RESUMO
Introduction: Controlling pulmonary Mycobacterium avium complex (MAC) disease is difficult because there is no way to know the clinical stage accurately. There have been few attempts to use cell-mediated immunity for diagnosing the stage. The objective of this study was to characterize cytokine profiles of CD4+T and CD19+B cells that recognize various Mycobacterium avium-associated antigens in different clinical stages of MAC. Methods: A total of 47 MAC patients at different stages based on clinical information (14 before-treatment, 16 on-treatment, and 17 after-treatment) and 17 healthy controls were recruited. Peripheral blood mononuclear cells were cultured with specific antigens (MAV0968, 1160, 1276, and 4925), and the cytokine profiles (IFN-γ, TNF-α, IL-2, IL-10, IL-13, and IL-17) of CD4+/CD3+ and CD19+ cells were analyzed by flow cytometry. Results: The response of Th1 cytokines such as IFN-γ and TNF-α against various antigens was significantly higher in both the on-treatment and after-treatment groups than in the before-treatment group and control (P < 0.01-0.0001 and P < 0.05-0.0001). An analysis of polyfunctional T cells suggested that the presence of IL-2 is closely related to the stage after the start of treatment (P = 0.0309-P < 0.0001) and is involved in memory function. Non-Th1 cytokines, such as IL-10 and IL-17, showed significantly higher responses in the before-treatment group (P < 0.0001 and P < 0.01-0.0001). These responses were not observed with purified protein derivative (PPD). CD19+B cells showed a response similar to that of CD4+T cells. Conclusion: There is a characteristic cytokine profile at each clinical stage of MAC.
Assuntos
Pneumopatias , Infecção por Mycobacterium avium-intracellulare , Humanos , Complexo Mycobacterium avium , Interleucina-10 , Interleucina-17 , Interleucina-2/uso terapêutico , Fator de Necrose Tumoral alfa/uso terapêutico , Leucócitos Mononucleares , CitocinasRESUMO
Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10-12), followed by an additional independent risk allele at HLA-DPß1 amino acid position 8 (OR = 0.28; P = 3.4 × 10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (ß = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.
Assuntos
Autoanticorpos/genética , Doenças Autoimunes/genética , Predisposição Genética para Doença , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Cadeias HLA-DRB1/genética , Proteinose Alveolar Pulmonar/genética , Adulto , Idoso , Alelos , Povo Asiático , Autoanticorpos/biossíntese , Doenças Autoimunes/etnologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Estudos de Casos e Controles , Cromossomos Humanos Par 6 , Feminino , Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Cadeias HLA-DRB1/imunologia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Razão de Chances , Isoformas de Proteínas/genética , Proteinose Alveolar Pulmonar/etnologia , Proteinose Alveolar Pulmonar/imunologia , Proteinose Alveolar Pulmonar/patologia , Surfactantes Pulmonares/imunologia , Surfactantes Pulmonares/metabolismo , RiscoRESUMO
BACKGROUND: A pneumatocele is a transient thin-walled lesion and rare complication in adult pneumonia. A variety of infectious pathogens have been reported in children with pneumatoceles. We report the first case of adult pneumonia with pneumatocele formation that is likely caused by Streptococcus pyogenes and coinfection with influenza A virus. CASE PRESENTATION: A 64-year-old Japanese man presented with a one-week history of fever, sore throat, and arthralgia. He was referred to our university hospital for respiratory distress. He required mechanical ventilation in the intensive care unit (ICU). Bacterial culture detected S. pyogenes in the bronchoscopic aspirates, which was not detected in blood. Although a rapid influenza antigen test was negative, an influenza A polymerase chain reaction (PCR) test was positive. Therefore, he was diagnosed with coinfection of influenza A and group A streptococcus (GAS) pneumonia complicated by probable streptococcal toxic shock syndrome. A chest radiograph on admission showed diffuse patchy opacification and consolidation in the bilateral lung fields. Multiple thin-walled cysts appeared in both middle lung fields on computed tomography (CT). On the following day, the bilateral cysts had turned into a mass-like opacity. The patient died despite intensive care. An autopsy was performed. The pathology investigation revealed multiple hematomas formed by bleeding in pneumatoceles. CONCLUSIONS: There have been no previous reports of a pneumatocele complicated by S. pyogenes in an adult patient coinfected with influenza A. Further molecular investigation revealed that the S. pyogenes isolate had the sequence type of emm3.
Assuntos
Coinfecção , Influenza Humana/complicações , Influenza Humana/patologia , Pneumopatias/etiologia , Pneumonia/complicações , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/patologia , Coinfecção/complicações , Coinfecção/patologia , Cistos/diagnóstico por imagem , Evolução Fatal , Humanos , Vírus da Influenza A , Influenza Humana/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Pneumopatias/patologia , Masculino , Pessoa de Meia-Idade , Pneumonia/diagnóstico por imagem , Pneumonia/microbiologia , Pneumonia/patologia , Choque Séptico/diagnóstico , Infecções Estreptocócicas/diagnóstico por imagem , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes , Tomografia Computadorizada por Raios XRESUMO
Impaired efferocytosis is a key mechanism of inflammatory lung diseases, including chronic obstructive pulmonary disease and cystic fibrosis. Cigarette smoking activates RhoA and impairs efferocytosis in alveolar macrophages, but the mechanism has not been fully elucidated. We investigated the role of endoplasmic reticulum (ER) stress induced by cigarette smoking in the disruption of efferocytosis. Both tunicamycin (10 µg/ml) and thapsigargin (0.1 and 1 µM), which are ER stress inducers, suppressed efferocytosis in J774 cells, and a Rho-associated coiled-coil-forming kinase (ROCK) inhibitor (Y27632) reversed this effect. We validated the effect of tunicamycin on efferocytosis in experiments using RAW264.7 cells. Then, we investigated the role of the unfolded protein response (UPR) in efferocytosis impaired by ER stress. A PERK inhibitor (GSK2606414) restored the efferocytosis that had been impaired by TM, and an eIF2α dephosphorylation inhibitor (salubrinal) suppressed efferocytosis. Cigarette smoke extract (CSE) induced ER stress in J774 macrophages and RhoA activation in J774 cells, and the CSE-induced ROCK activity was successfully reversed by GSK2606414 and tauroursodeoxycholic acid. Finally, we confirmed that ER stress suppresses efferocytosis in murine alveolar macrophages and that GSK2606414 could rescue this process. These data suggest that cigarette smoke-induced ER stress and the UPR play crucial roles in RhoA activation and suppression of efferocytosis in the lung.
Assuntos
Fumar Cigarros/efeitos adversos , Estresse do Retículo Endoplasmático , Macrófagos/patologia , Fagocitose , Proteína rhoA de Ligação ao GTP/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Linhagem Celular , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Indóis/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Modelos Biológicos , Fagocitose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ácido Tauroquenodesoxicólico/farmacologia , Tunicamicina/farmacologia , eIF-2 Quinase/metabolismo , Quinases Associadas a rho/metabolismoRESUMO
Lung abscess is usually treated with long-term antibiotic therapy. Due to the lack of a safe and easy drainage technique, drainage is only applied in refractory cases. We herein describe three cases in which drainage was successfully performed by endobronchial ultrasonography using a modified guide sheath. This procedure may have advantages in the detection of causative pathogens and early infection source control, and may therefore lead to the appropriate selection of antibiotics and reduce the duration of antibiotic therapy.