Activin-A: a novel critical regulator of allergic asthma.

Activin-A is a pleiotropic cytokine that belongs to the TGF-ß superfamily and plays an important role in fundamental biological processes, such as development and tissue repair. Growing evidence proposes a crucial role for activin-A in immune-mediated responses and associated diseases, with both enhancing and suppressive effects depending on the cell type, the cytokine micromilieu and the context of the response. Several recent studies have demonstrated a striking increase in activin-A expression in experimental models of asthma, as well as, in the asthmatic airway in humans. Importantly, a strong immunoregulatory role for activin-A in allergic airway disease, with suppression of T helper (Th) type 2 cell-driven allergic responses and protection against the development of cardinal features of the asthmatic phenotype was revealed by in vivo functional studies. Activin-A-mediated immunosuppression is associated with induction of functional allergen-specific regulatory T cells. In human asthma, although activin-A levels are increased in the airway epithelium and submucosal cells, the expression of its signalling components is markedly decreased, pointing to decreased regulation. Nevertheless, a rapid activation of the activin-A signalling pathway is observed in the airway of individuals with asthma following inhalational allergen challenge, suggestive of an inherent protective mechanism to control disease. In support, in vitro studies using human airway epithelial cells have demonstrated that endogenous activin-A suppresses the release of inflammatory mediators, while it induces epithelial repair. Collectively, compelling evidence suggests that activin-A orchestrates the regulation of key events involved in the pathogenesis of allergic asthma. The critical role of activin-A in allergic airway responses places this cytokine as an exciting new therapeutic target for asthma.

Osteopontin expression and relation to disease severity in human asthma.

Recent studies have associated osteopontin (OPN) with allergic inflammation; however, its role in human asthma remains unclear. The aim of this study was to measure OPN levels in the serum, bronchoalveolar lavage fluid (BALF) and bronchial tissue of healthy controls and asthmatics, identify cellular sources of OPN and examine possible correlations between OPN expression, disease severity and airway remodelling. Serum samples were obtained from 35 mild-to-moderate asthmatics, 19 severe asthmatics and 17 healthy controls in the steady state and in cases of exacerbation. Of these subjects, 29 asthmatics and nine controls underwent bronchoscopy with endobronchial biopsy and BALF collection. OPN expression was determined by ELISA and immunohistochemistry/immunofluorescence. Reticular basement membrane thickness and goblet cell hyperplasia were also determined. Serum and BALF OPN levels were significantly increased in all asthmatics in the steady state, whereas serum levels decreased during exacerbations. OPN was upregulated in the bronchial tissue of all patients, and expressed by epithelial, airway and vascular smooth muscle cells, myofibroblasts, T-lymphocytes and mast cells. OPN expression correlated with reticular basement membrane thickness and was more prominent in subepithelial inflammatory cells in severe compared to mild-to-moderate asthma. OPN expression is upregulated in human asthma and associated with remodelling changes, and its subepithelial expression correlates with disease severity.

Characterization of CD25-positive T cells during syngeneic pregnancy: production of stimulatory class II MHC molecules.

Various studies demonstrate that immunosuppression vis-à-vis paternal alloantigens may play a role for successful pregnancy. However, if this theory is true, the question that remains unanswered is how do syngeneic pregnancies manage to produce viable embryos. In allogeneic murine pregnancies immunosuppression is mediated by regulatory CD25(+)/Foxp3/CTLA-4 T cells. In order to evaluate whether these cells also play a role in syngeneic pregnancies, CD25(+)CD4(+) and CD25(+)CD8(+) were isolated from spleens of pregnant mice and examined as to the expression of specific suppressive and stimulatory markers, cytokine and soluble MHC class II antigen production. Interestingly, the CD25(+) cells and their products displayed an MHC-restricted stimulatory activity on total spleen cell proliferation assays. Although the CD25(+)CD4(+) and CD25(+)CD8(+) cells expressed Foxp3, they lacked CTLA-4, while expressing CD28. Non-specific proliferative effect was shown to be mediated by IL-3 and IL-4. The MHC-restricted proliferative effect; however, could be attributed to IA(d) molecules, which were detected in all culture supernatants of the T cell subpopulations tested and their elimination ablated the observed stimulatory activity. The detection of Ea, Eb1, Eb2 in addition to the Aa and Ab transcripts in these cells indicated the possible involvement of other class II gene combinations in this type of regulation. The results indicate that in the absence of paternal MHC alloantigens, maternal CD25(+) cells are involved in the development of immunostimulation to ensure foetal survival.