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Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.
Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Autoanticuerpos , Síndrome Post Agudo de COVID-19 , QuimiocinasRESUMEN
The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in coronavirus disease 2019 (COVID-19). The present study was designed to conduct a systematic investigation of the interaction of human humoral fluid-phase pattern recognition molecules (PRMs) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of 12 PRMs tested, the long pentraxin 3 (PTX3) and mannose-binding lectin (MBL) bound the viral nucleocapsid and spike proteins, respectively. MBL bound trimeric spike protein, including that of variants of concern (VoC), in a glycan-dependent manner and inhibited SARS-CoV-2 in three in vitro models. Moreover, after binding to spike protein, MBL activated the lectin pathway of complement activation. Based on retention of glycosylation sites and modeling, MBL was predicted to recognize the Omicron VoC. Genetic polymorphisms at the MBL2 locus were associated with disease severity. These results suggest that selected humoral fluid-phase PRMs can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.
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COVID-19/inmunología , Inmunidad Humoral , Receptores de Reconocimiento de Patrones/inmunología , SARS-CoV-2/inmunología , Animales , Proteína C-Reactiva/inmunología , Proteína C-Reactiva/metabolismo , COVID-19/metabolismo , COVID-19/virología , Estudios de Casos y Controles , Chlorocebus aethiops , Activación de Complemento , Proteínas de la Nucleocápside de Coronavirus/genética , Proteínas de la Nucleocápside de Coronavirus/inmunología , Proteínas de la Nucleocápside de Coronavirus/metabolismo , Femenino , Glicosilación , Células HEK293 , Interacciones Huésped-Patógeno , Humanos , Masculino , Lectina de Unión a Manosa/genética , Lectina de Unión a Manosa/inmunología , Lectina de Unión a Manosa/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/inmunología , Fosfoproteínas/metabolismo , Polimorfismo Genético , Unión Proteica , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidad , Componente Amiloide P Sérico/inmunología , Componente Amiloide P Sérico/metabolismo , Transducción de Señal , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Células VeroRESUMEN
Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αß T cells (UTCαß). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαß associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαß polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.
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Resistencia a la Enfermedad , Neoplasias/patología , Neutrófilos/inmunología , Sarcoma/patología , Linfocitos T/metabolismo , Animales , Cromonas/toxicidad , Resistencia a la Enfermedad/inmunología , Humanos , Inmunidad Innata , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Estimación de Kaplan-Meier , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/inmunología , Neoplasias/mortalidad , Infiltración Neutrófila , Neutrófilos/citología , Neutrófilos/metabolismo , Receptores del Factor Estimulante de Colonias/metabolismo , Sarcoma/inducido químicamente , Sarcoma/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Microambiente TumoralRESUMEN
Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation1-3. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19)4-7. RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.
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Proteína C-Reactiva/genética , COVID-19/genética , Perfilación de la Expresión Génica/métodos , Macrófagos/metabolismo , SARS-CoV-2/aislamiento & purificación , Componente Amiloide P Sérico/genética , Células A549 , Adulto , Proteína C-Reactiva/metabolismo , COVID-19/epidemiología , COVID-19/virología , Línea Celular Tumoral , Células Cultivadas , Estudios de Cohortes , Células Endoteliales/metabolismo , Epidemias , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Neutrófilos/metabolismo , Pronóstico , SARS-CoV-2/fisiología , Componente Amiloide P Sérico/metabolismoRESUMEN
The innate immune system consists of a cellular and a humoral arm. Pentraxins (e.g., the short pentraxin C reactive protein and the long pentraxin PTX3) are key components of the humoral arm of innate immunity which also includes complement components, collectins, and ficolins. In response to microorganisms and tissue damage, neutrophils, macrophages, and dendritic cells are major sources of fluid-phase pattern-recognition molecules (PRMs) belonging to different molecular classes. Humoral PRMs in turn interact with and regulate cellular effectors. Effector mechanisms of the humoral innate immune system include activation and regulation of the complement cascade; agglutination and neutralization; facilitation of recognition via cellular receptors (opsonization); and regulation of inflammation. Thus, the humoral arm of innate immunity is an integrated system consisting of different molecules and sharing functional outputs with antibodies.
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Proteína C-Reactiva/inmunología , Inmunidad Humoral , Inmunidad Innata , Animales , Anticuerpos/inmunología , Humanos , LigandosRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
The plasma membrane tetraspan molecule MS4A4A is selectively expressed by macrophage-lineage cells, but its function is unknown. Here we report that MS4A4A was restricted to murine and human mononuclear phagocytes and was induced during monocyte-to-macrophage differentiation in the presence of interleukin 4 or dexamethasone. Human MS4A4A was co-expressed with M2/M2-like molecules in subsets of normal tissue-resident macrophages, infiltrating macrophages from inflamed synovium and tumor-associated macrophages. MS4A4A interacted and colocalized with the ß-glucan receptor dectin-1 in lipid rafts. In response to dectin-1 ligands, Ms4a4a-deficient macrophages showed defective signaling and defective production of effector molecules. In experimental models of tumor progression and metastasis, Ms4a4a deficiency in macrophages had no impact on primary tumor growth, but was essential for dectin-1-mediated activation of macrophages and natural killer (NK) cell-mediated metastasis control. Thus, MS4A4A is a tetraspan molecule selectively expressed in macrophages during differentiation and polarization, essential for dectin-1-dependent activation of NK cell-mediated resistance to metastasis.
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Células Asesinas Naturales/inmunología , Lectinas Tipo C/metabolismo , Macrófagos/inmunología , Proteínas de la Membrana/metabolismo , Metástasis de la Neoplasia/inmunología , Neoplasias/inmunología , Animales , Diferenciación Celular/inmunología , Linaje de la Célula , Dexametasona/farmacología , Humanos , Interleucina-4/metabolismo , Activación de Linfocitos/inmunología , Activación de Macrófagos/inmunología , Macrófagos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Metástasis de la Neoplasia/prevención & control , Neoplasias/patologíaRESUMEN
PTX3 is an essential component of the humoral arm of innate immunity, playing a nonredundant role in resistance against selected microbes and in the regulation of inflammation. PTX3 activates and regulates the Complement cascade by interacting with C1q and with Factor H. PTX3 deficiency was associated with increased susceptibility to mesenchymal and epithelial carcinogenesis. Increased susceptibility of Ptx3(-/-) mice was associated with enhanced macrophage infiltration, cytokine production, angiogenesis, and Trp53 mutations. Correlative evidence, gene-targeted mice, and pharmacological blocking experiments indicated that PTX3 deficiency resulted in amplification of Complement activation, CCL2 production, and tumor-promoting macrophage recruitment. PTX3 expression was epigenetically regulated in selected human tumors (e.g., leiomyosarcomas and colorectal cancer) by methylation of the promoter region and of a putative enhancer. Thus, PTX3, an effector molecule belonging to the humoral arm of innate immunity, acts as an extrinsic oncosuppressor gene in mouse and man by regulating Complement-dependent, macrophage-sustained, tumor-promoting inflammation.
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Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Inflamación/metabolismo , Neoplasias/inmunología , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , Animales , Proteínas del Sistema Complemento/metabolismo , Metilación de ADN , Genes p53 , Humanos , Ratones , MutaciónRESUMEN
Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues.
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Enfermedades Transmisibles/inmunología , Inmunidad Celular/inmunología , Inmunidad Humoral/inmunología , Inflamación/inmunología , Enfermedad Aguda , Enfermedad Crónica , HumanosRESUMEN
Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.
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Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inflamación/inmunología , Neoplasias/inmunología , Escape del Tumor/inmunología , Animales , Dinoprostona/metabolismo , Humanos , Inmunoterapia , Inflamación/genética , Interferón gamma/metabolismo , Células Asesinas Naturales/inmunología , Ratones , Neoplasias/terapia , Fenotipo , Pronóstico , Prostaglandina-Endoperóxido Sintasas/genética , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Forty years after its naming, interleukin-1 (IL-1) is experiencing a renaissance brought on by the growing understanding of its context-dependent roles and advances in the clinic. Recent studies have identified important roles for members of the IL-1 family-IL-18, IL-33, IL-36, IL-37, and IL-38-in inflammation and immunity. Here, we review the complex functions of IL-1 family members in the orchestration of innate and adaptive immune responses and their diversity and plasticity. We discuss the varied roles of IL-1 family members in immune homeostasis and their contribution to pathologies, including autoimmunity and auto-inflammation, dysmetabolism, cardiovascular disorders, and cancer. The trans-disease therapeutic activity of anti-IL-1 strategies argues for immunity and inflammation as a metanarrative of modern medicine.
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Inmunidad Adaptativa/inmunología , Citocinas/fisiología , Inmunidad Innata/inmunología , Inflamación/inmunología , Interleucina-1/fisiología , Animales , Enfermedades Cardiovasculares/inmunología , Citocinas/genética , Citocinas/inmunología , Enfermedades Gastrointestinales/inmunología , Hematopoyesis/inmunología , Humanos , Interleucina-1/inmunología , Linfocitos/inmunología , Ratones , Ratones Noqueados , Familia de Multigenes , Neoplasias/inmunología , Enfermedades Neurodegenerativas/inmunología , Receptores de Citocinas/genética , Receptores de Citocinas/inmunologíaRESUMEN
Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.
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Subunidad alfa del Receptor de Interleucina-18/inmunología , Interleucina-1/inmunología , Leucocitos Mononucleares/inmunología , Receptores de Interleucina-1/inmunología , Transducción de Señal/inmunología , Animales , Línea Celular , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-1/genética , Subunidad alfa del Receptor de Interleucina-18/antagonistas & inhibidores , Subunidad alfa del Receptor de Interleucina-18/genética , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/patología , Lipopolisacáridos/farmacología , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/inmunología , Ratones , Ratones Transgénicos , FN-kappa B/genética , FN-kappa B/inmunología , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/inmunología , Unión Proteica , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/inmunología , Proteínas Proto-Oncogénicas c-fyn/genética , Proteínas Proto-Oncogénicas c-fyn/inmunología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/inmunología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/inmunología , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/inmunología , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores de Interleucina-1/deficiencia , Receptores de Interleucina-1/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/inmunología , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/inmunología , Tirosina Quinasa c-MerRESUMEN
Interleukin-1 receptor family members (ILRs) and Toll-Like Receptors (TLRs) play pivotal role in immunity and inflammation and are expressed by most cell types including cells of both the innate and adaptive immune system. In this context, IL-1 superfamily members are also important players in regulating function and differentiation of adaptive and innate lymphoid cells. This system is tightly regulated in order to avoid uncontrolled activation, which may lead to detrimental inflammation contributing to autoimmune or allergic responses. IL-1R8 (also known as TIR8 or SIGIRR) is a member of the IL-1R family that acts as a negative regulator dampening ILR and TLR signaling and as a co-receptor for human IL-37. Human and mouse NK cells, that are key players in immune surveillance of tumors and infections, express high level of IL-1R8. In this review, we will summarize our current understanding on the structure, expression and function of IL-1R8 and we will also discuss the emerging role of IL-1R8 as an important checkpoint regulating NK cells function in pathological conditions including cancer and viral infections.
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Inmunidad Innata , Neoplasias , Animales , Humanos , Inflamación , Células Asesinas Naturales , Neoplasias/metabolismo , Receptores de Interleucina-1/metabolismoRESUMEN
Vaccines have dramatically changed the COVID-19 pandemic. Over 30 vaccines that were developed on four main platforms are currently being used globally, but a deep dissection of the immunological mechanisms by which they operate is limited to only a few of them. Here, we review the evidence describing specific aspects of the modes of action of COVID-19 vaccines; these include innate immunity, trained innate immunity, and mucosal responses. We also discuss the use of COVID-19 vaccines in the African continent which is ridden with inequality in its access to vaccines and vaccine-related immunological research. We argue that strengthening immunology research in Africa should inform on fundamental aspects of vaccination, including the relevance of genetics, trained innate immunity, and microbiome diversity.
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COVID-19 , Vacunas , Humanos , Vacunas contra la COVID-19 , Pandemias/prevención & control , Inmunidad Innata , VacunaciónRESUMEN
Innate immunity includes a cellular and a humoral arm. PTX3 is a fluid-phase pattern recognition molecule conserved in evolution which acts as a key component of humoral innate immunity in infections of fungal, bacterial, and viral origin. PTX3 binds conserved microbial structures and self-components under conditions of inflammation and activates effector functions (complement, phagocytosis). Moreover, it has a complex regulatory role in inflammation, such as ischemia/reperfusion injury and cancer-related inflammation, as well as in extracellular matrix organization and remodeling, with profound implications in physiology and pathology. Finally, PTX3 acts as an extrinsic oncosuppressor gene by taming tumor-promoting inflammation in murine and selected human tumors. Thus evidence suggests that PTX3 is a key homeostatic component at the crossroad of innate immunity, inflammation, tissue repair, and cancer. Dissecting the complexity of PTX3 pathophysiology and human genetics paves the way to diagnostic and therapeutic exploitation.
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Proteína C-Reactiva/metabolismo , Inmunidad Innata/inmunología , Inflamación/inmunología , Neoplasias/metabolismo , Componente Amiloide P Sérico/metabolismo , Cicatrización de Heridas/inmunología , Animales , Humanos , Inmunidad Humoral/inmunología , Neoplasias/inmunologíaRESUMEN
Leading scientists from around the globe gathered on the Greek island of Kos in June 2013 to discuss the latest developments in the field of innate immunity and to explore new ideas and research collaborations.