RESUMEN
Understanding the pathophysiology of long COVID is one of the most intriguing challenges confronting contemporary medicine. Despite observations recently made in the relevant molecular, cellular, and physiological domains, it is still difficult to say whether the post-acute sequelae of COVID-19 directly correspond to the consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This work hypothesizes that neutrophils and neutrophil extracellular traps (NETs) production are at the interconnection of three positive feedback loops which are initiated in the acute phase of SARS-CoV-2 infection, and which involve inflammation, immunothrombosis, and autoimmunity. This phenomenon could be favored by the fact that SARS-CoV-2 may directly bind and penetrate neutrophils. The ensuing strong neutrophil stimulation leads to a progressive amplification of an exacerbated and uncontrolled NETs production, potentially persisting for months beyond the acute phase of infection. This continuous self-stimulation of neutrophils leads, in turn, to systemic inflammation, micro-thromboses, and the production of autoantibodies, whose significant consequences include the persistence of endothelial and multiorgan damage, and vascular complications.
Asunto(s)
Autoinmunidad , Retroalimentación Fisiológica , Inflamación , Neutrófilos , Síndrome Post Agudo de COVID-19 , Tromboinflamación , Inflamación/inmunología , Tromboinflamación/inmunología , Neutrófilos/inmunología , Síndrome Post Agudo de COVID-19/inmunología , Síndrome Post Agudo de COVID-19/fisiopatología , Trampas Extracelulares/inmunología , Enfermedades Transmisibles/patologíaRESUMEN
The persistence or recurrence of symptoms after acute SARS-CoV-2 infection, termed 'long COVID', presents a formidable challenge to global healthcare systems. Recent research by Cervia-Hasler and colleagues delves into the intricate immunological landscape in patients with long COVID, demonstrating an interplay between complement and coagulation, driven by antiviral antibodies and tissue damage.
Asunto(s)
COVID-19 , Proteínas del Sistema Complemento , SARS-CoV-2 , Humanos , COVID-19/inmunología , SARS-CoV-2/inmunología , Proteínas del Sistema Complemento/inmunología , Proteínas del Sistema Complemento/metabolismo , Tromboinflamación/inmunología , Coagulación Sanguínea/inmunología , Síndrome Post Agudo de COVID-19 , Activación de Complemento/inmunología , Anticuerpos Antivirales/inmunologíaRESUMEN
Long Covid is a debilitating condition of unknown etiology. We performed multimodal proteomics analyses of blood serum from COVID-19 patients followed up to 12 months after confirmed severe acute respiratory syndrome coronavirus 2 infection. Analysis of >6500 proteins in 268 longitudinal samples revealed dysregulated activation of the complement system, an innate immune protection and homeostasis mechanism, in individuals experiencing Long Covid. Thus, active Long Covid was characterized by terminal complement system dysregulation and ongoing activation of the alternative and classical complement pathways, the latter associated with increased antibody titers against several herpesviruses possibly stimulating this pathway. Moreover, markers of hemolysis, tissue injury, platelet activation, and monocyte-platelet aggregates were increased in Long Covid. Machine learning confirmed complement and thromboinflammatory proteins as top biomarkers, warranting diagnostic and therapeutic interrogation of these systems.
Asunto(s)
Activación de Complemento , Proteínas del Sistema Complemento , Síndrome Post Agudo de COVID-19 , Proteoma , Tromboinflamación , Humanos , Proteínas del Sistema Complemento/análisis , Proteínas del Sistema Complemento/metabolismo , Síndrome Post Agudo de COVID-19/sangre , Síndrome Post Agudo de COVID-19/complicaciones , Síndrome Post Agudo de COVID-19/inmunología , Tromboinflamación/sangre , Tromboinflamación/inmunología , Biomarcadores/sangre , Proteómica , Masculino , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , AncianoRESUMEN
Over the past 10 years, neutrophil extracellular traps (NETs) have become widely accepted as an integral player in immunothrombosis, due to their complex interplay with both pathogens and components of the coagulation system. While the release of NETs is an attempt by neutrophils to trap pathogens and constrain infections, NETs can have bystander effects on the host by inducing uncontrolled thrombosis, inflammation, and tissue damage. From an evolutionary perspective, pathogens have adapted to bypass the host innate immune response. Staphylococcus aureus (S. aureus), in particular, proficiently overcomes NET formation using several virulence factors. Here we review mechanisms of NET formation and how these are intertwined with platelet activation, the release of endothelial von Willebrand factor, and the activation of the coagulation system. We discuss the unique ability of S. aureus to modulate NET formation and alter released NETs, which helps S. aureus to escape from the host's defense mechanisms. We then discuss how platelets and the coagulation system could play a role in NET formation in S. aureus-induced infective endocarditis, and we explain how targeting these complex cellular interactions could reveal novel therapies to treat this disease and other immunothrombotic disorders.
Asunto(s)
Trampas Extracelulares/inmunología , Trampas Extracelulares/microbiología , Staphylococcus aureus/patogenicidad , Tromboinflamación/etiología , Animales , Factores de Coagulación Sanguínea/inmunología , Interacciones Microbiota-Huesped/inmunología , Humanos , Evasión Inmune , Ratones , Modelos Cardiovasculares , Modelos Inmunológicos , Neutrófilos/inmunología , Neutrófilos/microbiología , Activación Plaquetaria , Infecciones Estafilocócicas/complicaciones , Staphylococcus aureus/inmunología , Tromboinflamación/inmunología , Tromboinflamación/microbiología , Factores de Virulencia/inmunología , Factor de von Willebrand/inmunologíaRESUMEN
CD39/NTPDase1 has emerged as an important molecule that contributes to maintain inflammatory and coagulatory homeostasis. Various studies have hypothesized the possible role of CD39 in COVID-19 pathophysiology since no confirmatory data shed light in this regard. Therefore, we aimed to quantify CD39 expression on COVID-19 patients exploring its association with severity clinical parameters and ICU admission, while unraveling the role of purinergic signaling on thromboinflammation in COVID-19 patients. We selected a prospective cohort of patients hospitalized due to severe COVID-19 pneumonia (n=75), a historical cohort of Influenza A pneumonia patients (n=18) and sex/age-matched healthy controls (n=30). CD39 was overexpressed in COVID-19 patients' plasma and immune cell subsets and related to hypoxemia. Plasma soluble form of CD39 (sCD39) was related to length of hospital stay and independently associated with intensive care unit admission (adjusted odds ratio 1.04, 95%CI 1.0-1.08, p=0.038), with a net reclassification index of 0.229 (0.118-0.287; p=0.036). COVID-19 patients showed extracellular accumulation of adenosine nucleotides (ATP and ADP), resulting in systemic inflammation and pro-coagulant state, as a consequence of purinergic pathway dysregulation. Interestingly, we found that COVID-19 plasma caused platelet activation, which was successfully blocked by the P2Y12 receptor inhibitor, ticagrelor. Therefore, sCD39 is suggested as a promising biomarker for COVID-19 severity. As a conclusion, our study indicates that CD39 overexpression in COVID-19 patients could be indicating purinergic signaling dysregulation, which might be at the basis of COVID-19 thromboinflammation disorder.
Asunto(s)
Apirasa/sangre , Apirasa/metabolismo , COVID-19/patología , Receptores Purinérgicos P2Y/metabolismo , Tromboinflamación/patología , Adenosina Difosfato/análisis , Adenosina Trifosfato/análisis , Biomarcadores/sangre , Plaquetas/inmunología , Hipoxia de la Célula/fisiología , Cuidados Críticos/estadística & datos numéricos , Femenino , Humanos , Virus de la Influenza A/inmunología , Gripe Humana/patología , Tiempo de Internación , Masculino , Persona de Mediana Edad , Activación Plaquetaria/inmunología , Pronóstico , Estudios Prospectivos , Antagonistas del Receptor Purinérgico P2Y/farmacología , SARS-CoV-2/inmunología , Índice de Severidad de la Enfermedad , Transducción de Señal/inmunología , Tromboinflamación/inmunología , Ticagrelor/farmacologíaRESUMEN
BACKGROUND: Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia. The etiology underlying AF is still largely unknown. At the intersection of the innate immune system and hemostasis, immunothrombosis may be a possible cause of atrial remodeling, and therefore be an underlying cause of AF. METHODS: From 1990 to 2014, we followed participants aged 55 and over, free from AF at inclusion. Immunothrombosis factors fibrinogen, von Willebrand factor, ADAMTS13, and neutrophil extracellular traps (NETs) levels were measured at baseline. Participants were followed until either onset of AF, loss-to-follow-up, or reaching the end-date of 01-01-2014. Cox proportional hazard modelling was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for cardiovascular risk factors. RESULTS: We followed 6174 participants (mean age 69.1 years, 57% women) for a median follow-up time of 12.8 years. 364 men (13.7%, incidence rate 13.0/1000 person-years) and 365 women (10.4%, incidence rate 8.9/1000 person-years) developed AF. We found no significant association between markers of immunothrombosis and new-onset AF after adjusting for cardiovascular risk factors [HR 1.00 (95% CI 0.93-1.08) for fibrinogen, 1.04 (0.97-1.12) for von Willebrand factor, 1.00 (1.00-1.01) for ADAMTS13, and 1.01 (0.94-1.09) for NETs]. In addition, we found no differences in associations between men and women. CONCLUSION: We found no associations between markers of immunothrombosis and new-onset AF in the general population. Inflammation and immunothrombosis may be associated with AF through other cardiovascular risk factors or predisposing conditions of AF. Our findings challenge the added value of biomarkers in AF risk prediction.
Asunto(s)
Fibrilación Atrial/etiología , Fibrilación Atrial/inmunología , Tromboinflamación/complicaciones , Tromboinflamación/inmunología , Anciano , Fibrilación Atrial/epidemiología , Biomarcadores/sangre , Femenino , Humanos , Inmunidad Innata , Incidencia , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Estudios Prospectivos , Factores de Riesgo , Tromboinflamación/epidemiologíaAsunto(s)
COVID-19/inmunología , Activación Plaquetaria , SARS-CoV-2/inmunología , Tromboinflamación/inmunología , Plaquetas/inmunología , COVID-19/sangre , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Productos de Degradación de Fibrina-Fibrinógeno/inmunología , Humanos , Volúmen Plaquetario Medio , Recuento de Plaquetas , Estudios Retrospectivos , Tromboinflamación/sangreRESUMEN
Although initial immunophenotypical studies on peripheral blood and bronchoalveolar lavage samples have provided a glimpse into the immunopathology of COVID-19, analyses of pulmonary draining lymph nodes are currently scarce. 22 lethal COVID-19 cases and 28 controls were enrolled in this study. Pulmonary draining lymph nodes (mediastinal, tracheal, peribronchial) were collected at autopsy. Control lymph nodes were selected from a range of histomorphological sequelae [unremarkable histology, infectious mononucleosis, follicular hyperplasia, non-SARS related HLH, extrafollicular plasmablast activation, non-SARS related diffuse alveolar damage (DAD), pneumonia]. Samples were mounted on a tissue microarray and underwent immunohistochemical staining for a selection of immunological markers and in-situ hybridization for Epstein Barr Virus (EBV) and SARS-CoV-2. Gene expression profiling was performed using the HTG EdgeSeq Immune Response Panel. Characteristic patterns of a dysregulated immune response were detected in COVID-19: 1. An accumulation of extrafollicular plasmablasts with a relative paucity or depletion of germinal centers. 2. Evidence of T-cell dysregulation demonstrated by immunohistochemical paucity of FOXP3+, Tbet+ and LEF1+ positive T-cells and a downregulation of key genes responsible for T-cell crosstalk, maturation and migration as well as a reactivation of herpes viruses in 6 COVID-19 lymph nodes (EBV, HSV). 3. Macrophage activation by a M2-polarized, CD163+ phenotype and increased incidence of hemophagocytic activity. 4. Microvascular dysfunction, evidenced by an upregulation of hemostatic (CD36, PROCR, VWF) and proangiogenic (FLT1, TEK) genes and an increase of fibrin microthrombi and CD105+ microvessels. Taken together, these findings imply widespread dysregulation of both innate and adoptive pathways with concordant microvascular dysfunction in severe COVID-19.
Asunto(s)
COVID-19/inmunología , COVID-19/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Pulmón , Activación de Macrófagos/inmunología , Masculino , Persona de Mediana Edad , SARS-CoV-2 , Linfocitos T/inmunología , Linfocitos T/patología , Tromboinflamación/inmunología , Tromboinflamación/patología , Tromboinflamación/virologíaRESUMEN
Preeclampsia is a multifactorial vascular disease unique to human pregnancy. While genetic and antiangiogenic factors are important contributors to preeclampsia susceptibility, recent studies have shown that dysregulation and/or over-activation of the complement system has an integral role in disease etiology. Furthermore, the role of the coagulation cascade may be underappreciated in the development of the disease. Traditionally, for research purposes, the pool of preeclampsia cases has been divided into non-severe and severe disease depending on the onset and severity of the symptoms. However, of particular interest are a small but important minority of cases that present with symptoms likening to those of hemolysis, elevated liver enzymes and low platelets syndrome, atypical hemolytic uremic syndrome, or thrombotic thrombocytopenic purpura, all thrombotic microangiopathy (TMA) diseases, with the hallmark mechanisms of endothelial dysfunction and aberrant activation of complement and coagulation cascades. We therefore propose a third class, severe TMA-like preeclampsia to be included in the categorization of preeclampsia patients. Identifying these patients would target research, diagnostic differentiation, and novel treatment options to the subclass of patients with life-threatening disease that are most likely to benefit from next-generation drug development.
Asunto(s)
Plaquetas/inmunología , Endotelio Vascular/fisiología , Placenta/inmunología , Preeclampsia/inmunología , Embarazo/inmunología , Tromboinflamación/inmunología , Microangiopatías Trombóticas/inmunología , Animales , Síndrome Hemolítico Urémico Atípico , Activación de Complemento , Proteínas del Sistema Complemento/inmunología , Proteínas del Sistema Complemento/metabolismo , Femenino , Humanos , Modelos InmunológicosRESUMEN
Background: Endogenous DNA derived from nuclei or mitochondria is released into the blood circulation as cell-free DNA (cfDNA) following cell damage or death. cfDNA is associated with various pathological conditions; however, its clinical significance in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) remains unclear. This study aimed to evaluate the clinical significance of cfDNA in AAV. Methods: We enrolled 35 patients with AAV, including 10 with eosinophilic granulomatosis with polyangiitis (EGPA), 13 with microscopic polyangiitis, and 12 with granulomatosis with polyangiitis. Serum cf-nuclear DNA (cf-nDNA) and cf-mitochondrial DNA (cf-mtDNA) levels were measured by quantitative polymerase chain reaction before and after the initiation of immunosuppressive therapy. Tissue samples from EGPA patients were examined by immunofluorescence and transmission electron microscopy. The structure of eosinophil extracellular traps (EETs) and neutrophil extracellular traps (NETs) and stability against DNase were assessed in vitro. Platelet adhesion of EETs were also assessed. Results: Serum cf-nDNA and cf-mtDNA levels were significantly higher in AAV than in healthy controls, with the highest levels in EGPA; however, serum DNase activities were comparable among all groups. cf-nDNA and cf-mtDNA decreased after treatment and were associated with disease activity only in EGPA. Blood eosinophil count and plasma D-dimer levels were significantly correlated with cf-nDNA in EGPA and cf-mtDNA. EGPA tissue samples showed lytic eosinophils and EETs in small-vessel thrombi. The structure of EETs showed bolder net-like chromatin threads in vitro and EETs showed greater stability against DNase than NETs. EETs provided a scaffold for platelet adhesion. Conclusion: cfDNA was increased in EGPA, associated with disease activity. The presence of DNase-resistant EETs in small-vessel thrombi might contribute to higher concentration of cfDNA and the occurrence of immunothrombosis in EGPA.