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[The clonality and activation of T-cells in sarcoidosis]
Current concepts of the pathogenesis of sarcoidosis suggest that the expanded numbers of activated T-helper/inducer cells at sites of disease activity result, at least in part, from their proliferation in the local milieu. Normal clonal proliferation of T-cells involves activation and expression of the interleukin-2 receptor (IL-2R) gene; transcription products of which (IL-2R mRNA) are relatively long-lived. We have therefore investigated the hypothesis that sarcoid lung and blood T-cells may contain IL-2R mRNA transcripts and express functional surface IL-2R, because they are activated elsewhere. Northern analysis using a 32P-labeled cDNA probe for the IL-2R alpha chain demonstrated that blood T-cells from patients with active sarcoidosis, but not from normal subjects express 3.5 kb and 1.5 kb IL-2R mRNA transcripts, identical to the observation when normal T-cells are activated in vitro. Consistent with this, using flow cytometry and a monoclonal antibody directed against the IL-2R alpha-chain protein (2A3), significant levels of IL-2R protein were observed on the surface of blood T-cells from active sarcoidosis patients but rarely on blood T-cells of normals. Importantly, when the sarcoid blood T-cells were exposed to IL-2 in vitro, they proliferated at a rate greater than did normal blood T-cells under the same conditions, suggesting that the IL-2R spontaneously expressed by sarcoid blood T-cells were functionally active. When placed in the context of the known compartmentalization of spontaneously interleukin-2 production and T-cell proliferation at sites of disease in active pulmonary sarcoidosis, it is likely that these IL-2R positive blood T-cells would have a proliferative advantage if they travel to sites of active sarcoidosis such as the lower respiratory tract.
Current concepts of the pathogenesis of sarcoidosis suggest that the expanded numbers of activated T-helper/inducer cells at sites of disease activity result, at least in part, from their proliferation in the local milieu. Normal clonal proliferation of T-cells involves activation and expression of the interleukin-2 receptor (IL-2R) gene; transcription products of which (IL-2R mRNA) are relatively long-lived. We have therefore investigated the hypothesis that sarcoid lung and blood T-cells may contain IL-2R mRNA transcripts and express functional surface IL-2R, because they are activated elsewhere. Northern analysis using a 32P-labeled cDNA probe for the IL-2R alpha chain demonstrated that blood T-cells from patients with active sarcoidosis, but not from normal subjects express 3.5 kb and 1.5 kb IL-2R mRNA transcripts, identical to the observation when normal T-cells are activated in vitro. Consistent with this, using flow cytometry and a monoclonal antibody directed against the IL-2R alpha-chain protein (2A3), significant levels of IL-2R protein were observed on the surface of blood T-cells from active sarcoidosis patients but rarely on blood T-cells of normals. Importantly, when the sarcoid blood T-cells were exposed to IL-2 in vitro, they proliferated at a rate greater than did normal blood T-cells under the same conditions, suggesting that the IL-2R spontaneously expressed by sarcoid blood T-cells were functionally active. When placed in the context of the known compartmentalization of spontaneously interleukin-2 production and T-cell proliferation at sites of disease in active pulmonary sarcoidosis, it is likely that these IL-2R positive blood T-cells would have a proliferative advantage if they travel to sites of active sarcoidosis such as the lower respiratory tract.