Inflammatory mechansims in pulmonary sarcoidosis

Abstract: INFLAMMATORY MECHANISMS IN PULMONARY SARCOIDOSIS by Mary Berlin Department of Medicine, Division of Respiratory Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden Pulmonary sarcoidosis is an inflammatory disorder of unknown aetiology, characterised by an accumulation of CD4+ T-cells in the alveolar compartment and by granuloma formation and varying degrees of interstitial fibrosis. The initial clinical presentation may either be acute with fever, malaise, arthritis and/or erythema nodosum or insidious with cough, dyspnea, tiredness, and loss of weight. Although most patients have a good prognosis, a significant proportion runs a more severe and prolonged disease course. To analyse the inflammatory activity in the lung in sarcoidosis patients we measured the concentrations of vitronectin (ELISA), fibronectin (ELISA) and hyaluronan (RIA) in bronchoalveolar lavage (BAL) fluid, and found that the activity of the alveolitis was reflected by increased concentrations of all these soluble components. We also found high tryptase (RIA)' levels and an increased number of mast cells. High numbers of mast cells may be associated with the development of fibrosis and there is also evidence for a direct interaction between mast cells and fibroblasts. The mast-cell-specific enzyme tryptase has been reported to interfere with the metabolism of connective tissue. Additionally, sarcoidosis subjects were found to have an increased frequency of bronchial hyperreactivity. To further analyse the inflammatory reaction in the lung the TCR (T cell receptor) V gene usage by peripheral blood Iymphocytes (PBL) and BAL T cells was studied using TCR specific monoclonal antibodies and flow cytometry. A positive association was discovered between usage of the TCR Va2.3 gene segment by lung-accumulated CD4+ T cells, i.e. at the site of disease, and the HLA-DR17(3) haplotype. Moreover, the BAL/PBL Va 2.3+ T cell ratio correlated with the course of the disease. In extrinsic allergic alveolitis (EAA), another Iymphocyte-rich disseminated, inflammatory, interstitial lung disease the TCR V gene usage in PBL and BAL T cells was also analysed. We found a high frequency of T cell expansions, i.e. Iarge proportions of T cells with a certain TCR V gene usage in common. These were found primarily in the lung. Interestingly, in most cases they correlated well with clinical activity. The HLA class II type was determined (PCR-SSP) in sarcoidosis patients and correlated to clinical activity and disease outcome. The findings proved that Caucasians with the HLA-DR17(3) haplotype have a significantly increased risk to develop sarcoidosis. The vast majority of the HLA-DR17(3)+ patients recovered completely within two years. We also found a positive association between DR15(2) and DR14(6) and chronic disease The strong correlations between these alleles and the outcome of the disease, indicates that the mode of antigen presentation may be of vital importance in sarcoidosis. It is likely that a selective and temporal expression of adhesion molecules plays a crucial role in the recruitment of cells to the inflammatory site i.e. the lungs. We found increased expressions of ,B1-integrins on T cells in the lungs of sarcoidosis patients, accompanied by concomitantly elevated levels of VCAM-1 and fibronectin. These results in conjunction with observed differences between sarcoidosis patients and controls regarding the concentrations of selectins, offer some explanations as to how the cell-rich Iymphocytic alveolitis in sarcoidosis may occur. Key words: Adhesion molecules, alveolitis, bronchoalveolar lavage, bronchial hyperreactivity, extracellular matrix molecules, extrinsic allergic alveolitis, fibrosis, HLA-DR, sarcoidosis, TCR ISBN 91-628-2475-9