RESUMO
Adaptive immune processes have been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). We hypothesized that peripheral T cell abnormalities may be present in afflicted patients. We tested this hypothesis by characterizing circulating T cells in COPD patients and correlated these findings with disease severity, smoking status, and use of inhaled glucocorticosteroids (ICS). Compared with normal controls, a lesser proportion of peripheral CD4 T cells from COPD subjects produced IL-10, whereas the CD8 T cells from these patients were more often activated and more frequently produced both IFN-gamma and IL-4. COPD severity was significantly and inversely associated with the proportion of circulating CD4 T cells and directly correlated with CD4 production of IL-2, as well as frequency of CD8 T cell activation and CD8 IFN-gamma production. Adjustments for current smoking status and ICS use by linear regression showed independent, and generally inhibitory, effects of these clinical variables on the abnormal T cell functions of these patients. We conclude that circulating T cells from COPD patients are abnormally activated and elaborate proinflammatory mediators with admixed features of Th1 and Th2 responses. Furthermore, many of these effector processes are significantly correlated with disease severity. These findings further implicate adaptive immune processes in COPD progression and indicate that facile assays of peripheral lymphocytes may provide useful insights into disease mechanisms. Current smoking and ICS use had independent effects on T cell functions among the COPD subjects, illustrating the importance of controlling for clinical parameters as covariates in immunological studies of patients afflicted with this disease.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Fumar/imunologia , Administração por Inalação , Idoso , Complexo CD3/biossíntese , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Antígenos HLA-D/biossíntese , Humanos , Imunidade Inata/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/patologia , Índice de Gravidade de Doença , Fumar/tratamento farmacológico , Fumar/patologiaRESUMO
RATIONALE: Adaptive immune responses are present in patients with chronic obstructive pulmonary disease (COPD), and it has been postulated that these processes could be autoreactive. OBJECTIVES: To ascertain if humoral autoimmunity could play a role in COPD pathogenesis. METHODS: Circulating IgG autoantibodies were detected by immunofluorescence and immunoprecipitation. Immunohistochemistry and immunofluorescence were used to evaluate intrapulmonary IgG and complement (C3) deposition in human lung explants. Autoantibody pathogenicity was also investigated with an antibody-dependent cell-mediated cytotoxicity assay. MEASUREMENTS AND MAIN RESULTS: The prevalence of anti-HEp-2 epithelial cell autoantibodies in 47 smokers/former smokers with COPD (GOLD stages 1-4) was greater than among 8 subjects with a smoking history but normal spirometry and 21 healthy control subjects who had never smoked (68 vs. 13 vs. 10%, respectively; P < 0.0001). Antibodies against primary pulmonary epithelial cells were found in 12 of 12 patients with COPD versus 3 of 12 never-smoked control subjects (P < 0.001). Self-antigens immunoprecipitated from 34 of 35 (97%) of COPD plasmas (vs. 0/12 never-smoked controls). Antibodies against a particular 130-kD autoantigen (n = 7) were associated with decreased body mass index (23.2 +/- 2.1 vs. 29.5 +/- 1.0 kg/m(2), P = 0.007). Intrapulmonary immune complexes were present in six of six and C3 was seen in five of six COPD lung explants, unlike zero of six and one of six normals, respectively. Cytotoxicity of pulmonary epithelial cells by allogeneic mononuclear cells also increased 46% after incubation with COPD plasmas (n = 10), compared with identical treatments with eight normal specimens (P = 0.03). CONCLUSIONS: IgG autoantibodies with avidity for pulmonary epithelium, and the potential to mediate cytotoxicity, are prevalent in patients with COPD. Autoreactive adaptive immune responses may be important in the etiology of this disease.
Assuntos
Autoanticorpos/sangue , Epitélio/imunologia , Imunoglobulina G/sangue , Pulmão/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Idoso , Autoanticorpos/efeitos adversos , Estudos de Casos e Controles , Complemento C3/análise , Feminino , Humanos , Técnicas Imunológicas , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/etiologia , Fumar/imunologiaRESUMO
STUDY OBJECTIVE: To determine the effects of tobacco dust extract (TDE) on isolated guinea pig tracheal smooth muscle. DESIGN: A controlled, in vitro smooth-muscle study of the effect of pharmacologic agents on TDE. METHODS: The effect of TDE on isolated guinea pig tracheal smooth muscle was tested using water-soluble extracts of dust obtained from machines in a cigarette manufacturing plant. Dose-related contractions of nonsensitized guinea pig trachea were demonstrated using these extracts. The dust extracts contained significant quantities of bacterial components (eg, endotoxin). Pharmacologic studies were performed by pretreating guinea pig tracheal tissue with drugs known to modulate smooth-muscle contraction: atropine, indomethacin, pyrilamine, nordihydroguaretic acid, acivicin, bromophenacyl bromide, 3,4,5-trimethoxybenzoic acid-8-(diethylamino)octyl ester, captopril, and capsaicin. RESULTS: Atropine strikingly reduced the contractile effects of these extracts. Inhibition of contraction by blocking other mediators was less complete. There was no inhibition of contraction by hexamethonium (10(-4) mol/L, 10(-5) mol/L, 10(-6) mol/L), suggesting that nicotine was not the major contractile mediator of TDE. A separate analysis using different molecular weight fractions of TDE indicated that the constrictor activity appears to be primarily in the fraction with a molecular weight < 10 kd. Additionally, the constrictor effect resided entirely in the nonlipid fraction of the extract. We suggest that TDE causes dose-related airway smooth-muscle constriction by nonimmunologic mechanisms involving a variety of airway mediators and possibly cholinergic receptors. CONCLUSIONS: The bronchoconstrictor activity of TDE resides primarily in its low molecular weight, nonlipid fraction, and hexamethonium studies suggest that this agent is not nicotine.
Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Poeira , Músculo Liso/efeitos dos fármacos , Nicotiana/toxicidade , Extratos Vegetais/toxicidade , Traqueia/efeitos dos fármacos , Poluentes Ocupacionais do Ar/análise , Animais , Atropina/farmacologia , Broncoconstrição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Poeira/análise , Endotoxinas/análise , Cobaias , Técnicas In Vitro , Masculino , Extratos Vegetais/análiseRESUMO
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the US and a major worldwide healthcare problem. The pathophysiologic mechanisms that drive development and progression of this disease are complex and only poorly understood. While tobacco smoking is the primary risk factor, other disease processes also appear to play a role. Components of the innate immune system (eg, macrophages and neutrophils) have long been believed to be important in the development of COPD. More recent evidence also suggests involvement of the adaptive immune system in pathogenesis of this disease. Here we will review the literature supporting the participation of T-cells in the development of COPD, and comment on the potential antigenic stimuli that may account for these responses. We will further explore the prospective contributions of T-cell derived mediators that could contribute to the inflammation, alveolar wall destruction, and small airway fibrosis of advanced COPD. A better understanding of these complex immune processes will lead to new insights that could result in improved preventative and/or treatment strategies.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade Celular , Mediadores da Inflamação/metabolismo , Doença Pulmonar Obstrutiva Crônica/imunologia , Animais , Antígenos , Peptídeos Catiônicos Antimicrobianos/imunologia , Autoantígenos , Progressão da Doença , Elastina/imunologia , Humanos , Interferon gama/metabolismo , Interleucinas/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Fumar/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Idiopathic pulmonary fibrosis (IPF) is a morbid, refractory lung disorder with an unknown pathogenesis. To investigate potential adaptive immune mechanisms in IPF, we compared phenotypes and effector functions of peripheral CD4 T cells, autoantibody production, and proliferative responses of pulmonary hilar lymph node CD4 T cells to autologous lung extracts from afflicted patients and normals. Our results show that greater proportions of peripheral CD4 T lymphocytes in IPF subjects expressed MHC class II and CD154 (CD40L), and they more frequently elaborated TGF-beta1, IL-10, and TNF-alpha. Abnormal CD4 T cell clonal expansions were found in all IPF patients, and 82% of these subjects also had IgG autoantibodies against cellular Ags. IPF lung extracts stimulated proliferations of autologous CD4 T cells, unlike preparations from normals or those with other lung diseases, and the IPF proliferative responses were enhanced by repeated cycles of stimulation. Thus, CD4 T cells from IPF patients have characteristics typical of cell-mediated pathologic responses, including augmented effector functions, provision of facultative help for autoantibody production, oligoclonal expansions, and proliferations driven by an Ag present in diseased tissues. Recognition that an autoreactive immune process is present in IPF can productively focus efforts toward identifying the responsible Ag, and implementing more effective therapies.
Assuntos
Formação de Anticorpos/imunologia , Autoanticorpos/imunologia , Autoimunidade , Linfócitos T CD4-Positivos/imunologia , Imunoglobulina G/imunologia , Fibrose Pulmonar/imunologia , Adulto , Idoso , Autoantígenos/imunologia , Linfócitos T CD4-Positivos/patologia , Proliferação de Células , Citocinas/imunologia , Feminino , Humanos , Pulmão/imunologia , Pulmão/patologia , Linfonodos/imunologia , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/patologia , Fibrose Pulmonar/terapiaRESUMO
The role of pre-existing airway inflammation in the pathogenesis of occupational airway disease is poorly understood. Previously we studied an extract of tobacco dust (TDE) and determined that it causes concentration dependent contractions of nonsensitized guinea pig trachea (GPT). In the present study animals were sensitized using Ovalbumin (OA) and subsequently challenged with an aerosol of 2.5% OA on day 21. A control group of nonsensitized GPs were divided into rings in which the epithelium was retained (EPI+) or removed (EPI-). Concentration related contractions of sensitized and nonsensitized GPTs were elicited with TDE. Sensitized GPTs demonstrated a greater contractile response to TDE than did nonsensitized GPTs. In nonsensitized animals the EPI- GPTs demonstrated a lesser response to TDE than did the EPI+. Similar findings were demonstrated in sensitized GPTs with and without epithelium. When epithelium was removed, sensitized and nonsensitized GPTs behaved similarly. Moreover, sensitized GPTs without epithelium and nonsensitized with epithelium responded similarly. These findings suggest that presensitization with an unrelated antigen enhances the response to an occupational agent and that in sensitized animals at least part of the enhanced response is mediated by the epithelial layer.