Targeting Key Factors Involved in Immune Reactions mediated by Tick Bites to the Carbohydrate alpha-Gal

点击翻译按钮获取中文摘要

Delayed anaphylaxis to red meat is dependent on the presence of IgE-antibodies to galactose-alpha-1,3-galactose (Alpha-Gal). Clinical symptoms are triggered by contact to red meat or innards but also gelatin or Alpha-Gal carrying therapeutic antibodies. Recently we could identify the Alpha-Gal carrying proteins Aminopeptidase N and Angiotensin converting enzyme I from pork kidney and show their clinical relevance by inducing basophil activation and positive responses in skin prick tests in patients with Alpha-Gal allergy. In contrast to IgG antibodies directed to Alpha-Gal, which are physiologically induced by contact to microbes in early life, the currently accepted hypothesis is that the induction of IgE directed to Alpha-Gal is mediated by tick bites. This is supported by several lines of evidence: a strong correlation between Alpha-Gal allergy and tick bites from Amblyomma, Ixodes and Haemaphysalis species in different parts of the world, a boosting of IgE directed against Alpha-Gal after a tick bite and the detection of Alpha-Gal in the gastrointestinal tract of Ixodes ricinus. The objectives of the present proposal are i) analysing the allergenicity of Alpha-gal carrying natural and engineered molecules, ii) the phenotyping of cells implicated in immune responses to Alpha-gal epitopes in healthy, sensitized and recently exposed individuals, iii) the analysis of the sensitizing mechanism in an alpha-1,3-galactosyltransferase deficient mouse by inducing immune reactions to Alpha-gal. To this end, different routes of antigen contact via the skin, mimicking a tick bite, will be investigated with and without addition of tick saliva as natural adjuvant. The identification of IgE reactive molecules in ticks will contribute to a better diagnosis and risk management of patients. More important, using Alpha-Gal allergy as a model disease, our results will elucidate the basic mechanisms eliciting immune responses and sensitization to carbohydrate allergens via the skin.