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INTRODUCTION AND HYPOTHESIS: Retropubic midurethral sling (MUS) placement is the gold standard for the treatment of stress urinary incontinence in the USA. The procedure can be approached from either a top-down or a bottom-up direction, but there is a paucity of contemporary data regarding outcomes between these approaches. The aim of this study was to provide updated clinical outcomes data. METHODS: This was a retrospective cohort study of women undergoing the retropubic MUS procedure alone or at the time of pelvic organ prolapse repair between 2010 and 2020 at a single academic medical center. The electronic medical record was used to extract demographic data, operative approach, and perioperative complications. The primary outcome was a composite incidence of any perioperative complication. RESULTS: Of the 309 patients analyzed, 140 (45.3%) underwent top-down and 169 (54.7%) underwent bottom-up retropubic MUS placement. Patients undergoing top-down MUS placement were more likely to be older (mean age 58 vs 54, p=0.02), have a history of diabetes mellitus (20% vs 8.9%, p=0.004), and have had a prior hysterectomy (27% vs 16%, p=0.02). They were less likely to have a concurrent anterior (p<0.001) or posterior repair (p<0.001). Patients undergoing the top-down procedure were less likely to experience sling exposure (p=0.02); complications in the two groups were otherwise similar. CONCLUSIONS: The top-down approach to retropubic MUS placement was associated with lower rates of mesh erosion in this population of patients. Neither approach is associated with an increased overall risk of complications or de novo overactive bladder symptoms.
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Slings Suburetrais , Incontinência Urinária por Estresse , Humanos , Slings Suburetrais/efeitos adversos , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Incontinência Urinária por Estresse/cirurgia , Resultado do Tratamento , Idoso , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Prolapso de Órgão Pélvico/cirurgia , AdultoRESUMO
Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post-COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP-COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP-COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83-155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05-1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00-1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07-1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6-9.5), rising to 11.7% (95% CrI, 10.3-13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19-related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.
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COVID-19 , Doenças Pulmonares Intersticiais , Humanos , SARS-CoV-2 , COVID-19/epidemiologia , Teorema de Bayes , Pulmão/diagnóstico por imagem , HospitalizaçãoRESUMO
Based on preflight laboratory testing, an unexpectedly large positional offset between the two midinfrared (mid-IR) detector arrays in the Cassini composite infrared spectrometer (CIRS) instrument has been noted in the literature. A much smaller offset was measured in-flight. We investigate this discrepancy by estimating several spatial relationships among the detectors and comparing these results with three independent data sets. This enables us to infer the probable cause of this offset and to derive a new reduced value. We comment on the effect that this change could have on previously published results involving CIRS data. We also present a graphical display of the arrays projected on the sky as CIRS would see it.
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This publisher's note serves to correct Appl. Opt.62, 5882 (2023).APOPAI0003-693510.1364/AO.491970.
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BACKGROUND: Ewing sarcoma (EWS) is an aggressive soft-tissue and bone malignancy. Congenital EWS is extremely rare, and its presenting features can be unique from that of EWS occurring in older children. CLINICAL FINDINGS: A full-term female infant with a neck mass present at birth was admitted to a level I nursery with an otherwise well appearance and normal vital signs. After consultation with a neonatologist, she was transferred to a neonatal intensive care unit where she developed sudden respiratory collapse from rapid growth of the mass causing airway obstruction, leading to emergent intubation. Ultrasound and MRI scans of the neck mass demonstrated cystic and vascular components, and a timely biopsy revealed small round blue cells with diffuse CD99 expression and chromosomal translocation 11;22. PRIMARY DIAGNOSIS: Ewing sarcoma. INTERVENTIONS: An accelerated workup for EWS was done due to the patient's critical status. On day of life (DOL) 8, she was started on treatment of EWS as per the current standard-of-care AEWS0031. On DOL 24, she underwent tracheostomy placement. OUTCOMES: The patient completed 14 total cycles of chemotherapy and is more than 12 months old. Her tracheostomy was decannulated at 6 months of age. PRACTICE RECOMMENDATIONS: The rarity of EWS in neonates and its presentation as a neck mass make this disease difficult to recognize unless clinicians have a high index of suspicion. The aims of this case report are to increase awareness of malignancy as a potential cause of neck masses in neonates and to prompt nurses and physicians to prepare for airway stabilization at appropriate levels of care if a neck mass is present at birth.
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Sarcoma de Ewing , Criança , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/terapiaRESUMO
Animals lacking the inducible nitric oxide synthase gene (nos2(-/-)) are less susceptible to Mycobacterium avium strain 25291 and lack nitric oxide-mediated immunomodulation of CD4(+) T cells. Here we show that the absence of nos2 results in increased accumulation of neutrophils and both CD4(+) and CD8(+) T cells within the M. avium containing granuloma. Examination of the T-cell phenotype in M. avium infected mice demonstrated that CD4(+)CD44(hi) effector T cells expressing the Th1 transcriptional regulator T-bet (T-bet(+)) were specifically reduced by the presence of nitric oxide. Importantly, the T-bet(+) effector population could be separated into CD69(hi) and CD69(lo) populations, with the CD69(lo) population only able to accumulate during chronic infection within infected nos2(-/-) mice. Transcriptomic comparison between CD4(+)CD44(hi)CD69(hi) and CD4(+)CD44(hi)CD69(lo) populations revealed that CD4(+)CD44(hi)CD69(lo) cells had higher expression of the integrin itgb1/itga4 (VLA-4, CD49d/CD29). Inhibition of Nos2 activity allowed increased accumulation of the CD4(+) CD44(hi)T-bet(+)CD69(lo) population in WT mice as well as increased expression of VLA-4. These data support the hypothesis that effector T cells in mycobacterial granulomata are not a uniform effector population but exist in distinct subsets with differential susceptibility to the regulatory effects of nitric oxide.
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Mycobacterium avium/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico/imunologia , Células Th1/imunologia , Tuberculose Pulmonar/imunologia , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD8-Positivos/imunologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/imunologia , Granuloma do Sistema Respiratório/genética , Granuloma do Sistema Respiratório/imunologia , Granuloma do Sistema Respiratório/microbiologia , Granuloma do Sistema Respiratório/veterinária , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Camundongos , Camundongos Knockout , Óxido Nítrico/genética , Óxido Nítrico Sintase Tipo II/genética , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/veterináriaRESUMO
IL-23 is required for the IL-17 response to infection with Mycobacterium tuberculosis, but is not required for the early control of bacterial growth. However, mice deficient for the p19 component of IL-23 (Il23a(-/-)) exhibit increased bacterial growth late in infection that is temporally associated with smaller B cell follicles in the lungs. Cxcl13 is required for B cell follicle formation and immunity during tuberculosis. The absence of IL-23 results in decreased expression of Cxcl13 within M. tuberculosis-induced lymphocyte follicles in the lungs, and this deficiency was associated with increased cuffing of T cells around the vessels in the lungs of these mice. Il23a(-/-) mice also poorly expressed IL-17A and IL-22 mRNA. These cytokines were able to induce Cxcl13 in mouse primary lung fibroblasts, suggesting that these cytokines are likely involved in B cell follicle formation. Indeed, IL-17RA-deficient mice generated smaller B cell follicles early in the response, whereas IL-22-deficient mice had smaller B cell follicles at an intermediate time postinfection; however, only Il23a(-/-) mice had a sustained deficiency in B cell follicle formation and reduced immunity. We propose that in the absence of IL-23, expression of long-term immunity to tuberculosis is compromised due to reduced expression of Cxcl13 in B cell follicles and reduced ability of T cells to migrate from the vessels and into the lesion. Further, although IL-17 and IL-22 can both contribute to Cxcl13 production and B cell follicle formation, it is IL-23 that is critical in this regard.
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Centro Germinativo/imunologia , Centro Germinativo/patologia , Interleucina-23/fisiologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Animais , Células Cultivadas , Quimiocina CXCL13/biossíntese , Centro Germinativo/microbiologia , Interleucina-23/deficiência , Interleucina-23/genética , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/crescimento & desenvolvimento , Fatores de Tempo , Tuberculose Pulmonar/microbiologiaRESUMO
Introduction: The large family of PE and PPE proteins accounts for as much as 10% of the genome of Mycobacterium tuberculosis. In this study, we explored the immunogenicity of three proteins from this family, PE18, PE31, and PPE26, in humans and mice. Methods: The investigation involved analyzing the immunoreactivity of the selected proteins using sera from TB patients, IGRA-positive household contacts, and IGRA-negative BCG vaccinated healthy donors from the TB endemic country Mozambique. Antigen-recall responses were examined in PBMC from these groups, including the evaluation of cellular responses in healthy unexposed individuals. Moreover, systemic priming and intranasal boosting with each protein, combined with the Quil-A adjuvant, were conducted in mice. Results: We found that all three proteins are immunoreactive with sera from TB patients, IGRA-positive household contacts, and IGRA-negative BCG vaccinated healthy controls. Likewise, antigen-recall responses were induced in PBMC from all groups, and the proteins stimulated proliferation of peripheral blood mononuclear cells from healthy unexposed individuals. In mice, all three antigens induced IgG antibody responses in sera and predominantly IgG, rather than IgA, responses in bronchoalveolar lavage. Additionally, CD4+ and CD8+ effector memory T cell responses were observed in the spleen, with PE18 demonstrating the ability to induce tissue-resident memory T cells in the lungs. Discussion: Having demonstrated immunogenicity in both humans and mice, the protective capacity of these antigens was evaluated by challenging immunized mice with low-dose aerosol of Mycobacterium tuberculosis H37Rv. The in vitro Mycobacterial Growth Inhibition Assay (MGIA) and assessment of viable bacteria in the lung did not demonstrate any ability of the vaccination protocol to reduce bacterial growth. We therefore concluded that these three specific PE/PPE proteins, while immunogenic in both humans and mice, were unable to confer protective immunity under these conditions.
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Mycobacterium tuberculosis , Humanos , Camundongos , Animais , Leucócitos Mononucleares , Vacina BCG , Antígenos de Bactérias , Imunoglobulina GRESUMO
Migration of dendritic cells (DCs) to the draining lymph node (DLN) is required for the activation of naive T cells. We show here that migration of DCs from the lung to the DLN after Mycobacterium tuberculosis (Mtb) exposure is defective in mice lacking interleukin (IL)-12p40. This defect compromises the ability of IL-12p40-deficient DCs to activate naive T cells in vivo; however, DCs that express IL-12p40 alone can activate naive T cells. Treatment of IL-12p40-deficient DCs with IL-12p40 homodimer (IL-12(p40)(2)) restores Mtb-induced DC migration and the ability of IL-12p40-deficient DCs to activate naive T cells. These data define a novel and fundamental role for IL-12p40 in the pathogen-induced activation of pulmonary DCs.
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Linfócitos T CD4-Positivos/imunologia , Movimento Celular/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Interleucina-12/fisiologia , Ativação Linfocitária/imunologia , Mycobacterium tuberculosis/imunologia , Subunidades Proteicas/fisiologia , Tuberculose Pulmonar/imunologia , Animais , Células Cultivadas , Células Dendríticas/metabolismo , Interleucina-12/deficiência , Interleucina-12/genética , Subunidade p40 da Interleucina-12 , Linfonodos/citologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subunidades Proteicas/deficiência , Subunidades Proteicas/genética , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologiaRESUMO
Mycobacterium tuberculosis infection (Mtb) results in the generation of protective cellular immunity and formation of granulomatous structures in the lung. CXCL13, CCL21, and CCL19 are constitutively expressed in the secondary lymphoid organs and play a dominant role in the homing of lymphocytes and dendritic cells. Although it is known that dendritic cell transport of Mtb from the lung to the draining lymph node is dependent on CCL19/CCL21, we show in this study that CCL19/CCL21 is also important for the accumulation of Ag-specific IFN-gamma-producing T cells in the lung, development of the granuloma, and control of mycobacteria. Importantly, we also show that CXCL13 is not required for generation of IFN-gamma responses, but is essential for the spatial arrangement of lymphocytes within granulomas, optimal activation of phagocytes, and subsequent control of mycobacterial growth. Furthermore, we show that these chemokines are also induced in the lung during the early immune responses following pulmonary Mtb infection. These results demonstrate that homeostatic chemokines perform distinct functions that cooperate to mediate effective expression of immunity against Mtb infection.
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Quimiocina CCL19/deficiência , Quimiocina CCL21/deficiência , Quimiocina CXCL13/deficiência , Granuloma/imunologia , Homeostase/imunologia , Tuberculose Pulmonar/imunologia , Animais , Quimiocina CCL19/biossíntese , Quimiocina CCL19/genética , Quimiocina CCL21/biossíntese , Quimiocina CCL21/genética , Quimiocina CXCL13/biossíntese , Quimiocina CXCL13/genética , Modelos Animais de Doenças , Granuloma/genética , Granuloma/patologia , Homeostase/genética , Imunidade Celular/genética , Imunidade Inata/genética , Linfócitos/imunologia , Linfócitos/patologia , Ativação de Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/imunologia , Fatores de Tempo , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/patologiaRESUMO
CD4(+) T cell responses to aerosol Mycobacterium tuberculosis (Mtb) infection are characterized by the relatively delayed appearance of effector T cells in the lungs. This delay in the adaptive response is likely critical in allowing the bacteria to establish persistent infection. Because of limitations associated with the detection of low frequencies of naïve T cells, it had not been possible to precisely determine when and where naïve antigen-specific T cells are first activated. We have addressed this problem by using early secreted antigenic target 6 (ESAT-6)-specific transgenic CD4 T cells to monitor early T cell activation in vivo. By using an adoptive transfer approach, we directly show that T cell priming to ESAT-6 occurs only after 10 days of infection, is initially restricted to the mediastinal lymph nodes, and does not involve other lymph nodes or the lungs. Primed CD4 T cells rapidly differentiated into proliferating effector cells and ultimately acquired the ability to produce IFN-gamma and TNF-alpha ex vivo. Initiation of T cell priming was enhanced by two full days depending on the magnitude of the challenge inoculum, which suggests that antigen availability is a factor limiting the early CD4 T cell response. These data define a key period in the adaptive immune response to Mtb infection.
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Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfonodos/imunologia , Mediastino , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Transferência Adotiva , Animais , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Citometria de Fluxo , Cinética , Ativação Linfocitária/imunologia , Camundongos , Camundongos TransgênicosRESUMO
BACKGROUND: Atrial fibrillation (AF) of new onset during acute illness (AFNOAI) has a variable incidence of 1%-44% in hospitalized patients. This study assesses the risk factors for persistence of AFNOAI in the 5 years after hospital discharge for critically ill patients. METHODS: This was a retrospective cohort study. All patients ≥18 years old admitted to the medical intensive care unit (MICU) of a tertiary care hospital from January 1, 2012, to October 31, 2015, were screened. Those designated with AF for the first time during the hospital admission were included. Risk factors for persistent AFNOAI were assessed using a Cox's proportional hazards model. RESULTS: Two-hundred and fifty-one (1.8%) of 13,983 unique MICU admissions had AFNOAI. After exclusions, 108 patients remained. Forty-one patients (38%) had persistence of AFNOAI. Age (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.01-1.08), hyperlipidemia (HR, 2.27; 95% CI, 1.02-5.05) and immunosuppression (HR, 2.29; 95% CI, 1.02-5.16) were associated with AFNOAI persistence. Diastolic dysfunction (HR, 1.46; 95% CI, 0.71-3.00) and mitral regurgitation (HR, 2.00; 95% CI, 0.91-4.37) also showed a trend towards association with AFNOAI persistence. CONCLUSIONS: Our study showed that AFNOAI has a high rate of persistence after discharge and that certain comorbid and cardiac factors may increase the risk of persistence. Anticoagulation should be considered, based on a patient's individual AFNOAI persistence risk.
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Tuberculosis vaccines capable of reducing disease worldwide have proven difficult to develop. BCG is effective in limiting childhood disease, but adult TB is still a major public health issue. Development of new vaccines requires identification of antigens that are both spatially and temporally available throughout infection, and immune responses to which reduce bacterial burden without increasing pathologic outcomes. Subunit vaccines containing antigen require adjuvants to drive appropriate long-lived responses. We generated a triple-antigen fusion containing the virulence-associated EsxN (Rv1793), the PPE42 (Rv2608), and the latency associated Rv2628 to investigate the balance between bacterial reduction and weight loss in an animal model of aerosol infection. We found that in both a low pattern recognition receptor (PRR) engaging adjuvant and a high PRR-engaging adjuvant (MPL/TDM/DDA) the triple-antigen fusion could reduce the bacterial burden, but also induced weight loss in the mice upon aerosol infection. The weight loss was associated with an imbalance between TNFα and IL-17 transcription in the lung upon challenge. These data indicate the need to assess both protective and pathogenic responses when investigating subunit vaccine activity.
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Accurate prediction of which patient will progress from a sub-clinical Mycobacterium tuberculosis infection to active tuberculosis represents an elusive, yet critical, clinical research objective. From the individual perspective, progression can be considered to be the product of a series of unfortunate events or even a run of bad luck. Here, we identify the subtle physiological relationships that can influence the odds of progression to active TB and how this progression may reflect directed dysbiosis in a number of interrelated systems. Most infected individuals who progress to disease have apparently good immune responses, but these responses are, at times, compromised by either local or systemic environmental factors. Obvious disease promoting processes, such as tissue-damaging granulomata, usually manifest in the lung, but illness is systemic. This apparent dichotomy between local and systemic reflects a clear need to define the factors that promote progression to active disease within the context of the body as a physiological whole. We discuss aspects of the host environment that can impact expression of immunity, including the microbiome, glucocorticoid-mediated regulation, catecholamines and interaction between the gut, liver and lung. We suggest the importance of integrating precision medicine into our analyses of experimental outcomes such that apparently conflicting results are not contentious, but rather reflect the impact of these subtle relationships with our environment and microbiota.
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Pulmão/patologia , Microbiota , Mycobacterium tuberculosis/fisiologia , Tuberculose/imunologia , Animais , Progressão da Doença , Jogo de Azar , Granuloma do Sistema Respiratório , Interações Hospedeiro-Patógeno , Humanos , Medicina de PrecisãoRESUMO
CD4+ T cells mediate protection against Mycobacterium tuberculosis (Mtb); however, the phenotype of protective T cells is undefined, thereby confounding vaccination efforts. IL-27 is highly expressed during human tuberculosis (TB), and absence of IL-27R (Il27ra) specifically on T cells results in increased protection. IL-27R deficiency during chronic Mtb infection does not impact antigen-specific CD4+ T cell number but maintains programmed death-1 (PD-1), CD69, and CD127 expression while reducing T-bet and killer cell lectin-like receptor G1 (KLRG1) expression. Furthermore, T-bet haploinsufficiency results in failure to generate KLRG1+, antigen-specific CD4+ T cells, and in improved protection. T cells in Il27ra(-/-) mice accumulate preferentially in the lung parenchyma within close proximity to Mtb, and antigen-specific CD4+ T cells lacking IL-27R are intrinsically more fit than intact T cells and maintain IL-2 production. Improved fitness of IL-27R-deficient T cells is not associated with increased proliferation but with decreased expression of cell death-associated markers. Therefore, during Mtb infection, IL-27R acts intrinsically on T cells to limit protection and reduce fitness, whereas the IL-27R-deficient environment alters the phenotype and location of T cells. The significant expression of IL-27 in TB and the negative influence of IL-27R on T cell function demonstrate the pathway by which this cytokine/receptor pair is detrimental in TB.
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Linfócitos T CD4-Positivos/imunologia , Mycobacterium tuberculosis/imunologia , Receptores de Citocinas/imunologia , Receptores de Interleucina/imunologia , Tuberculose/imunologia , Adulto , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Interleucinas/genética , Interleucinas/imunologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Masculino , Camundongos , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores de Citocinas/genética , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores de Interleucina/genética , Transativadores/genética , Transativadores/imunologia , Tuberculose/genética , Tuberculose/patologiaRESUMO
Cell-mediated immune responses are known to be critical for control of mycobacterial infections whereas the role of B cells and humoral immunity is unclear. B cells can modulate immune responses by secretion of immunoglobulin, production of cytokines and antigen-presentation. To define the impact of B cells in the absence of secreted immunoglobulin, we analyzed the progression of Mycobacterium tuberculosis (Mtb) infection in mice that have B cells but which lack secretory immunoglobulin (AID(-/-)µS(-/-)mice). AID(-/-)µS(-/-) mice accumulated a population of activated B cells in the lungs when infected and were more susceptible to aerosol Mtb when compared to wild type (C57BL/6) mice or indeed mice that totally lack B cells. The enhanced susceptibility of AID(-/-)µS(-/-) mice was not associated with defective T cell activation or expression of a type 1 immune response. While delivery of normal serum to AID(-/-)µS(-/-) mice did not reverse susceptibility, susceptibility in the spleen was dependent upon the presence of B cells and susceptibility in the lungs of AID(-/-)µS(-/-)mice was associated with elevated expression of the cytokines IL-6, GM-CSF, IL-10 and molecules made by alternatively activated macrophages. Blocking of IL-10 signaling resulted in reversal of susceptibility in the spleens and lungs of AID(-/-)µS(-/-) mice. These data support the hypothesis that B cells can modulate immunity to Mtb in an organ specific manner via the modulation of cytokine production and macrophage activation.
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Linfócitos B/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Animais , Linfócitos B/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , CamundongosRESUMO
RNA splicing is an increasingly recognized regulator of immunity. Here, we demonstrate that after Mycobacterium tuberculosis infection (mRNA) il12rb1 is spliced by dendritic cells (DCs) to form an alternative (mRNA) il12rb1Deltatm that encodes the protein IL-12Rbeta1DeltaTM. Compared with IL-12Rbeta1, IL-12Rbeta1DeltaTM contains an altered C-terminal sequence and lacks a transmembrane domain. Expression of IL-12Rbeta1DeltaTM occurs in CD11c(+) cells in the lungs during M. tuberculosis infection. Selective reconstitution of il12rb1(-/-) DCs with (mRNA) il12rb1 and/or (mRNA) il12rb1Deltatm demonstrates that IL-12Rbeta1DeltaTM augments IL-12Rbeta1-dependent DC migration and activation of M. tuberculosis-specific T cells. It cannot mediate these activities independently of IL12Rbeta1. We hypothesize that M. tuberculosis-exposed DCs express IL-12Rbeta1DeltaTM to enhance IL-12Rbeta1-dependent migration and promote M. tuberculosis-specific T cell activation. IL-12Rbeta1DeltaTM thus represents a novel positive-regulator of IL12Rbeta1-dependent DC function and of the immune response to M. tuberculosis.
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Células Dendríticas/imunologia , Mycobacterium tuberculosis/genética , Receptores de Interleucina-12/genética , Processamento Alternativo , Animais , Células da Medula Óssea/fisiologia , Movimento Celular , Quimiocina CCL19/fisiologia , Células Dendríticas/fisiologia , Cinética , Pulmão/imunologia , Pulmão/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/imunologia , RNA Mensageiro/genética , Receptores de Interleucina-12/deficiência , Receptores de Interleucina-12/imunologiaRESUMO
CD8+ T cells are a major source of IFN-gamma, a key effector cytokine in immune responses against many viruses and protozoa. Although the transcription factor T-bet is required for IFN-gamma expression in CD4+ T cells, it is reportedly dispensable in CD8+ T cells, where the transcription factor Eomesodermin is thought to be sufficient. The diverse functions of IFN-gamma are mediated through the IFN-gammaR and STAT1. In CD4+ T cells, STAT1 appears to be critical for the activation of T-bet and IFN-gamma, suggesting an IFN-gamma-dependent positive feedback loop. However, STAT1 can also be activated by other cytokines, including IL-27. In the present study we show that, in contrast to in vitro conditions and the prevailing paradigm, T-bet is critical for the in vivo IFN-gamma production by CD8+ T cells upon infection of mice with diverse pathogens. Whereas IFN-gammaR signals are dispensable for the T-bet-dependent IFN-gamma production, direct IL-27Ralpha signals are critical.
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Linfócitos T CD8-Positivos/imunologia , Infecções/imunologia , Interferon gama/metabolismo , Receptores de Citocinas/fisiologia , Proteínas com Domínio T/fisiologia , Animais , Humanos , Infecções/microbiologia , Infecções/parasitologia , Influenza Humana/imunologia , Interferon gama/genética , Camundongos , Camundongos Mutantes , Receptores de Citocinas/genética , Receptores de Interleucina , Fator de Transcrição STAT1/metabolismo , Proteínas com Domínio T/genética , Toxoplasmose/imunologiaRESUMO
Interferon-gamma is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon-gamma response by CD4(+) T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing CD4(+) T cell population in the lung. The recall response of the IL-17-producing CD4(+) T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of CD4(+) T cells producing interferon-gamma in the lung. We propose that vaccination induces IL-17-producing CD4(+) T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4(+) T cells producing interferon-gamma, which ultimately restrict bacterial growth.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos TransgênicosRESUMO
T cell responses are important to the control of infection but are deleterious if not regulated. IFN-gamma-deficient mice infected with mycobacteria exhibit enhanced accumulation of activated effector T cells and neutrophils within granulomatous lesions. These cells do not control bacterial growth and compromise the integrity of the infected tissue. We show that IFN-gamma-deficient mice have increased numbers of IL-17-producing T cells following infection with Mycobacterium bovis bacille Calmette Guérin. Furthermore, exogenous IFN-gamma increases IL-12 and decreases IL-23 production by bacille Calmette Guérin-infected bone marrow-derived dendritic cells and reduces the frequency of IL-17-producing T cells induced by these bone marrow-derived dendritic cells. These data support the hypothesis that, during mycobacterial infection, both IFN-gamma- and IL-17-producing T cells are induced, but that IFN-gamma serves to limit the IL-17-producing T cell population. This counterregulation pathway may be an important factor in limiting mycobacterially associated immune-mediated pathology.