RESUMEN
Tissue-resident memory T cells (TRM cells) are crucial mediators of adaptive immunity in nonlymphoid tissues. However, the functional heterogeneity and pathogenic roles of CD4+ TRM cells that reside within chronic inflammatory lesions remain unknown. We found that CD69hiCD103lo CD4+ TRM cells produced effector cytokines and promoted the inflammation and fibrotic responses induced by chronic exposure to Aspergillus fumigatus. Simultaneously, immunosuppressive CD69hiCD103hiFoxp3+ CD4+ regulatory T cells were induced and constrained the ability of pathogenic CD103lo TRM cells to cause fibrosis. Thus, lung tissue-resident CD4+ T cells play crucial roles in the pathology of chronic lung inflammation, and CD103 expression defines pathogenic effector and immunosuppressive tissue-resident cell subpopulations in the inflamed lung.
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Comunicación Celular/inmunología , Tolerancia Inmunológica , Memoria Inmunológica , Fibrosis Pulmonar/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos CD/metabolismo , Antígenos Fúngicos/inmunología , Aspergillus fumigatus/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Cadenas alfa de Integrinas/metabolismo , Pulmón/citología , Pulmón/inmunología , Pulmón/patología , Masculino , Ratones Transgénicos , Fibrosis Pulmonar/patología , Linfocitos T Reguladores/metabolismoRESUMEN
The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1-expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)-containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.
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COVID-19 , Pulmón , Cadenas Ligeras de Miosina , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Tromboinflamación , Vasculitis , COVID-19/sangre , COVID-19/complicaciones , COVID-19/patología , Humanos , Leucocitos Mononucleares , Pulmón/irrigación sanguínea , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Cadenas Ligeras de Miosina/sangre , RNA-Seq , SARS-CoV-2/aislamiento & purificación , Análisis de la Célula Individual , Espectrometría por Rayos X , Tromboinflamación/patología , Tromboinflamación/virología , Vasculitis/patología , Vasculitis/virologíaRESUMEN
PURPOSE: Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs. METHODS: We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs. RESULTS: Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor. CONCLUSION: Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.
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Autoanticuerpos , COVID-19 , Interferón Tipo I , Células Mieloides , Femenino , Humanos , Masculino , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , COVID-19/inmunología , Células Dendríticas/inmunología , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Células Mieloides/inmunología , SARS-CoV-2/inmunología , Índice de Severidad de la Enfermedad , Transducción de Señal/inmunologíaRESUMEN
INTRODUCTION: Mucus plugs are associated with airway obstruction in severe asthma and are involved in the formation of activated eosinophils. Benralizumab, an anti-interleukin-5 receptor antibody, markedly reduces not only peripheral blood eosinophils but also airway eosinophils; however, its effects on mucus plugs have not been clarified. In this study, we examined the efficacy of benralizumab on mucus plugs using computed tomography (CT) imaging. METHODS: Twelve patients who were administered benralizumab and underwent CT before and approximately 4 months after the introduction of benralizumab were included in this study, and the number of mucus plugs before and after benralizumab administration was compared. The correlation between the clinical background and treatment effect was also examined. RESULTS: The number of mucus plugs significantly decreased after the introduction of benralizumab. The number of mucus plugs was correlated with sputum eosinophil percentage and eosinophil cationic protein in the sputum supernatants and inversely correlated with forced expiratory volume in 1 s (FEV1). Benralizumab induction resulted in a marked decrease in blood and sputum eosinophil levels and a significant improvement in asthma symptoms, quality of life scores, FEV1, and exacerbation frequency. Furthermore, there was a significant correlation between the reduction in mucus plugs and changes in the symptom score or FEV1. DISCUSSION/CONCLUSION: These data suggest that benralizumab may have the potential to improve symptoms and respiratory function in patients with severe eosinophilic asthma by reducing mucus plugs.
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Antiasmáticos , Asma , Eosinofilia Pulmonar , Humanos , Antiasmáticos/uso terapéutico , Antiasmáticos/farmacología , Calidad de Vida , Asma/tratamiento farmacológico , Asma/complicaciones , Eosinófilos , Eosinofilia Pulmonar/tratamiento farmacológico , Moco , Progresión de la EnfermedadRESUMEN
INTRODUCTION: Benralizumab, an anti-interleukin-5 receptor chain monoclonal antibody, is used to treat severe asthma and control asthma symptoms or exacerbations. The aim of this study was to examine the changes in airway morphology using computed tomography (CT) images in accordance with clinical efficacy following the administration of benralizumab. METHODS: The clinical efficacy of benralizumab was evaluated in 11 patients with severe asthma by analyzing the changes in parameters, such as the asthma control test, asthma quality of life questionnaire, pulmonary function, and exacerbation count. We also investigated the airway wall thickness of the right bronchus (B1) and the total airway count (TAC) using CT images. RESULTS: Most patients treated with benralizumab showed improvements in asthma symptoms and exacerbations. CT imaging analyses showed a decrease in the right B1 airway wall thickness and an increase in the TAC. Correlations between blood eosinophil count and changes in CT imaging were observed. DISCUSSION/CONCLUSION: The data suggested that benralizumab has the potential to improve airway wall thickening and ventilation by alleviating the obstruction and clearing an obstructed airway.
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Antiasmáticos , Asma , Eosinofilia Pulmonar , Humanos , Antiasmáticos/uso terapéutico , Calidad de Vida , Progresión de la Enfermedad , Método Doble Ciego , Asma/tratamiento farmacológico , Eosinofilia Pulmonar/tratamiento farmacológico , Eosinófilos , Tomografía Computarizada por Rayos XRESUMEN
Eosinophils are multifunctional leukocytes, being involved in the host defense against helminth infection, tissue homeostasis and repair of injured tissue. However, eosinophils also play critical roles in shaping the pathogenesis of allergic diseases, including fibrotic responses in allergic diseases. Eosinophils consist of various granules that are a source of cytokines, chemokines, enzymes, extracellular matrix and growth factors. Recent studies have revealed that eosinophil extracellular trap cell death (EETosis) exacerbates eosinophilic inflammation by releasing the products, including Charcot-Leyden crystals (CLCs). In type 2 inflammatory diseases, memory-type pathogenic helper T (Tpath) cells are involved in shaping the pathogenesis of eosinophilic inflammation by recruiting and activating eosinophils in vivo. We herein review the molecular mechanisms underlying the development of eosinophils and the various functions of granules, including CLCs, during eosinophilic inflammation. We also discuss the double-edged roles of eosinophils in tissue repair and type 2 immune inflammation.
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Eosinófilos/citología , Eosinófilos/fisiología , Animales , Biomarcadores , Comunicación Celular/inmunología , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Interacciones Huésped-Patógeno/inmunología , Humanos , Mediadores de Inflamación/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismoRESUMEN
Intractable chronic inflammatory diseases, including autoimmune diseases, autoinflammatory diseases and allergic diseases, are caused by disruption or failure of the immune system. Pathogenic immune cells are presumed to be closely related to the pathogenesis of intractable diseases, but the precise cellular and molecular mechanisms underlying the pathogenesis of these diseases remain unclear. The balance between the T helper type 1 (Th1) and Th2 cell fractions has been believed to be responsible for the differences among inflammatory diseases. However, an analysis of the cells infiltrating inflammatory lesions in mice and humans revealed the generation of pathogenic Th cells with different characteristics at the memory T-cell stage in the peripheral tissues in various inflammatory diseases. In this review, we will summarize and discuss recent progress regarding the characteristics of pathogenic Th cells, their mode of action, and the molecular mechanisms that regulate the pathology of intractable chronic inflammatory diseases, particularly those with tissue fibrosis. We hope this article will help clarify the pathogenesis of these diseases and propose a future direction for research.
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Linfocitos T Colaboradores-Inductores/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Fibrosis , Humanos , Hipersensibilidad/inmunología , Memoria Inmunológica , Inflamación/inmunologíaRESUMEN
PURPOSE: In the past decade, the relationship between naturally occurring interferon-γ-neutralizing autoantibodies (IFNγ-Ab) and disseminated non-tuberculous mycobacteria (NTM) infection has been established. Furthermore, immune suppressive therapy aimed at the suppression of antibody production has shown efficacy as a supportive treatment. However, the nature of antibody behavior and antibody titer during the course of this disease, as well as the pathophysiological significance of IFNγ-Ab, has not yet been fully elucidated. METHODS: Thirteen Japanese subjects suffering from disseminated NTM (dNTM) infection with IFNγ-Ab were evaluated. The fluctuation of IFNγ-Ab titer and the neutralizing capacity against IFN-γ during the course of the disease were retrospectively analyzed. IFNγ-Ab titers in the sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. RESULTS: Serum antibody titers were not constant during the treatment period and varied over the course of the disease. The antibody titer decreased when the disease was improved by anti-mycobacterial treatment (p < 0.01) and increased as the disease progressed (p < 0.05). Even after the antibody titer decreased, the neutralizing capacity against IFN-γ was maintained by individual sera. CONCLUSIONS: Despite the improvement in the pathological condition via treatment, the patients' sera maintained neutralizing capacity against IFN-γ. Antibody titer fluctuated over the course of the disease and exhibited potential as a biomarker for judgment of the disease state.
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Autoanticuerpos/sangre , Biomarcadores Farmacológicos/sangre , Biomarcadores/sangre , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Micobacterias no Tuberculosas/fisiología , Anciano , Antituberculosos/uso terapéutico , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Interferón gamma/inmunología , Japón , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/inmunología , Estudios RetrospectivosRESUMEN
BACKGROUND: Natural killer T (NKT) cells express a T-cell receptor that recognizes endogenous and environmental glycolipid antigens. Several subsets of NKT cells have been identified, including IFN-γ-producing NKT1 cells, IL-4-producing NKT2 cells, and IL-17-producing NKT17 cells. However, little is known about the factors that regulate their differentiation and respective functions within the immune system. OBJECTIVE: We sought to determine whether the polycomb repressive complex 2 protein enhancer of zeste homolog 2 (Ezh2) restrains pathogenicity of NKT cells in the context of asthma-like lung disease. METHODS: Numbers of invariant natural killer T (iNKT) 1, iNKT2, and iNKT17 cells and tissue distribution, cytokine production, lymphoid tissue localization, and transcriptional profiles of iNKT cells from wild-type and Ezh2 knockout (KO) iNKT mice were determined. The contribution of NKT cells to development of spontaneous and house dust mite-induced airways pathology, including airways hyperreactivity (AHR) to methacholine, was also assessed in wild-type, Ezh2 KO, and Ezh2 KO mice lacking NKT cells. RESULTS: Ezh2 restrains development of pathogenic NKT cells, which induce spontaneous asthma-like disease in mice. Deletion of Ezh2 increased production of IL-4 and IL-13 and induced spontaneous AHR, lung inflammation, mucus production, and IgE. Increased IL-4 and IL-13 levels, AHR, lung inflammation, and IgE levels were all dependent on iNKT cells. In house dust mite-exposed animals Ezh2 KO resulted in enhanced AHR that was also dependent on iNKT cells. CONCLUSION: Ezh2 is a central regulator of iNKT pathogenicity and suppresses the ability of iNKT cells to induce asthma-like pathology.
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Asma/inmunología , Proteína Potenciadora del Homólogo Zeste 2/inmunología , Pulmón/inmunología , Células T Asesinas Naturales/inmunología , Animales , Asma/genética , Asma/patología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Proteína Potenciadora del Homólogo Zeste 2/genética , Inmunoglobulina E/genética , Inmunoglobulina E/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Pulmón/patología , Ratones , Ratones Noqueados , Células T Asesinas Naturales/patología , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/inmunologíaRESUMEN
We report a case of non-AIDS (acquired immunodeficiency syndrome), non-CAPD (Continuous Ambulatory Peritoneal Dialysis), non-cirrhotic, Mycobacterium avium peritonitis, which is a rare form of mycobacterial infection. A 66-year-old Japanese man who had been treated previously for angioimmunoblastic T-cell lymphoma (AITL), had developed disseminated M. avium infection. Antimycobacterial regimen improved his symptoms; however, following an interruption in treatment, he developed chylous ascites. The patient died of uncontrolled peritonitis despite intensive treatment. Anti-interferon-γ autoantibody was positive, and AITL was presumed to be involved in autoantibody production. A rare coexistence of chylous ascites, autoantibody, and AITL taught us an intriguing lesson on the pathogenesis of M. avium infection. Particularly, we conclude that treatment strategies for M. avium infection should aim to restore immunity.
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Autoanticuerpos/inmunología , Ascitis Quilosa/diagnóstico , Huésped Inmunocomprometido , Interferón gamma/antagonistas & inhibidores , Linfoma de Células T/tratamiento farmacológico , Mycobacterium avium/aislamiento & purificación , Peritonitis Tuberculosa/diagnóstico , Anciano , Antituberculosos/uso terapéutico , Ascitis Quilosa/patología , Resultado Fatal , Humanos , Linfoma de Células T/complicaciones , Masculino , Peritonitis Tuberculosa/complicaciones , Peritonitis Tuberculosa/patologíaRESUMEN
Background: Interferon-γ neutralizing autoantibodies (nIFNγ-autoAbs) are reported in patients with disseminated nontuberculous mycobacteria (NTM) infection and may function by increasing the infection risk. Notwithstanding, the prevalence of nIFNγ-autoAbs as well as the clinical presentation, diagnosis, and natural history of disseminated NTM infection in these patients is poorly understood. Methods: In this retrospective observational study, data and sera for 331 Japanese subjects with mycobacterial infection were collected and analyzed. IFNγ-autoAb titers in sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. Results: Disseminated NTM was identified in 50 human immunodeficiency virus-uninfected patients. Of these, 30 of 37 (81%) immunocompetent patients had an increased nIFNγ-autoAb titer whereas only 1 of 13 (7.7%) immunodeficient patients had an increased nIFNγ-autoAb titer (P < .0001, χ2 test). Presenting symptoms were nonspecific and NTM infection was not included in the differential diagnosis in most cases. All patients with disseminated NTM and an increased serum nIFNγ-autoAb level received prolonged antimicrobial therapy. In 6 cases when antibiotic treatment was discontinued, NTM infection recurred and required resumption of antibiotic therapy for infection control. The mortality rate was 3.2% in disseminated NTM patients with nIFNγ-autoAbs and 21% in those without. Conclusions: nIFNγ-autoAbs were present in most patients with disseminated NTM infection without a diagnosis of clinical immunodeficiency. Diagnosis of disseminated NTM requires a high degree of suspicion and can be improved by measuring serum nIFNγ-autoAb titer. Long-term antibiotic therapy helps prevent recrudescent NTM infection.
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Anticuerpos Neutralizantes/sangre , Autoanticuerpos/sangre , Interferón gamma/inmunología , Infecciones por Mycobacterium no Tuberculosas/inmunología , Micobacterias no Tuberculosas/inmunología , Adulto , Anciano , Antibacterianos/uso terapéutico , Profilaxis Antibiótica , Diagnóstico Diferencial , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Síndromes de Inmunodeficiencia , Japón , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no Tuberculosas/efectos de los fármacos , Estudios RetrospectivosAsunto(s)
Pólipos Nasales , Rinitis , Sinusitis , Humanos , Eosinófilos , Células Asesinas Naturales , Enfermedad CrónicaAsunto(s)
Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Inmunidad Innata , Memoria Inmunológica , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Animales , Biomarcadores , Citocinas/metabolismo , Susceptibilidad a Enfermedades/inmunología , Humanos , Hipersensibilidad/patología , Especificidad de ÓrganosRESUMEN
A 59-year-old woman presented with a rash on the top part of her hands and pain in the wrist joint and was diagnosed with dermatomyositis complicated by interstitial pneumonia positive for anti-melanoma differentiation-associated gene 5 (MDA-5) antibody. However, the patient reported a severe headache following treatment with oral prednisolone and tacrolimus. Posterior reversible encephalopathy syndrome (PRES) was diagnosed based on the brain magnetic resonance imaging findings. Tacrolimus was discontinued, and mycophenolate mofetil was instead administered with a favorable outcome. Mycophenolate mofetil should therefore be considered as an alternative treatment for anti-MDA-5-positive interstitial lung disease in cases where calcineurin inhibitors cannot be used.
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BACKGROUND: Pulmonary alveolar proteinosis (PAP) is characterized by an abnormal accumulation of surfactants in the alveoli. Most cases are classified as autoimmune PAP (APAP) because they are associated with autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). However, GM-CSF autoantibody levels are unlikely to correlate with the disease severity or prognosis of APAP. METHODS: We collected clinical records and measured 38 serum cytokine concentrations for consecutive patients with APAP. After exclusion of 21 cytokines because of undetectable levels, 17 cytokine levels were compared between low and high disease severity scores (DSSs). We also compared whole lung lavage (WLL)-free survival with cut-off values defined by receiver operating characteristic (ROC) curves of cytokine levels and WLL administration at 11 months. RESULTS: Nineteen patients with APAP were enrolled in the study. Five were classified as DSS 1 or 2, while the others were classified as DSS 4 or 5. Comparison between DSS 1-2 and 4-5 revealed that the concentrations of IP-10 and GRO increased in the latter groups (p < 0.05). Fifteen patients underwent WLL. Comparison between those who underwent WLL within 11 months and the others showed that IP-10 and TNF-α were tended to be elevated in the former group (p = 0.082 and 0.057, respectively). The cut-off values of IP-10, 308.8 pg/mL and TNF-α, 19.1 pg/mL, defined by the ROC curves, significantly separated WLL-free survivals with log-rank analyses (p = 0.005). CONCLUSIONS: The concentrations of IP-10 and GRO may reflect the DSSs of APAP. A combination of IP-10 and TNF-α levels could be a biomarker to predict WLL-free survival.
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Enfermedades Autoinmunes , Citocinas , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Proteinosis Alveolar Pulmonar , Índice de Severidad de la Enfermedad , Humanos , Proteinosis Alveolar Pulmonar/inmunología , Proteinosis Alveolar Pulmonar/diagnóstico , Proteinosis Alveolar Pulmonar/sangre , Proteinosis Alveolar Pulmonar/terapia , Pronóstico , Citocinas/sangre , Masculino , Femenino , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/diagnóstico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/sangre , Persona de Mediana Edad , Adulto , Autoanticuerpos/sangre , Quimiocina CXCL10/sangre , Anciano , Factor de Necrosis Tumoral alfa/sangre , Biomarcadores/sangre , Lavado Broncoalveolar , Adulto JovenRESUMEN
Tumor-specific CD8+ T cells play a pivotal role in antitumor immunity and are a key target of immunotherapeutic approaches. Intratumoral CD8+ T cells are heterogeneous; Tcf1+ stemlike CD8+ T cells give rise to their cytotoxic progeny-Tim-3+ terminally differentiated CD8+ T cells. However, where and how this differentiation process occurs has not been elucidated. We herein show that terminally differentiated CD8+ T cells can be generated within tumor-draining lymph nodes (TDLN) and that CD69 expression on tumor-specific CD8+ T cells controls its differentiation process through regulating the expression of the transcription factor TOX. In TDLNs, CD69 deficiency diminished TOX expression in tumor-specific CD8+ T cells, and consequently promoted generation of functional terminally differentiated CD8+ T cells. Anti-CD69 administration promoted the generation of terminally differentiated CD8+ T cells, and the combined use of anti-CD69 and anti-programmed cell death protein 1 (PD-1) showed an efficient antitumor effect. Thus, CD69 is an attractive target for cancer immunotherapy that synergizes with immune checkpoint blockade.
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Linfocitos T CD8-positivos , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/patología , Diferenciación Celular , Ganglios LinfáticosRESUMEN
We herein report a 45-year-old-man with multiple foreign body granulomas in the lungs caused by polytetrafluoroethylene (PTFE). A mass in the right lower lobe of the lung and bilateral centrilobular lung nodules were found unexpectedly during the patient's visit to a hospital for a respiratory infection. The patient's occupation for 26 years involved spraying PTFE. A lung biopsy using bronchoscopy revealed granulomatous lesions and giant cells. The presence of fluorine in the granulomatous lesions was confirmed using an electron probe microanalyzer with wavelength dispersive spectrometer. Fluorine is a component of PTFE and is not found in normal lung tissue.
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Enfermedades Pulmonares , Enfermedades Profesionales , Humanos , Persona de Mediana Edad , Politetrafluoroetileno/efectos adversos , Flúor , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/patología , Enfermedades Profesionales/complicaciones , Pulmón/diagnóstico por imagen , Pulmón/patología , Granuloma/patologíaRESUMEN
Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2-16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients.
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Memory T cells are crucial for both local and systemic protection against pathogens over a long period of time. Three major subsets of memory T cells; effector memory T (TEM) cells, central memory T (TCM) cells, and tissue-resident memory T (TRM) cells have been identified. The most recently identified subset, TRM cells, is characterized by the expression of the C-type lectin CD69 and/or the integrin CD103. TRM cells persist locally at sites of mucosal tissue, such as the lung, where they provide frontline defense against various pathogens. Importantly, however, TRM cells are also involved in shaping the pathology of inflammatory diseases. A number of pioneering studies revealed important roles of CD8+ TRM cells, particularly those in the local control of viral infection. However, the protective function and pathogenic role of CD4+ TRM cells that reside within the mucosal tissue remain largely unknown. In this review, we discuss the ambivalent feature of CD4+ TRM cells in the protective and pathological immune responses. We also review the transcriptional and epigenetic characteristics of CD4+ TRM cells in the lung that have been elucidated by recent technical approaches. A better understanding of the function of CD4+ TRM cells is crucial for the development of both effective vaccination against pathogens and new therapeutic strategies for intractable inflammatory diseases, such as inflammatory bowel diseases and chronic allergic diseases.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Inmunidad Mucosa , Memoria Inmunológica , Membrana Mucosa/inmunología , Membrana Mucosa/metabolismo , Plasticidad de la Célula/inmunología , Susceptibilidad a Enfermedades , Epigénesis Genética , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno , Humanos , Especificidad de Órganos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
INTRODUCTION/OBJECTIVES: Interstitial lung disease (ILD) is a significant cause of mortality among patients with dermatomyositis (DM) or polymyositis (PM). There are two subtypes of PM and DM often complicated with ILD: those with anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies and those with anti-MDA-5-associated amyopathic DM (ADM). Our aim is to clarify the inflammatory and immunological differences between the disorders. METHODS: We retrospectively collected consecutive patients with anti-ARS-ILD and those with anti-MDA-5 antibody-positive ADM-ILD. The serum concentration of 38 cytokines was measured using a cytokine panel. The relative risks for anti-MDA-5 antibody-positive ADM-ILD were examined with univariate and multivariate logistic regression models. Spearman's rank correlation coefficient was calculated between cytokine levels and clinical parameters in the disease. Levels of cytokines were compared between anti-ARS-ILD and anti-MDA-5-positive ADM-ILD patients (alive or dead) using Dunnett's test. RESULTS: Twenty-three patients with anti-ARS-ILD and the same number of patients with anti-MDA-5-positive ADM-ILD were enrolled. The anti-MDA-5 group had poor survival (p = 0.025). Univariate logistic regression models showed that eotaxin, IL-10, IP-10, and MCP-1 were associated with the diagnosis of anti-MDA-5-positive ADM-ILD. Multivariate logistic regression models revealed that IP-10 was the most significantly associated (p = 0.001). Relationship analyses showed that IL-10 had significant positive correlations with CK (r = 0.5267, p = 0.009) and ferritin (r = 0.4528, p = 0.045). A comparison of the cytokine levels found that IP-10 was elevated in both patients who were alive and patients who had died with ADM-ILD compared with the levels in those with ARS-ILD (p = 0.003 and p = 0.001, respectively). CONCLUSIONS: Anti-MDA-5-positive ADM-ILD had poorer survival than anti-ARS-ILD. IP-10 seems to be most deeply involved in the pathophysiology of anti-MDA-5-associated ADM-ILD.Key Points⢠To clarify differences in the inflammatory and immunological features of anti-MDA-5-positive ADM-ILD and anti-ARS-ILD, we performed an observational study to measure serum cytokine concentrations before treatment using a multiplex immunoassay system.⢠Multivariate logistic regression models revealed that IP-10 was associated with the most significant relative risk for ADM-ILD with anti-MDA-5 antibodies.⢠Levels of IP-10 were elevated considerably in anti-MDA-5-positive survivors and nonsurvivors compared with the levels in anti-ARS patients.⢠These results suggest that IP-10 is the most deeply involved in the pathophysiology of anti-MDA-5-positive ADM-ILD.