different from that in WT animals, antibody-mediated neutralization of IL-36γ in IL-36α−/−mice resulted in mortality similar to that observed in IL-36R−/−mice, indicating redundant and overlapping roles for these cytokines in experimental murineL. pneumophilapneumonia.

scholarly journals Intracranial Haemorrhage as a Fatal Complication of Evans Syndrome: A Case Report

2019 ◽  
Vol 2 (2) ◽  
pp. 66-69
Author(s):  
Olita Shilpakar ◽  
Bibek Rajbhandari ◽  
Bipin Karki ◽  
Umesh Bogati
Keyword(s):  
Intracranial Haemorrhage ◽  
Early Recognition ◽  
Clinical Manifestations ◽  
Health Care Facilities ◽  
Evans Syndrome ◽  
Fatal Complication ◽  
Hematologic Disorder ◽  
Immune Mediated ◽  
Life Threatening ◽  
Immune Neutropenia

Evans syndrome is a rare hematologic disorder characterized by the presence of simultaneous or sequential direct Coombs-positive autoimmune hemolytic anemia (AIHA), immune-mediated thrombocytopenia and/or immune neutropenia without any known underlying etiology. Spontaneous intracranial hemorrhage is a rare and life-threatening complication in patients with Evans syndrome and very few cases have been reported to date. We report a case of a thirty-two- year-old female with intracranial haemorrhage with underlying Evans syndrome who presented with the clinical manifestations of headache, vomiting and altered sensorium and succumbed to the fatal complication despite resuscitative measures. This also emphasizes the importance of early recognition of symptoms and immediate presentation to health care facilities for aggressive management of the patient.

scholarly journals DNA damage independent inhibition of NF-κB transcription by anthracyclines

2020 ◽  
Author(s):  
Angelo Chora ◽  
Dora Pedroso ◽  
Nadja Pejanovic ◽  
Eleni Kyriakou ◽  
Henrique Colaço ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factors ◽  
Binding Sites ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Anticancer Properties ◽  
Dna Binding Sites ◽  
Immune Mediated ◽  
Life Threatening ◽  
Molecular Patterns

AbstractTranscriptional programs leading to induction of a large number of genes can be rapidly initiated by the activation of only few selected transcription factors. Upon stimulation of macrophages with microbial-associated molecular patterns (MAMPs), the activation of the nuclear factor kappa B (NF-κB) family of transcription factors triggers inflammatory responses that, left uncontrolled, can lead to excessive inflammation with life-threatening consequences for the host. Here we identify and characterize a novel effect of Anthracyclines, a class of drugs currently used as potent anticancer drugs, in the regulation of NF-κB transcriptional activity in BMDMs, in addition to the previously reported DNA damage and histone eviction. Anthracyclines, including Doxorubicin, Daunorubicin and Epirubicin, disturb the complexes formed between the NF-κB subunit RelA and its DNA binding sites, to limit NF-κB-dependent gene transcription during inflammatory responses, including of pivotal pro-inflammatory mediators such as TNF. We observed that suppression of inflammation can also be mediated by Aclarubicin, Doxorubicinone and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other Anthracyclines, but do not induce DNA damage in the tested concentrations. This novel mechanism of action of Anthracyclines, contributing to the reduction of inflammation, is thus independent of the activation of DNA damage responses and may be relevant for the development of novel strategies targeting immune-mediated inflammatory diseases.

scholarly journals Membranoproliferative Glomerulonephritis Type 1 Secondary to an Infected Ventriculoperitoneal Shunt: a Case Report

2014 ◽  
Vol 12 (2) ◽  
pp. 119-121
Author(s):  
Christos Paliouras ◽  
Foteini Lamprianou ◽  
Georgios Ntetskas ◽  
Georgios Mattas ◽  
Nikolaos Karvouniaris ◽  
...  
Keyword(s):  
Ventriculoperitoneal Shunt ◽  
Membranoproliferative Glomerulonephritis ◽  
Classical Pathway ◽  
Glomerular Injury ◽  
Laboratory Findings ◽  
Immune Mediated ◽  
Histologic Pattern ◽  
Life Threatening ◽  
Subsequent Activation

AbstractVentricular shunting is the usual method for treatment of congenital or acquired hydrocephalus. Immune-mediated glomerulonephritis (shunt nephritis) is a rare but life-threatening complication of this neurosurgical technique. Intraglomerular deposition of circulating immune complexes and the subsequent activation of the classical pathway of serum complement’s cascade result in glomerular inflammation. Membranoproliferative gomerulonephritis is the most common histologic pattern observed in renal biopsy. The diagnosis needs high suspicion and is based on clinical and laboratory findings. Deterioration of renal function in association with signs of infection and low levels of serum complement’s proteins C3 and C4 make the diagnosis possible. The prognosis is variable and depends on the time of diagnosis after the onset of glomerular injury. The optimal treatment includes timely removal of the infected shunt in combination with aggressive antibiotic therapy. In this paper we present the case of a membranoproliferative glomerulonephritis type 1 in a patient with a ventriculoperitoneal shunt. Although this type of shunting is considered safer than the ventriculoatrial one, the risk of complications such as an immune-mediated glomerulonephritis still exists.

scholarly journals Influence of replacing tuberculin skin test with ex vivo interferon γ release assays on decision to administer prophylactic antituberculosis antibiotics before anti-TNF therapy

2012 ◽  
Vol 71 (11) ◽  
pp. 1783-1790 ◽  
Author(s):  
Xavier Mariette ◽  
Gabriel Baron ◽  
Florence Tubach ◽  
Frédéric Lioté ◽  
Bernard Combe ◽  
...  
Keyword(s):  
Antibiotic Prophylaxis ◽  
Tuberculin Skin Test ◽  
Skin Test ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Tertiary Care ◽  
Latent Tuberculosis ◽  
Interferon Γ ◽  
Specificity And Sensitivity ◽  
Immune Mediated

BackgroundThe recommendations for detecting latent tuberculosis infection (LTBI) before antitumour necrosis factor (anti-TNF) therapy are based on the tuberculin skin test (TST), which lacks both specificity and sensitivity and can lead to unnecessary treatment with antibiotics. A study was undertaken to investigate the effect of replacing TST with interferon γ (IFNγ) release assays (IGRA) in screening for LTBI and deciding to begin prophylactic antituberculosis (TB) antibiotics before anti-TNF therapy in immune-mediated inflammatory diseases.MethodsIn 15 tertiary care hospitals, consecutive patients with rheumatoid arthritis, spondylarthropathies or Crohn's disease were screened for LTBI before anti-TNF therapy with TST, QuantiFERON TB Gold in tube (QTF-Gold IT) and T-SPOT.TB at the same time. The potential diagnosis of LTBI and the effect on the decision to begin antibiotic prophylaxis were assessed.ResultsAmong 429 patients, 392 had results for the three tests. The results for TST, T-SPOT.TB and QTF Gold IT were positive for 35.2%, 15.1% and 9.9% of patients, respectively (p<0.0001). Antibiotics were required for 177 patients (45.2%) if positive TST results were included in the LTBI definition, 107 patients (27.3%) if TST results were replaced with results from one of the IGRA tests and 84 patients (21.4%) if TST results were replaced with QTF-Gold IT results (p<0.0001). The decision on the use of antibiotic prophylaxis was changed for 113 patients (28.8%, 95% CI 24.4% to 33.6%) if TST results were replaced with QTF-Gold IT results.ConclusionsReplacing TST with IGRA for determining LTBI allowed the proportion of patients with immune-mediated inflammatory diseases needing prophylactic anti-TB antibiotics before beginning anti-TNF agents to be reduced by half.TrialRegNo: NCT00811343.

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