Activation of human eosinophils by exogenous danger signals

Sammanfattning: Eosinophilic granulocytes are leukocytes that reside in the gastrointestinal and respiratory tracts. Their function in health is unknown. They are involved in variety of diseases with no clear common denominator: allergic disorders, parasitic and other microbial infections, autoimmune maladies, malignancies, toxic reactions and inflammatory bowel disease. In sickness, eosinophils upregulate adhesion molecules, migrate into afflicted tissues, release substances stored in their granules and produce oxygen radicals. The aim of this thesis was to identify compounds perceived by eosinophils to be exogenous danger signals. More precisely, the reactivity of eosinophils from healthy human beings to substances derived from allergen extracts and bacteria was studied.Eosinophils selectively recognized and became activated by bacteria belonging to different taxonomic groups. There was a hierarchy among the 11 bacterial species tested regarding their capacity to activate eosinophils. Furthermore, several eosinophilic activation patterns were evoked by the different species. The strongest eosinophil activator was E. coli, which elicited chemotaxis, degranulation and generation of free oxygen radicals. Low numbers of bacteria sufficed to cause the release of the granule proteins major basic protein (MBP) and eosinophil peroxidase (EPO), whereas high numbers were required for the release of eosinophil cationic protein (ECP). Eosinophils did not seem to discriminate between grampositive and gramnegative bacteria, unlike monocytes. High concentrations of lipopolysaccharide and serum were needed for eosinophils to respond to this danger signal of gramnegative bacteria.Eosinophils also released oxygen radicals and migrated toward a putative danger signal, the D-methionine-containing hexapeptide WKYMVm. This peptide engaged different members of the formyl peptide receptor family on eosinophils (formyl peptide receptor, FPR) and neutrophils (formyl peptide receptor-like 1, FPRL-1).An important finding was that common aeroallergens derived from birch, cat dander, grass and house dust mite (HDM), were able to directly mobilize and activate eosinophils from non-allergic individuals. Moreover, the capacity to migrate toward allergen extracts was a trait inherent to eosinophils, not shared by neutrophils and monocytes. The allergen extract-mediated activation of eosinophils gave rise to chemotaxis, mobilization of the adhesion molecule complement receptor 3 (CR3) and the release of EPO and MBP, but not ECP. No respiratory burst was generated in eosinophils exposed to allergens. The eosinophilic migration and activation induced by HDM and birch allergen extracts seemed to occur via the FPR, as was the case for bacterially induced eosinophil activation.To conclude, we have demonstrated that certain bacterial species and allergens contain as yet unidentified substances which constitute potent exogenous danger signals to eosinophils. These compounds activate eosinophils via the FPR. Our findings may help explain the pathophysiological mechanisms behind the various disease entities eosinophils are involved in.