[Pathophysiology of asthma: data concerning regulation of IGE and Th2 responses in the lung]

Asthma is one of the most common chronic diseases, affecting 5-10% of the population worldwide. It is closely associated with the "atopic" hypersensitivity to environmental antigens ('allergens'), which is mediated by specific IgE driven by a T helper 2-type immune response, also promoting recruitment of eosinophils and mast cells and mucus overproduction. Our first research axis showed that allergen immunotherapy in patients with allergic rhinitis and asthma to grass pollen induces inhibition of the IL-9/ mast cells axis and a selective induction of allergen-specific IgA2 antibodies in serum, which correlated to nasal tissue expression of TGF-beta. We further showed that these IgA antibodies, whilst unable to inhibit IgE-facilitated allergen presentation by B cells as achieved by IgG4 antibodies, could trigger IL-10 expression in monocytes and dendritic cells through activation of p38 MAP-kinase and recruitment of sp1 and NFkappaB transcription factors. In addition, results in a murine model of asthma suggested a protective role of secretory IgA. A second research axis, exploring local immune responses to lung allergen exposure, identified the CCR4 pathway as critically mediating the recruitment of Th2 cells into the lung of atopic asthmatics. In patients with non-atopic (intrinsic) asthma, we recently reported on the local production of specific IgE to mite allergens (Der p), able to activate basophils in vitro, while lung challenge to Der p in vivo did not result into asthmatic responses. Altogether, we showed (1) that allergen immunotherapy triggers production of IgA2, which could be protective through induction of IL-10 in monocytes/dendritic cells and/ or by scavenging allergens within secretions, and (2) that allergen exposure, which triggers the recruitment of Th2 cells through the CCR4 pathway, induces locally the production of specific IgE, irrespectively of systemic atopic features, supporting the concept according which "second signals" condition in vivo the inception and exacerbations of asthma.