Interleukin-2 Receptor Gene Expression by Bronchoalveolar Lavage Lymphocytes in Pulmonary Sarcoidosis

Abstract

Current concepts of the immunopathogenesis of sarcoidosis favor a central role of activated, interleukin-2 (IL-2) producing helper T-cells at sites of inflammation. Normally, activated T-cells release IL-2 and express IL-2 receptors (IL-2R). IL-2R+ cells, however, are not uniformly found in patients with clinically active disease. To determine whether the lack of IL-2R+ cells is caused by a dysregulation of the IL-2R gene or by the mode of T-cell activation in pulmonary sarcoidosis, we quantified IL-2 and IL-2R m-RNA transcripts, IL-2 release, and IL-2R surface protein in peripheral blood lymphocytes of patients with sarcoidosis and normal control subjects before and after in vitro stimulation as a function of time. Additionally, we determined the percentage of IL-2R+ bronchoalveolar lavage (BAL) and peripheral blood lymphocytes in our study population and evaluated the in vivo transcriptional activity of the IL-2R gene. In peripheral blood lymphocytes, maximal IL-2R mRNA accumulation is found between 6 and 24 h, and maximal accumulation of IL-2 mRNA is found between 24 and 48 h. No differences emerged between normal subjects and patients with sarcoidosis. In six of 19 patients, we observed elevated numbers of IL-2R+ BAL lymphocytes and found IL-2R mRNA in those cells. These results are in accordance with the concept of a compartmentalized T-cell activation in sarcoidosis, resulting in IL-2 and IL-2R positive BAL cells and quiescent peripheral blood lymphocytes.

Sarcoidosis: immunopathogenetic concepts and their clinical application

“…In spite of the systemic nature of the disease only the alveolar T-cells and not those of the peripheral blood spontaneously secreted IL-2. Interestingly, the regulation of the transcription of the IL-2 gene appeared to be normal, indicating a stimulation of the cells in a physiological fashion [88,137]. This view is supported by the finding of DU BOIS et al [138], who demonstrated a capping of the TCR of alveolar Tcells in sarcoidosis, suggesting a recent activation of the cells via this complex.…”

“…In some cases of sarcoidosis >50% of T-cells with a CD4/CD8 ratio >10 which exhibit markers of activation, such as increased HLA-DR, very late activation antigen-1 (VLA-1), and IL-2 receptor expression and capping of the T-cell antigen receptor (TCR), can be observed [4,[135][136][137][138]. The Tcells of the granuloma exhibit a layer-like distribution, with CD4+ cells expressing an abundance of activation markers predominantly in the inner area and an accumulation of CD8+ cells with smaller numbers of those markers in the outer area [139,140].…”

“…Only a moderate increase in IL-2R+ T-cells, with only a few cells going through the S-phase of the cell cycle, was observed [88,137,145], suggesting the presence of a small number of activated cells in the alveolar space or a dysregulation in the expression of the IL-2R. Results obtained by an in vitro study with sarcoid T-cells excluded the latter possibility [137]. However, the milieu of the lower respiratory tract generated by type II epithelial cells modulates the reactivity of the T-cells.…”

Lung Lymphocytes Proliferate Minimally in the Murine Pulmonary Immune Response to Intratracheal Sheep Erythrocytes

“…We now conclude that most lung lymphocytes are in fact probably very recently reactivated cells, as CD69 expression peaks at 18-24 hours and decays with a half-life of 24 hours (28) , and CD25 surface expression persists for only a few days after lymphocyte activation in vitro (29) . Significant expression of CD25 by lung lymphocytes is a feature of several human immunologic lung diseases (30)(31)(32) . Because the vast majority of lymphocytes at any site of inflammation are not specific for the inciting antigens, it is unlikely that the high percentage of CD25+ cells results from lymphocyte activation within lung parenchyma.…”

Inhibitor kappa B-alpha (IκB-α) promoter polymorphisms in UK and Dutch sarcoidosis

“…8,9 Bronchoalveolar lavage (BAL) studies have disclosed prominent activation of alveolar macrophages and T cells, with a predominant Th1 cytokine profile. 10,11 The inflammatory response is characterized by increased production of proinflammatory cytokines, including interleukin (IL)-2, interferon (IFN-g), tumour necrosis factor (TNF)-a, interleukin IL1b, interleukin (IL)-6, and chemokines that amplify the inflammatory process and recruit monocytes from the periphery. [12][13][14][15][16][17] Cytokine gene expression is regulated via several mechanisms.…”