Lung T cells in inflammatory disorders : an approach to interstitial lung disease, multiple sclerosis and smoking induced inflammation

摘要

The lungs are constantly exposed to microorganisms and environmental irritants. Pulmonary inflammation is the result of an immune process to protect the body, and may sometimes eventually result in disease. T cells including various subsets are of major importance for orchestrating the protection of the lung as well as for inflammatory reactions. Activated pulmonary T cells not only have the potential to affect the lungs themselves, but they could contribute to immune responses in other organs as well. The overall aim of the study presented in this thesis was to investigate the potential effect of T cell immune responses for chronic lung inflammation from two different aspects. We thus first investigated antigen- specific T cell responses in patients with pulmonary sarcoidosis, and in the second part determined how smoking affected lung T-cell immunity, with regard to the influence of smoking in the development of autoimmunity.Sarcoidosis is a granulomatous systemic inflammatory disorder which commonly affects the lungs. T cells and particularly activated CD4+ T cells are considered to be involved in the pathogenesis of the disease. A subgroup of sarcoidosis patients known as Löfgren’s syndrome differs strikingly from other patients by particular clinical symptoms. Spontaneous recovery within two years is particularly common in Löfgren ́s syndrome patients who are HLA-DRB1*0301positive, and these patients virtually always have accumulations of T cells expressing a particular T cell receptor (TCR) V gene segment, termed AV2S3, in the lungs. The aetiology of sarcoidosis is still not known. However, recently a specific mycobacterial protein, M. tuberculosis catalase-peroxidase (mKatG) was identified in sarcoidosis tissues.BAL CD4+ T cells from HLA-DRB1*0301positive Löfgren’s syndrome responded to mKatG with a more pronounced multifunctional cytokine profile, i.e. with simultaneous production of IFNγ and TNF compared to non-Löfgren’s syndrome patients. Non-Löfgren’s syndrome patients instead responded with a higher proportion of cells producing single cytokines, i.e. production of IFNγ alone. Moreover, AV2S3+ CD4+ T cells from both BAL and blood had a higher IFNγ production in response to mKatG compared to AV2S3- CD4+ T cells, while the opposite was found for BAL AV2S3+ CD4+ cells in response to PPD. Furthermore, BAL T cells from Löfgren ́s syndrome patients had compared to T cells of non Löfgren ́s syndrome higher frequencies of IL-17-producing cells in response to mKatG. Löfgren ́s syndrome HLA- DRB1*03 positive patients clearly had higher levels of IL-17 in BAL fluid compared to healthy controls and to patients without Löfgren’s syndrome. Our results indicate that the quality of the T cell response in sarcoidosis patients may play a key role in disease presentation and clinical outcome. These findings imply that the presence of multifunctional BAL CD4+ T cells, higher activities of TCR AV2S3+ CD4+ T cells, and more pronounced IL-17 production in particular subgroups of sarcoidosis patients are involved in antigen elimination at the site of inflammation and may play a role in spontaneous recovery, typical for patients with Löfgren ́s syndrome (in particular DRB1*03 positive).Cigarette smoking is a well-known risk factor for several inflammatory and autoimmune disorders. The risk of developing multiple sclerosis (MS) is strongly increased by smoking in people with genetic susceptibility. Smoking is associated with both release and inhibition of pro-inflammatory and anti- inflammatory mediators that influence different T cell subsets. Our results indicate that cigarette smoke induces a decline in lung Th17 cells and alters the phenotype of T regulatory cells by decreasing the proportion of IL-10 producing Foxp3+ CD4+ cells and increasing the fraction of lung Foxp3+ Helios negative T cells. Thus, an imbalance between Th17/Tregs may be caused by cigarette smoking, which could result in an increased risk for infection and may also have consequences for autoimmune processes postulated to be initiated in the lung. Furthermore we studied the effect of smoking and conventional treatment in the lungs and blood of MS patients compared to healthy individuals. We found that the frequency of Foxp3+Helios+ regulatory T cells, important in the context of autoimmunity, was reduced in BAL of MS patients. However, the frequencies of both this subset of Tregs and of total Foxp3+ CD4+ BAL Treg cells was increased after treatment particularly in IFNβ treated MS patients. If the lungs are involved in initiation and propagation of inflammatory processes in MS, the observed effects in IFNβ- treated patients may be involved in disease amelioration in MS patients following such treatment.