Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia.

Abstract

Increasing evidence suggests an important role for cytokines in the regulation of eosinophilic inflammation. In the present study we investigated the distribution of leukocytes, lymphocyte subsets, their activation state, and the cytokine profile present in BAL fluid from patients with various lung diseases associated with eosinophilia. For this purpose, we analyzed the levels of IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, GM-CSF, TNF-alpha, and IFN-gamma, as well as soluble IL-2 and TNF receptors, in concentrated bronchoalveolar lavage (BAL) fluid obtained from clearly defined patients with allergic and nonallergic asthma, eosinophilic pneumonia, allergic bronchopulmonary aspergillosis (ABPA), hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis. BAL fluid from normal individuals and sarcoidosis patients was analyzed as noneosinophilic controls. BAL cytokine levels were compared with the cellular infiltrate and the activation state of CD4+ and CD8+ T cells as measured by the expression of IL-2 receptors (CD25), HLA-DR, and the very late activation antigen VLA-1. Beside the characteristic leukocyte infiltrate in the various lung diseases, all patients demonstrated significantly increased numbers of activated CD4 and CD8 T cells compared with normal individuals. The analysis of the cytokine profile present in BAL fluid revealed a T helper type 2 (Th2) cell cytokine pattern, with elevated IL-4 and IL-5 but normal levels of IL-2 or IFN-gamma in allergic asthma. ABPA patients demonstrated significantly increased levels of IL-4 and IL-5, with low but significantly elevated concentrations of IL-2 and IFN-gamma. In contrast, the analysis of the cytokine profile in sarcoidosis patients revealed a Th1 cell cytokine pattern characterized by increased concentrations of IL-2 and IFN-gamma but normal levels of IL-4 or IL-5. All other patient groups showed a cytokine pattern incompatible with a pure Th1 or Th2 cell response, because IL-5, IL-2, and IFN-gamma were found to be significantly increased. The BAL fluid analysis of the other, mainly non-T cell-derived cytokines and soluble receptors showed increased levels in all patients compared with normal individuals and may represent the ongoing inflammatory responses. In conclusion, whereas increased IL-4 levels were found only in diseases characterized by increased IgE production, IL-5 was elevated in all patients with increased numbers of eosinophils. The close correlation between IL-5 levels, number of eosinophils, and activated T cells further supports a role for IL-5 in causing tissue eosinophilia.

Enhanced IgE allergic response to Aspergillus fumigatus in CFTR−/− mice

“…Interestingly, mRNA gene expression analysis also demonstrated a higher IL-2 and IFN-gamma response in the CFTRÀ/À Af-sensitized mice. Moreover, BAL samples from CF patients with ABPA demonstrate usually a mixed inflammatory pattern composed of a more complex Th1/Th2 lymphocyte 34 This mixed Th1/ Th2 response is more evident in the CFTRÀ/À mice showing higher levels of IL-2 and IFN-gamma along with IL-4 and IL-13 cytokines mimicking what is seen in the clinical setting. In addition to the upregulation of Th1/Th2 cytokines, there was also a fourfold increase in the levels of the chemokine KC.…”

Fine mapping and single nucleotide polymorphism association results of candidate genes for asthma and related phenotypes

“…TNFα expression is increased in the sputum, bronchoalveolar fluid, and serum of asthmatic patients [Broide et al, 1992]. It is upregulated by lymphotoxin alpha (LTα), which also plays a role in the destruction of tumor cells and virally infected cells Walker et al, 1994]. The tested polymorphism, NcoI, is located in the 3′UTR of the gene in close vicinity to the coding region of LTA.…”

IL-5 and IL-5 receptor in asthma

“…Indeed, there a large similarities in the inflammatory cells that are present in asthma of diverse aetiology-extrinsic, intrinsic, and occupational (Bentley et al 1994). Moreover, several studies have now demonstrated increased levels of IL-5 mRNA and protein in the tissue and BAL fluid of intrinsic asthmatics, thereby supporting the role of this cytokine in both intrinsic as well as atopic asthma (Marini et al 1992, Walker et al 1994. These findings support a common T cell mediated basis for airway inflammation in both forms of asthma.…”

“…Although total serum IgE levels have been noted to be increased in the serum of patients with intrinsic asthma (Burrows et al 1989) this is not a uniform finding with high positive predictive value (Butcher et al 1980, Klink et al 1990). There is evidence that IL-5 but not IL-4 is increased in the BAL fluid from intrinsic asthmatics (Walker et al 1994), thus supporting the hypothesis that IL-5 and eosinophilia are key features in both forms of asthma and that differences in the type of cytokine synthesis may undermine the differences in immune pathology that exist between intrinsic and atopic asthma. However, more recent studies examining the expression of high-affinity IgE receptor (Humbert et al 1996a), and IL-5 and IL-4 mRNA and protein expression in bronchial biopsies from patients with atopic and non-atopic asthma found no difference between atopic and intrinsic asthmatics (Humbert et al 1996b).…”

“…Other allergic pulmonary and non-pulmonary allergic diseases -There is a strong association between IL-5 and eosinophilia in a number of allergic human diseases, including parasitic infections (Coffman et al 1989, Limaye et al 1993, Hagan et al 1996, atopic dermatitis (Frew & Kay 1988, Hamid et al 1994, eosinopilic myocarditis (Desreumaux et al 1993), hypereosinopilic syndrome (Schrezenmeier et al 1993, Satoh et al 1994) eosinophilic gastroenteritis (Quan et al 1993, Dubucquoi et al 1995, allergic rhinitis , chronic eosinophilic pneumonia and other eosinophilic lung diseases (Walker et al 1994) (Fig. 1).…”