Th1 cytokine pattern in sarcoidosis is expressed by bronchoalveolar CD4+ and CD8+ T cells

Abstract

SUMMARYThe pathogenesis of pulmonary sarcoidosis has been related to an increased production of Th1-like cytokines. However, cytokine expression in sarcoidosis has not been systematically studied at a singlecell level. We therefore investigated the expression of IL-2, IL-4, IL-13, tumour necrosis factor-alpha (TNF-a ) and interferon-gamma (IFN-g) intracellularly in bronchoalveolar lavage (BAL) and peripheral blood CD31 T lymphocytes from patients with pulmonary sarcoidosis (radiologic stage II±III, n 8) and normal controls (n 9) by flow cytometry. In contrast to IL-4 and IL-13, the percentage of T lymphocytes expressing intracellular IL-2 (49´3^21´3% versus 14´5^15´6%), IFN-g (75´5^14´9% versus 32´6^18´7%) and TNF-a (68´3^18´7% versus 36´8^20´8%) was significantly higher in patients with sarcoidosis than in normal controls (each P , 0´005). In contrast to BAL lymphocytes, expression of these cytokines in peripheral blood lymphocytes did not differ between patients with sarcoidosis and normal controls. Close correlations were observed between the percentages of BAL lymphocytes expressing intracellular IL-2, IFN-g and TNF-a , but not for IL-4 or IL-13. Analysis of the expression of these cytokines in T lymphocyte subsets revealed IL-2, IFN-g, and TNF-a in CD41 as well as CD8 1 T lymphocytes, suggesting a contribution of TC1 cells to the production of proinflammatory cytokines in sarcoidosis. We conclude that a Th1-like cytokine pattern can be observed in CD41 as well as in CD8 1 BAL T lymphocytes in patients with pulmonary sarcoidosis.

Alveolar macrophages are the main source for tumour necrosis factor‐α in patients with sarcoidosis

“…The pattern of T-cell cytokine production is indicative of sarcoidosis being a T-helper cell-1-mediated disease [12,32]. Although no significant T-cell immunoreactivity for TNF-a was observed, a recent study reported that increased fractions of T-cells, which intracellularly expressed TNF-a, were observed by fluorescence activated cell sorting (FACS) in BAL but not in peripheral blood of sarcoidosis patients compared with control subjects [11]. On the contrary, another study using FACS failed to detect any significant difference between sarcoidosis patients and healthy controls in the frequency of T-cells that intracellularly expressed TNF-a [13].…”

“…The spontaneous release of TNF-a [8], interleukin (IL)-1 [9], and IL-2 [10] by activated macrophages and T-cells is considered pivotal to the formation of immune granulomas. Activated T-cells may also contribute to the release of pro-inflammatory cytokines like TNF-a into the BAL fluid [11][12][13]. In addition, pulmonary epithelial cells, which are able to act as accessory cells in T-cell activation, and in immunoregulation cells of the lung [14] may also release TNF-a under certain conditions [15][16][17].…”

Induction of Macrophage Insulin-Like Growth Factor-I Expression by the Th2 Cytokines IL-4 and IL-13

“…Animal model studies of interstitial fibrosis using bleomycin, silica, and thoracic irradiation support these conclusions (16 -18). In contrast, expression of the Th1 cytokine, IFN-␥, has been found to be reduced or absent in IPF yet is prominent in granulomatous lung disorders such as sarcoid (13,19,20). These findings are consistent with previous observations that IFN-␥ 1) inhibits IGF-I production by macrophages (21), 2) inhibits collagen synthesis by fibroblasts (22), 3) is efficacious in ameliorating pulmonary fibrosis in the bleomycin model in mice (23), and 4) modestly improves pulmonary function and survival in IPF patients (24).…”

Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice

“…CD4+ T-lymphocytes are divided into two subgroups, T helper (Th)1 and Th2 cells, on the basis of cytokine production [5]. Based on the Th1/ Th2 paradigm, sarcoidosis is considered a typical Th1-dominant disease, since T-lymphocytes in bronchoalveolar lavage fluid (BALF) and lymph nodes from patients with sarcoidosis predominantly produce interferon (IFN)-c, interleukin (IL)-2 and tumour necrosis factor (TNF)-a or -b [6][7][8]. We and others have reported that levels of Th1 chemokines, including CXCL9/IFN-c (Mig), CXCL10/interferon-c-inducible protein-10 (IP-10) and CXCL11/interferon-inducible T-cell a-chemoattractant (I-TAC), were elevated in BALF of patients with sarcoidosis [9][10][11][12][13].…”