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2.
Nat Commun ; 11(1): 1539, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210242

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown etiology; however, apoptosis of lung alveolar epithelial cells plays a role in disease progression. This intractable disease is associated with increased abundance of Staphylococcus and Streptococcus in the lungs, yet their roles in disease pathogenesis remain elusive. Here, we report that Staphylococcus nepalensis releases corisin, a peptide conserved in diverse staphylococci, to induce apoptosis of lung epithelial cells. The disease in mice exhibits acute exacerbation after intrapulmonary instillation of corisin or after lung infection with corisin-harboring S. nepalensis compared to untreated mice or mice infected with bacteria lacking corisin. Correspondingly, the lung corisin levels are significantly increased in human IPF patients with acute exacerbation compared to patients without disease exacerbation. Our results suggest that bacteria shedding corisin are involved in acute exacerbation of IPF, yielding insights to the molecular basis for the elevation of staphylococci in pulmonary fibrosis.


Assuntos
Proteínas Reguladoras de Apoptose/imunologia , Proteínas de Bactérias/imunologia , Fibrose Pulmonar Idiopática/imunologia , Peptídeos/imunologia , Staphylococcus/imunologia , Idoso , Animais , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/análise , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Bactérias/análise , Proteínas de Bactérias/metabolismo , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Voluntários Saudáveis , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/microbiologia , Fibrose Pulmonar Idiopática/patologia , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Peptídeos/análise , Peptídeos/metabolismo , Staphylococcus/metabolismo , Staphylococcus/patogenicidade , Exacerbação dos Sintomas , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia
4.
Rev. chil. enferm. respir ; 35(4): 278-281, dic. 2019. tab
Artigo em Espanhol | LILACS | ID: biblio-1092707

RESUMO

Las Enfermedades del Tejido Conectivo (ETC) comprenden un grupo heterogéneo de patologías multisistémicas de origen autoinmune. La Enfermedad pulmonar intersticial (EPI) asociada a ETC (EPI-ETC) es frecuente y empeora el pronóstico de la ETC. Las EPI-ETC representan aproximadamente 15-30% del total las EPI y se presentan con las mismas formas histopatológicas y radiológicas descritas para las EPI idiopáticas. Esto pone en evidencia la importancia de incorporar en forma rutinaria a reumatología en el comité multidisciplinario para el diagnóstico y manejo de las EPI.


Connective Tissue Diseases (CTD) comprise a heterogeneous group of multisystemic pathologies of autoimmune origin. Interstitial lung disease (ILD) associated with CTD (CTD-ILD) is common and and it worsens the prognosis of CTD. CTD-ILD represent approximately 15-30% of the universe of ILD and have the same histopathological and radiological forms described for idiopathic ILD. This highlights the importance of routinely incorporate a rheumatologist into the multidisciplinary committee for the diagnosis and management of ILD.


Assuntos
Humanos , Doenças Reumáticas/complicações , Doenças do Tecido Conjuntivo/complicações , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/imunologia , Doenças Reumáticas/diagnóstico , Doenças do Tecido Conjuntivo/diagnóstico
5.
Respir Res ; 20(1): 244, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694639

RESUMO

BACKGROUND: T follicular helper (Tfh) cells have been identified as a new category of helper T cells, which express CXCR5 on their surface and induce the production of antigen-specific antibodies. Many investigations have found morbid proliferation and/or activation of Tfh cells in systemic autoimmune and allergic diseases. It is also known that Tfh cells are regulated by regulatory B (Breg) cells in the deteriorating such diseases. Recently, CXCL13, a ligand of CXCR5, has been reported to increase in the peripheral blood and lungs of patients with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the involvement of Tfh cells and Breg cells in IPF. METHODS: Peripheral blood samples were obtained from 18 patients with IPF. We isolated heparinized peripheral blood mononuclear cells and investigated the proportions of Breg cells, Tfh cells, PD-1+ICOS+ Tfh cells (activated form of Tfh cells), and the Tfh-cell subsets by flow cytometry. These cell profiles were compared with those of 21 healthy controls. Furthermore, we investigated the correlations between profiles of lymphocytes and lung physiology. RESULTS: The median proportions of Tfh cells per total CD4+ T cells and of PD-1+ICOS+ proportion of Tfh cells per total Tfh cells was significantly more in the IPF patients (20.4 and 5.2%, respectively) compared with healthy controls (15.4 and 2.1%, respectively; p = 0.042 and p = 0.004, respectively). The proportion of Tfh2 cells per total Tfh cells was significantly higher and the proportion of Tfh17 was smaller in the IPF patients than healthy controls. The percentage of Breg cells to total B cells was significantly decreased in the IPF patients (median, 8.5%) compared with that in the controls (median, 19.7%; p < 0.001). The proportion of Breg cells was positively correlated with the annual relative change in diffusing capacity of the lungs for carbon monoxide in the IPF patients (r = 0.583, p = 0.018). CONCLUSION: Proliferation and activation of Tfh cells and a decrease in Breg cells were observed in the peripheral blood of patients with IPF. The profile of the Tfh-cell subset also changed. Specific humoral immunity aberration would likely underlie complicated pathophysiology of IPF.


Assuntos
Autoimunidade , Linfócitos B Reguladores/imunologia , Proliferação de Células , Fibrose Pulmonar Idiopática/imunologia , Imunidade Humoral , Ativação Linfocitária , Linfócitos T Auxiliares-Indutores/imunologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos B Reguladores/metabolismo , Biomarcadores/sangue , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Feminino , Humanos , Fibrose Pulmonar Idiopática/sangue , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/fisiopatologia , Proteína Coestimuladora de Linfócitos T Induzíveis/sangue , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptor de Morte Celular Programada 1/sangue , Capacidade de Difusão Pulmonar , Receptores CXCR5/sangue , Linfócitos T Auxiliares-Indutores/metabolismo
6.
PLoS One ; 14(10): e0221905, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31584949

RESUMO

BACKGROUND: The processes that result in progression of idiopathic pulmonary fibrosis (IPF) remain enigmatic. Moreover, the course of this disease can be highly variable and difficult to accurately predict. We hypothesized analyses of body mass index (BMI), a simple, routine clinical measure, may also have prognostic value in these patients, and might provide mechanistic insights. We investigated the associations of BMI changes with outcome, plasma adipokines, and adaptive immune activation among IPF patients. METHODS: Data were analyzed in an IPF discovery cohort (n = 131) from the University of Pittsburgh, and findings confirmed in patients from the University of Alabama at Birmingham (n = 148). Plasma adipokines were measured by ELISA and T-cell phenotypes determined by flow cytometry. RESULTS: Transplant-free one-year survivals in subjects with the greatest rates of BMI decrements, as percentages of initial BMI (>0.68%/month), were worse than among those with more stable BMI in both discovery (HR = 1.8, 95%CI = 1.1-3.2, p = 0.038) and replication cohorts (HR = 2.5, 95%CI = 1.2-5.2, p = 0.02), when adjusted for age, baseline BMI, and pulmonary function. BMI decrements >0.68%/month were also associated with greater mortality after later lung transplantations (HR = 4.6, 95%CI = 1.7-12.5, p = 0.003). Circulating leptin and adiponectin levels correlated with BMI, but neither adipokine was prognostic per se. BMI decrements were significantly associated with increased proportions of circulating end-differentiated (CD28null) CD4 T-cells (CD28%), a validated marker of repetitive T-cell activation and IPF prognoses. CONCLUSIONS: IPF patients with greatest BMI decrements had worse outcomes, and this effect persisted after lung transplantation. Weight loss in these patients is a harbinger of poor prognoses, and may reflect an underlying systemic process, such as adaptive immune activation.


Assuntos
Adipocinas , Índice de Massa Corporal , Fibrose Pulmonar Idiopática , Ativação Linfocitária , Linfócitos T , Adipocinas/sangue , Adipocinas/imunologia , Fatores Etários , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Fibrose Pulmonar Idiopática/sangue , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/mortalidade , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de Sobrevida , Linfócitos T/imunologia , Linfócitos T/metabolismo
7.
BMJ Case Rep ; 12(9)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31494587

RESUMO

Interstitial pneumonia with autoimmune features (IPAF) is a recently proposed terminology for interstitial lung disease (ILD) with evidence of autoimmunity that does not meet the criteria for a defined connective tissue disease (CTD). Although ILD is well recognised in patients with established CTD, it is rarely the sole presenting feature of CTD. We report a case of 22-year-old male patient, who presented with progressive shortness of breath for 2 months and had features suggestive of platypnea-orthodeoxia syndrome (POS). Imaging revealed ILD with usual interstitial pneumonia pattern. Patient had features of autoimmune disorder but did not fulfil the criteria for any CTD and hence was labelled as IPAF. His POS was attributed predominantly to the lower lobe disease. The patient responded well to immunosuppressive treatment. A systematic review of literature of all cases with POS due to pulmonary parenchymal involvement has also been done.


Assuntos
Doenças Autoimunes/diagnóstico , Fibrose Pulmonar Idiopática/diagnóstico , Imunossupressores/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Dispneia/imunologia , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/fisiopatologia , Masculino , Síndrome , Resultado do Tratamento , Adulto Jovem
8.
Respir Med ; 155: 43-48, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31299466

RESUMO

RATIONALE: The concept of interstitial pneumonia with autoimmune features (IPAF) was recently proposed by the American Thoracic Society. However, the clinical significance of the serologic domain of IPAF has not yet been established in idiopathic pulmonary fibrosis (IPF). OBJECTIVES: We aimed to investigate the clinical significance of autoantibody positivity in IPF. METHODS: We retrospectively reviewed the records of 512 patients diagnosed as IPF from January 2007 through March 2014. The patients were divided into two subgroups: (i) an autoantibody-positive IPF subgroup (n = 138), consisting of patients with anti-neutrophil cytoplasmic antibody (ANCA) or autoantibodies that met the criteria for the IPAF serologic domain; (ii) a lone IPF subgroup (n = 374), consisting of the rest of the IPF patients. MEASUREMENTS AND MAIN RESULTS: Autoantibody-positivity (HR 0.736, p = 0.043) was an independent risk factors for 5-year mortality on multivariable analysis in the overall IPF patients. In the autoantibody-positive IPF patients, use of glucocorticoid (not for management of acute exacerbation, HR 2.121, p = 0.019), use of immunomodulators (HR 0.310, p = 0.002), malignancy (HR 3.359, p = 0.002), baseline forced vital capacity (HR 0.974, p = 0.017), baseline diffusing capacity of the lung for carbon monoxide (HR 0.981, p = 0.041), and baseline 6-min walk test distance (HR 0.996, p = 0.002) were independent risk factors for 5-year mortality. CONCLUSIONS: Presence of ANCA or autoantibodies of the IPAF serologic domain in IPF patients is associated with better survival outcomes, and the use of immunomodulators is associated with superior survival outcomes.


Assuntos
Autoanticorpos/sangue , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/imunologia , Doenças Pulmonares Intersticiais/diagnóstico , Idoso , Anticorpos Anticitoplasma de Neutrófilos/sangue , Monóxido de Carbono/metabolismo , Feminino , Glucocorticoides/uso terapêutico , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/fisiopatologia , Fatores Imunológicos/uso terapêutico , Doenças Pulmonares Intersticiais/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Capacidade de Difusão Pulmonar/fisiologia , Estudos Retrospectivos , Fatores de Risco , Capacidade Vital/fisiologia , Teste de Caminhada/métodos
9.
BMJ Open ; 9(5): e027849, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31147365

RESUMO

OBJECTIVE: To clarify clinical significance of the sole presence of autoantibodies for idiopathic pulmonary fibrosis (IPF) without any other symptoms or signs suggestive of autoimmune disease. DESIGN: Systematic review and meta-analysis DATA SOURCES: Medline, EMBASE, Science Citation Index Expanded and Google Scholar were searched from 1 January 2002 through 12 February 2019. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Primary studies addressing all-cause mortality and the development of a defined autoimmune disease for IPF with autoantibodies were included for the review. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted relevant data and assessed risk of bias independently. Meta-analysis was conducted using a random-effects model if three or more studies reported the same outcome for a certain autoantibody. The quality of evidence was assessed by the Grades of Recommendation, Assessment, Development and Evaluation system. RESULTS: Out of 4603 records retrieved nine studies were included in this review. All studies contained some risk of bias. Based on pooled data myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) was significantly associated with microscopic polyangiitis incidence with risk ratio (RR) of 20.2 (95% CI: 7.22 to 56.4) and antinuclear antibody (ANA) was also significantly associated with the development of connective tissue diseases with RR of 7.11 (p=0.001) (10 cases in 157 patients with ANA) in one study. However, there was no significant association of autoantibodies with all-cause mortality aside from MPO-ANCA and proteinase 3-ANCA in one study each. MPO-ANCA was not demonstrated to be associated with all-cause mortality by meta-analysis. The quality of evidence was deemed as either low or very low. CONCLUSIONS: The presence of autoantibodies such as MPO-ANCA and ANA was demonstrated to be associated with the development of some autoimmune diseases for patients with IPF although there was no difference of all-cause mortality. However, the results should be interpreted with caution due to low evidence level. PROSPERO REGISTRATION NUMBER: CRD42017077336.


Assuntos
Autoanticorpos/metabolismo , Doenças Autoimunes/diagnóstico , Fibrose Pulmonar Idiopática/diagnóstico , Idoso , Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/mortalidade , Métodos Epidemiológicos , Feminino , Humanos , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/mortalidade , Masculino , Pessoa de Meia-Idade , Peroxidase/imunologia , Prognóstico
10.
J Immunol Res ; 2019: 1845128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31098385

RESUMO

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease, with high mortality. Currently, the aetiology and the pathology of IPF are poorly understood, with both innate and adaptive responses previously being implicated in the disease pathogenesis. Heat shock proteins (Hsp) and antibodies to Hsp in patients with IPF have been suggested as therapeutic targets and prognostic biomarkers, respectively. We aimed to study the relationship between the expression of Hsp72 and anti-Hsp72 antibodies in the BAL fluid and serum Aw disease progression in patients with IPF. Methods: A novel indirect ELISA to measure anti-Hsp72 IgG was developed and together with commercially available ELISAs used to detect Hsp72 IgG, Hsp72 IgGAM, and Hsp72 antigen, in the serum and BALf of a cohort of IPF (n = 107) and other interstitial lung disease (ILD) patients (n = 66). Immunohistochemistry was used to detect Hsp72 in lung tissue. The cytokine expression from monocyte-derived macrophages was measured by ELISA. Results: Anti-Hsp72 IgG was detectable in the serum and BALf of IPF (n = 107) and other ILDs (n = 66). Total immunoglobulin concentrations in the BALf showed an excessive adaptive response in IPF compared to other ILDs and healthy controls (p = 0.026). Immunohistochemistry detection of C4d and Hsp72 showed that these antibodies may be targeting high expressing Hsp72 type II alveolar epithelial cells. However, detection of anti-Hsp72 antibodies in the BALf revealed that increasing concentrations were associated with improved patient survival (adjusted HR 0.62, 95% CI 0.45-0.85; p = 0.003). In vitro experiments demonstrate that anti-Hsp72 complexes stimulate macrophages to secrete CXCL8 and CCL18. Conclusion: Our results indicate that intrapulmonary anti-Hsp72 antibodies are associated with improved outcomes in IPF. These may represent natural autoantibodies, and anti-Hsp72 IgM and IgA may provide a beneficial role in disease pathogenesis, though the mechanism of action for this has yet to be determined.


Assuntos
Células Epiteliais Alveolares/metabolismo , Autoanticorpos/metabolismo , Proteínas de Choque Térmico HSP72/metabolismo , Fibrose Pulmonar Idiopática/imunologia , Pulmão/imunologia , Macrófagos/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Quimiocinas CC/metabolismo , Progressão da Doença , Feminino , Proteínas de Choque Térmico HSP72/genética , Proteínas de Choque Térmico HSP72/imunologia , Humanos , Fibrose Pulmonar Idiopática/mortalidade , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
11.
Respir Med ; 150: 154-160, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30961944

RESUMO

BACKGROUND: The term Interstitial Pneumonia with Autoimmune Features (IPAF) describes patients with Interstitial Lung Diseases (ILDs) and clinical or serological features of autoimmune diseases insufficient to reach a specific classification of a Connective Tissue Disease (CTD). Currently, retrospective studies on IPAF patients have proven to be heterogeneous in general characteristics, outcomes and High-Resolution Computed Tomography (HRCT) pattern. This study aims to describe for the first time the clinical, serological and radiological features of a prospective cohort of IPAF patients. This cohort is then compared to a group of patients with Idiopathic Pulmonary Fibrosis (IPF). MATERIAL AND METHODS: From 626 consecutive ILD patients evaluated, 45 IPAF and a comparison cohort of 143 IPF patients were enrolled. All patients underwent clinical assessment with rheumatologic and respiratory evaluation, HRCT, Pulmonary Function Tests and Nailfold Videocapillaroscopy. RESULTS: The IPAF patients had a predominance of female gender (62.12%) with a median age of 66 years. The most common findings were: Nonspecific Interstitial Pneumonia (NSIP, 68.89%), Antinuclear Antibody positivity (17.77%) and Raynaud Phenomenon (31.11%). In comparison with IPF, IPAF patients showed younger age, better performances in Pulmonary Function Tests, less necessity of O2 support and predominance of female sex and NSIP pattern. DISCUSSION: This is the first report of a prospective cohort of IPAF patients. IPAF patients seem to have a less severe lung disease than IPF. IPAF criteria probably need to be revisited and validated, but their capacity to recruit patients with incomplete forms or early onset of CTD could be useful for further research.


Assuntos
Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/imunologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/imunologia , Idoso , Anticorpos Antinucleares/imunologia , Doenças Autoimunes/imunologia , Doenças do Tecido Conjuntivo/classificação , Doenças do Tecido Conjuntivo/epidemiologia , Feminino , Humanos , Fibrose Pulmonar Idiopática/sangue , Fibrose Pulmonar Idiopática/fisiopatologia , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Angioscopia Microscópica/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Radiografia/métodos , Doença de Raynaud/epidemiologia , Testes de Função Respiratória/métodos , Tomografia Computadorizada por Raios X/métodos
12.
Lung ; 197(3): 277-284, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30838434

RESUMO

PURPOSE: International guidelines recommend screening for connective tissue disease (CTD) with autoantibodies when evaluating patients with idiopathic interstitial lung disease (ILD). Idiopathic inflammatory myositis comprises of a subgroup of CTD diagnosed with myositis antibodies (MA), often presenting with ILD. Our aim was to evaluate the utility of MA screening in patients with idiopathic ILD. METHODS: A retrospective analysis was conducted on patients referred with idiopathic ILD to a tertiary centre ILD clinic who were screened for MA. Patients with known or suspected CTD were excluded. Descriptive statistics, univariate analysis and multivariable logistic regression were used to detect associations between MA and patient characteristics. RESULTS: Of 360 patients, 165 met inclusion criteria and 44 (26.7%) were identified to have MA. Fourteen patients (8.5%) had a change in diagnosis as a result of MA screening. Multivariable logistic regression identified the presence of MA to be associated with current smoking [OR 6.87 (1.65-28.64), p = 0.008] and a diffusing capacity of < 70% predicted [OR 2.55 (1.09-5.97), p = 0.03]. In patients with a change in diagnosis due to MA screening, 3 (1.8%) underwent a surgical lung biopsy and 2 (1.2%) were previously treated with antifibrotic therapy. CONCLUSIONS: Screening for MA in patients with idiopathic ILD can contribute to a change in patient diagnosis, and may prevent invasive testing and unproven use of antifibrotic therapy. These results support the addition of MA to CTD screening panels during the initial evaluation of idiopathic ILD.


Assuntos
Autoanticorpos/imunologia , Doenças do Tecido Conjuntivo/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico , Miosite/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Doenças do Tecido Conjuntivo/imunologia , Feminino , Histidina-tRNA Ligase/imunologia , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/imunologia , Modelos Logísticos , Doenças Pulmonares Intersticiais/imunologia , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Análise Multivariada , Miosite/imunologia , Estudos Retrospectivos , Ribonucleoproteínas/imunologia
13.
Int Immunopharmacol ; 70: 208-215, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30851700

RESUMO

OBJECTIVE: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is of concern because of its propensity for rapid deterioration and high mortality. Its aetiology and mechanism are still unclear. The aims of this study were to clarify the pathophysiology differences between AE-IPF and stable IPF (S-IPF) by comparing the serum levels of various cytokines and chemokines in the two groups and to identify those involvement in the occurrence of acute exacerbation and associated with mortality. METHODS: The study included 28 patients with AE-IPF, 32 patients with S-IPF, and 18 healthy control subjects. We measured the serum cytokine and chemokine levels in all cases by multiplex assay. Serum levels of cytokines and chemokines were compared between AE-IPF and S-IPF subjects. Logistic regression analysis was applied to identify the ability of these variables to predict acute exacerbation. Kaplan-Meier curves were used to analyse survival and Cox proportional hazard regression was used to identify predictors of survival. RESULTS: Levels of several cytokines and chemokines were significantly higher in both patient groups with IPF (with the exception of interleukin-2 [IL-2], chemokine cc-motif ligand 3, and RANTES [regulation upon activation normal T-cell express sequence]) than in healthy controls. Serum IL-1ß (p = 0.008) and interferon (IFN)-γ (p = 0.007) levels tended to be higher in patients with AE-IPF than in those with S-IPF. The concentration of chemokine cc-motif ligand (CCL) 2 was significantly higher in bronchoalveolar lavage fluid than in serum (p = 0.001). Higher C-reactive protein, lactate dehydrogenase, percent forced vital capacity, percent diffusing capacity of the lung for carbon monoxide, and IFN-γ values in the patients with IPF were correlated with acute exacerbation status, with respective odds ratios of 1.241 (p = 0.011), 1.050 (p = 0.004), 1.043 (p = 0.001), 0.927 (p = 0.014), and 0.929 (p = 0.020). Acute exacerbation status was associated with an increased risk of mortality (hazard ratio 0.107, 95% confidence interval 0.036-0.314; p < 0.001). Univariate Cox regression demonstrated an association of IFN-γ, CCL2, C-X-C motif chemokine 10 (CXCL10) and sCD163 levels with an increased mortality risk (p = 0.015, p = 0.002, p = 0.001, and p = 0.030, respectively). CONCLUSIONS: Our data demonstrate that serum levels of some pro-inflammatory cytokines and macrophage chemokines are upregulated during acute exacerbations of IPF and that these exacerbations are associated with the serum IFN-γ level. Chemokines and protein such as sCD163, CCL2, and CXCL10 are associated with activation of macrophages and may have a serious impact on overall survival in patients with IPF.


Assuntos
Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Quimiocina CCL2/sangue , Quimiocina CXCL10/sangue , Fibrose Pulmonar Idiopática/diagnóstico , Inflamação/diagnóstico , Interferon gama/sangue , Macrófagos/imunologia , Receptores de Superfície Celular/sangue , Doença Aguda , Idoso , Progressão da Doença , Feminino , Humanos , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/mortalidade , Inflamação/imunologia , Inflamação/mortalidade , Ativação de Macrófagos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida
14.
Respir Med ; 147: 79-91, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30704705

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive, and ultimately fatal, chronic interstitial lung disease characterized by enhanced extracellular matrix deposition. Repetitive alveolar epithelial injury triggers the early development of fibrosis. These injuries, in combination with dysregulated wound repair and fibroblast dysfunction, lead to ongoing tissue remodelling and fibrosis seen in end-stage pulmonary fibrosis. Although the exact etiology in IPF is unknown and probably diverse, all stages of fibrosis are accompanied by innate and adaptive immune responses. The role of inflammation as an important component in IPF etiology is controversial and sometimes seen as an epiphenomenon of fibrosis. This view is partly the result of negative multicenter trials of anti-inflammatory drugs for IPF treatment. However, new insights on the role of macrophages, the loss of T-cell and B-cell tolerance leading auto-immune responses in IPF, and the interaction of immune cells with (myo)fibroblasts have led to a slow change of this opinion. Clearly, more insight is needed to integrate basic immune mechanisms into translational research and finally new IPF therapies. In this concise review, we will focus on the role of our innate and adaptive immune system in the initiation and perpetuation of IPF pathobiology. Next, we will discuss how immune responses are influenced by current anti-fibrotic treatments, such as pirfenidone and nintedanib and end with an overview of recent and upcoming therapeutic trials that target and modulate our immune system in patients with IPF.


Assuntos
Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/fisiopatologia , Inflamação/imunologia , Imunidade Adaptativa/imunologia , Anti-Inflamatórios/uso terapêutico , Ensaios Clínicos como Assunto , Matriz Extracelular/patologia , Fibroblastos/patologia , Fibrose/classificação , Fibrose/patologia , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/etiologia , Imunidade Inata/imunologia , Indóis/uso terapêutico , Inflamação/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico
16.
Nat Immunol ; 20(2): 163-172, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643263

RESUMO

Tissue fibrosis is a major cause of mortality that results from the deposition of matrix proteins by an activated mesenchyme. Macrophages accumulate in fibrosis, but the role of specific subgroups in supporting fibrogenesis has not been investigated in vivo. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis in mice. A novel computational framework for the annotation of scRNA-seq by reference to bulk transcriptomes (SingleR) enabled the subclustering of macrophages and revealed a disease-associated subgroup with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages. These CX3CR1+SiglecF+ transitional macrophages localized to the fibrotic niche and had a profibrotic effect in vivo. Human orthologs of genes expressed by the transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis. Thus, we have identified a pathological subgroup of transitional macrophages that are required for the fibrotic response to injury.


Assuntos
Fibrose Pulmonar Idiopática/imunologia , Pulmão/patologia , Ativação de Macrófagos , Macrófagos Alveolares/imunologia , Animais , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Antígenos de Diferenciação Mielomonocítica/metabolismo , Bleomicina/imunologia , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/imunologia , Receptor 1 de Quimiocina CX3C/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/citologia , Pulmão/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Regulação para Cima
17.
Mucosal Immunol ; 12(1): 212-222, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30315241

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease, with unknown etiopathogenesis and suboptimal therapeutic options. Previous reports have shown that increased T-cell numbers and CD28null phenotype is predictive of prognosis in IPF, suggesting that these cells might have a role in this disease. Flow cytometric analysis of explanted lung cellular suspensions showed a significant increase in CD8+ CD28null T cells in IPF relative to normal lung explants. Transcriptomic analysis of CD3+ T cells isolated from IPF lung explants revealed a loss of CD28-transcript expression and elevation of pro-inflammatory cytokine expression in IPF relative to normal T cells. IPF lung explant-derived T cells (enriched with CD28null T cells), but not normal donor lung CD28+ T cells induced dexamethasone-resistant lung remodeling in humanized NSG mice. Finally, CD28null T cells expressed similar CTLA4 and significantly higher levels of PD-1 proteins relative to CD28+ T cells and blockade of either proteins in humanized NSG mice, using anti-CTLA4, or anti-PD1, mAb treatment-accelerated lung fibrosis. Together, these results demonstrate that IPF CD28null T cells may promote lung fibrosis but the immune checkpoint proteins, CTLA-4 and PD-1, appears to limit this effect.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/metabolismo , Fibrose Pulmonar Idiopática/imunologia , Pulmão/patologia , Receptor de Morte Celular Programada 1/metabolismo , Subpopulações de Linfócitos T/imunologia , Remodelação das Vias Aéreas , Animais , Anticorpos Monoclonais/metabolismo , Antígenos CD28/metabolismo , Antígeno CTLA-4/imunologia , Separação Celular , Células Cultivadas , Citometria de Fluxo , Humanos , Imunofenotipagem , Camundongos , Camundongos SCID , Receptor de Morte Celular Programada 1/imunologia
18.
Genomics ; 111(6): 1343-1350, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30261315

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive decline of lung function. Here, we tested the importance of differential proportions of blood immune cells to IPF clinical outcomes. We used Cibersort to deconvolute immune cell components based on PBMCs or whole blood IPF genomics datasets. We found that a higher proportion of resting memory (RM) T cells was associated with a better survival and a higher DLco (diffusing capacity for carbon monoxide) in IPF patients. The association was also found in opposite direction for monocytes. Additionally, in IPF patients as compared to healthy controls, proportions of monocytes were observed to be higher, yet RM T cells were observed to be lower. Taken together, our result suggests a beneficial effect of RM T cells and a detrimental effect of monocytes for IPF. Future genomics studies of IPF should be more focused on these two types of cells.


Assuntos
Fibrose Pulmonar Idiopática/mortalidade , Monócitos/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/imunologia , Memória Imunológica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico
19.
Am J Respir Crit Care Med ; 199(3): 362-376, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30088779

RESUMO

RATIONALE: Cytomegalovirus (CMV)-related morbidities remain one of the most common complications after lung transplantation and have been linked to allograft dysfunction, but the factors that predict high risk for CMV complications and effective immunity are incompletely understood. OBJECTIVES: To determine if short telomeres in idiopathic pulmonary fibrosis (IPF) lung transplant recipients (LTRs) predict the risk for CMV-specific T-cell immunity and viral control. METHODS: We studied IPF-LTRs (n = 42) and age-matched non-IPF-LTRs (n = 42) and assessed CMV outcomes. We measured lymphocyte telomere length and DNA sequencing, and assessed CMV-specific T-cell immunity in LTRs at high risk for CMV events, using flow cytometry and fluorescence in situ hybridization. MEASUREMENTS AND MAIN RESULTS: We identified a high prevalence of relapsing CMV viremia in IPF-LTRs compared with non-IPF-LTRs (69% vs. 31%; odds ratio, 4.98; 95% confidence interval, 1.95-12.50; P < 0.001). Within this subset, IPF-LTRs who had short telomeres had the highest risk of CMV complications (P < 0.01) including relapsing-viremia episodes, end-organ disease, and CMV resistance to therapy, as well as shorter time to viremia versus age-matched non-IPF control subjects (P < 0.001). The short telomere defect in IPF-LTRs was associated with significantly impaired CMV-specific proliferative responses, T-cell effector functions, and induction of the major type-1 transcription factor T-bet (T-box 21;TBX21). CONCLUSIONS: Because the short telomere defect has been linked to the pathogenesis of IPF in some cases, our data indicate that impaired CMV immunity may be a systemic manifestation of telomere-mediated disease in these patients. Identifying this high-risk subset of LTRs has implications for risk assessment, management, and potential strategies for averting post-transplant CMV morbidities.


Assuntos
Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/imunologia , Fibrose Pulmonar Idiopática/complicações , Transplante de Pulmão , Telômero/imunologia , Transplantados/estatística & dados numéricos , Adulto , Idoso , Citomegalovirus/imunologia , Feminino , Humanos , Fibrose Pulmonar Idiopática/imunologia , Imunidade , Masculino , Pessoa de Meia-Idade
20.
Lung Cancer ; 126: 162-169, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30527182

RESUMO

BACKGROUND: Lung cancer with usual interstitial pneumonia (UIP) pattern is a disease with poor prognosis. This study aimed to characterize the tumor microenvironment of lung adenocarcinoma associated with UIP (UIP-ADC). METHODS: A total of 1341 consecutive patients with ADC who had undergone complete surgical resection were enrolled in this study, and the clinicopathological features of UIP-ADC were examined. Further, we selected 17 cases of UIP-ADC and non-UIP ADC each (adjusted for age, smoking status, pathological stage, and invasive size of lesion) for immunohistochemical analysis, and the biological differences between UIP-ADC and non-UIP ADC groups were analyzed. RESULTS: UIP-ADC was detected in 18 patients (1.3%). Patients with UIP-ADC had shorter cancer-specific survival (CSS) (5 yrs CSS; UIP-ADC 52.9% vs non-UIP ADC 81.8%, p < 0.01). Evaluation of tumor-infiltrating lymphocytes (TILs) in cancer stroma showed that the number of CD8+ TILs in UIP-ADC group was significantly lower than that in the non-UIP ADC group (median number 91 vs 121, p < 0.01). In contrast, levels of Foxp3+ TILs were not significantly different between the two groups. The CD8+/Foxp3+ T cell ratio was significantly lower in UIP-ADC than in the non-UIP ADC population (1.9 vs 2.7, p < 0.01). Additionally, among UIP-ADC patients, the CD8+/Foxp3+ T cell ratio was significantly higher in the non-cancerous UIP lesions than in the cancer stroma from the same patient (2.4 vs 1.7, p < 0.01). CONCLUSION: In the current study, we have demonstrated that the tumor microenvironment of UIP-ADC acquires an immunosuppressive state, and this could be one of the possible explanations for poor prognosis of this disease.


Assuntos
Adenocarcinoma/imunologia , Fibrose Pulmonar Idiopática/imunologia , Neoplasias Pulmonares/imunologia , Microambiente Tumoral/imunologia , Adenocarcinoma/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Fibrose Pulmonar Idiopática/complicações , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/complicações , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto Jovem
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