Anaphylaxis is a systemic acute hypersensitivity reaction that is considered to depend on allergen-specific immunoglobulin E (IgE) antibodies and histamine release by mast cells and basophils. Nevertheless, allergen-specific IgG antibodies have been proposed to contribute when the allergen is an abundant circulating large molecule, e.g., after infusions of therapeutic antibodies or dextran. Data from animal models demonstrate a pathway involving platelet-activating factor (PAF) release by monocytes/macrophages and neutrophils activated via their Fc gamma receptors (FcγRs). We hypothesized that such a pathway may also apply to small drugs and could be responsible for non–IgE-mediated anaphylaxis and influence anaphylaxis severity in humans. We prospectively conducted a multicentric study of 86 patients with suspected anaphylaxis to neuromuscular-blocking agents (NMBAs) during general anesthesia and 86 matched controls. We found that concentrations of anti-NMBA IgG and markers of FcγR activation, PAF release, and neutrophil activation correlated with anaphylaxis severity. Neutrophils underwent degranulation and NETosis early after anaphylaxis onset, and plasma-purified anti-NMBA IgG triggered neutrophil activation ex vivo in the presence of NMBA. Neutrophil activation could also be observed in patients lacking evidence of classical IgE-dependent anaphylaxis. This study supports the existence of an IgG-neutrophil pathway in human NMBA-induced anaphylaxis, which may aggravate anaphylaxis in combination with the IgE pathway or underlie anaphylaxis in the absence of specific IgE. These results reconcile clinical and experimental data on the role of antibody classes in anaphylaxis and could inform diagnostic approaches to NMBA-induced acute hypersensitivity reactions.

Neutrophil extracellular traps (NETs) are extracellular DNA filaments formed during neutrophil activation. This process, called netosis, was originally associated with neutrophil antibacterial properties. However, several lines of evidence now suggest a major role for netosis in thrombosis, autoimmune diseases, and cancer. We demonstrate here that highly purified human blood monocytes are also capable of extracellular trap (ET) release in response to several stimuli. Monocyte ETs display a morphology analogous to NETs and are associated with myeloperoxidase (MPO), lactoferrin (LF), citrullinated histones, and elastase. Monocyte ET release depends on oxidative burst but not on MPO activity, in contrast to neutrophils. Moreover, we demonstrate procoagulant activity for monocyte ETs, a feature that could be relevant to monocyte thrombogenic properties. This new cellular mechanism is likely to have implications in the multiple pathologic contexts where monocytes are implicated, such as inflammatory disorders, infection, or thrombosis.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Neutrophil extracellular traps have been associated with tissue damage. Whether these are involved in the pathogenesis of human acute respiratory distress syndrome (ARDS) and could be a potential therapeutic target is unknown. The authors quantified bronchoalveolar and blood neutrophil extracellular traps in patients with pneumonia-related ARDS and assessed their relationship with ventilator-free days. Methods Immunocompetent patients with pneumonia and moderate or severe ARDS (n = 35) and controls (n = 4) were included in a prospective monocentric study. Neutrophil extracellular trap concentrations were quantified (as DNA–myeloperoxidase complexes) in bronchoalveolar lavage fluid and serum by enzyme-linked immunosorbent assay. The relationship between bronchoalveolar lavage neutrophil extracellular trap concentrations and the primary clinical endpoint (i.e., the number of live ventilator-free days at day 28) was assessed using linear regression analyses. Results There was no significant relationship between bronchoalveolar lavage neutrophil extracellular trap concentrations and ventilator-free days by multiple regression analysis (β coefficient = 2.40; 95% CI, −2.13 to 6.92; P = 0.288). Neutrophil extracellular trap concentrations were significantly higher in bronchoalveolar lavage than in blood of ARDS patients (median [first to third quartiles]:154 [74 to 1,000] vs. 26 [4 to 68] arbitrary units, difference: −94; 95% CI, −341 to −57; P < 0.0001). Bronchoalveolar concentrations of patients were higher than those of controls (154 [74 to 1,000] vs. 4 [4 to 4] arbitrary units, difference: −150; 95% CI, −996 to −64; P < 0.001) and associated with bronchoalveolar interleukin-8 (Spearman’s ρ = 0.42; P = 0.012) and neutrophil concentrations (ρ = 0.57; P < 0.0001). Intensive care unit mortality (12%, n = 2 of 17 vs. 17%, n = 3 of 18; P > 0.99) and the number of ventilator-free days at day 28 (22 [14 to 25] vs. 14 [0 to 21] days; difference: −5; 95% CI, −15 to 0; P = 0.066) did not significantly differ between patients with higher (n = 17) versus lower (n = 18) bronchoalveolar neutrophil extracellular trap concentrations. Conclusions Bronchoalveolar neutrophil extracellular trap concentration was not significantly associated with mechanical ventilation duration in pneumonia-related ARDS.

Neutrophil extracellular traps (NETs) have been initially described as main actors in host defense owing to their ability to immobilize and sometimes kill microorganisms. Subsequent studies have demonstrated their implication in the pathophysiology of various diseases, due to the toxic effects of their main components on surrounding tissues. Several distinct NETosis pathways have been described in response to various triggers. Among these triggers, IgG immune complexes (IC) play an important role since they induce robust NET release upon binding to activating FcγRs on neutrophils. Few in vitro studies have documented the mechanisms of IC-induced NET release and evidence about the partners involved is controversial. In vivo, animal models and clinical studies have strongly suggested the importance of IgG IC-induced NET release for autoimmunity and anaphylaxis. In this review, we will focus on two autoimmune diseases in which NETs are undoubtedly major players, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). We will also discuss anaphylaxis as another example of disease recently associated with IC-induced NET release. Understanding the role of IC-induced NETs in these settings will pave the way for new diagnostic tools and therapeutic strategies.

BackgroundVenous thrombo-embolic events (VTE) frequently occur in patients with pancreatic ductal adenocarcinoma (PDAC) and contribute to high morbidity and mortality.ObjectivesTo determine whether VTE biomarkers are related to cancer, inflammation or precancerous states and to assess their relevance to predict VTE in PDAC.Patients and MethodsWe compared VTE biomarkers in patients with PDAC (n = 42), intraductal papillary mucinous neoplasm of the pancreas (IPMN, n = 48) or chronic pancreatitis (n = 50). PDAC patients were followed-up for 6 months.ResultsFactor VIII, D-dimers, von Willebrand factor, free tissue factor pathway inhibitor and microvesicle-tissue factor (MV-TF) activity were higher in PDAC patients compared to patients with IPMN or chronic pancreatitis. PDAC patients with metastasis presented higher D-dimers and MV-TF activity compared to patients with localized lesions, but elevation of D-dimers was dependent on tumor size. In multivariate analysis, elevated D-dimers (≥2.16 µg/mL) or MV-TF activity (≥2.37 pg/mL) were significant risk factors for VTE in PDAC patients, after adjustment for age and sex (HR 4.9 [1.0–23.1] or HR 10.5 [1.5–72.4], mean [interquartile range], respectively). Cumulative probability of VTE at 6 months was higher in patients with elevated D-dimers (56.3% vs 15.6%, p = 0.009) and in patients with high MV-TF activity (74.3% vs 21.7%, p = 0.01).ConclusionsVTE biomarkers including D-dimers and MV-TF activity are not related to inflammation but rather to cancer process and dissemination. D-dimers and MV-TF activity are associated to future VTE in PDAC patients and could help identify patients who could benefit from thromboprophylaxis.

COVID-19 can cause acute respiratory distress syndrome, leading to death in many individuals. Evidence of a deleterious role of the innate immune system is accumulating, but the precise mechanisms involved remain unclear. In this study, we investigated the links between circulating innate phagocytes and severity in COVID-19 patients. We performed in-depth phenotyping of neutrophil and monocyte subpopulations and measured soluble activation markers in plasma. Additionally, anti-microbial functions (phagocytosis, oxidative burst, and NETosis) were evaluated on fresh cells from patients. Neutrophils and monocytes had a strikingly disturbed phenotype, and elevated concentrations of activation markers (calprotectin, myeloperoxidase, and neutrophil extracellular traps) were measured in plasma. Critical patients had increased CD13low immature neutrophils, LOX-1 + and CCR5 + immunosuppressive neutrophils, and HLA-DRlow downregulated monocytes. Markers of immature and immunosuppressive neutrophils were strongly associated with severity. Moreover, neutrophils and monocytes of critical patients had impaired antimicrobial functions, which correlated with organ dysfunction, severe infections, and mortality. Together, our results strongly argue in favor of a pivotal role of innate immunity in COVID-19 severe infections and pleads for targeted therapeutic options.

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NCT01637220.