Circulating Human Basophils and Dendritic Cell Subsets. Aspects of antigen recognition and presentation in type I allergic immune responses

Sammanfattning: Allergic diseases currently affect a third of the population in the industrialized parts of the world. Despite this, the cellular and molecular mechanisms involved in the induction and activation of allergic diseases are not fully clarified. Dendritic cells (DCs) link the innate and adaptive immunity and play vital roles in protective immunity against pathogens, as well as in inducing tolerance to self-antigens, by regulating T cell responses. In allergic reactions, a dysregulated immune response is mounted against harmless compounds, such as pollen. Basophils are mainly known as effector cells in allergic responses where they release e.g. histamine after allergen-recognition, but basophils are also thought to be involved in other human disorders such as parasite infections and organ rejection, and were recently proposed to act as allergen-presenting cells in mice. This thesis, based upon five original papers, describes the role of DCs and basophils in allergy and immune regulation and give insights into mechanisms underlying allergic responses. In Paper I, we demonstrate a potent ability of human CD1c+ DCs, in contrast to plasmacytoid DCs and basophils, to activate Th2 responses in vitro, upon grass pollen stimulation of cells from allergic individuals. By performing phenotypical profiling of multiple pattern recognition receptors (PRRs) on four DC subsets, as well as basophils, isolated from human peripheral blood from allergic and non-allergic individuals, we demonstrate discriminative PRR expression profiles of the DC subsets and basophils in Paper II and IV, respectively. In Paper III and IV, we describe how the cellular frequencies of DC subsets and basophils, as well as their expression levels of PRRs and Fc receptors, alter during the first year of allergen-specific immunotherapy (AIT), proposing a modified ability of DC subsets and basophils to interact with allergens. Furthermore, in Paper V, we designed and produced a hypoallergen and used the basophil activation test to confirm its hypoallergenicity. This hypoallergen could potentially be used in AIT, instead of allergen extracts, to decrease the risk of adverse systemic reactions. In conclusion, we have identified subset-specific characteristics within the DC population in both function and phenotype, implying subset-specific responsiveness when targeted for treatment of immunological disorders such as allergy. We further propose new ways in which basophils interact with their surroundings.

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