Signals for regulatory B cell activation in helminth infection and their application in experimental allergic asthma therapy
Zusammenfassung der Projektergebnisse
The prevalence of allergic diseases is on the rise in westernized countries. Field studies have shown an inverse correlation between chronic infections with the parasitic helminth Schistosoma spp and allergic diseases. We showed earlier that infection with S. mansoni induces the development of regulatory B cells (Breg cells) in mice and men, which suppressed allergic airway inflammation in a mouse model by release of interleukin-10. However, the exact mechanisms that promote the development of protective Breg cells are still ill-defined. The aim of the project was to define the optimal conditions that induce Breg cells, in order to be able to artificially boost their activity as a novel therapy against allergic diseases by employing helminth antigens. Possible mechanisms of Breg cell induction include direct interaction of B cells with antigens, as known for bacterial ligands, and activation of B cells by interaction with other cell types. Our results show that schistosomal egg antigens, among which the molecule IPSE, potently induce Breg cell development in vivo and in vitro, without the context of natural infection. Surprisingly, schistosome antigens were found to directly interact with murine B cells, as B cells bound and internalized antigen, and upregulated the expression of IL-10 and surface activation markers. The major murine Breg cell population was found in the marginal zone B cell subset of the spleen. While marginal zone macrophages, which are known to interact with marginal zone B cells in manifold ways, also highly bound SEA, these cells were not required for marginal zone Breg cell development as was shown by specific cell depletion. In contrast, CD40 ligation of B cells synergistically enhanced Breg cell development in vitro, and was essential for Breg cell development in vivo. Of note, also human B cells bound IPSE and expressed IL-10 upon CD40 co-ligation. In order to identify receptors and pathways in B cells involved in Breg cell development, schistosome antigens were tested on B cells from specific gene-deficient mice. A reduction of interleukin-10 expression in Myd88-deficient cells indicated the involvement of a new toll-like receptor (TLR) ligand, whereas TLR2, TLR4 and TRIF-signaling were not involved. Importantly, schistosomal antigen-induced Breg cells triggered development of regulatory T cells, which makes them dual potent regulators of immunity. To the best of our knowledge, this is the first report to describe a direct interaction of B cells and helminth antigens which leads to Breg cell development. The identified Breg-inducing antigens and co-signals can be used to develop a new therapy of allergic diseases, such as allergic airway inflammation, by boosting Breg cell activity.
Projektbezogene Publikationen (Auswahl)
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2014. Toll-like receptor ligation for the induction of regulatory B cells. Methods Mol Biol. 1190:127-41
van der Vlugt LE, Haeberlein S, de Graaf W, Martha TE, Smits HH
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2015. Chronic helminth infection and helminth-derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice. FASEB J., Vol. 29, No. 7, July 2015, 3027-3039
Hussaarts L, García-Tardón N, van Beek L, Heemskerk MM, Haeberlein S, van der Zon GC, Ozir-Fazalalikhan A, Berbée JF, Willems van Dijk K, van Harmelen V, Yazdanbakhsh M, Guigas B
