Mechanisms and Diagnosis of Mast Cell and Basophil Activation in Rare Hypersensitivity Disorders

Hypersensitivity is an exaggerated response of the immune system to harmless triggers. In Type I hypersensitivity or allergy, effector cells (mast cells and basophils) are activated through allergen-induced cross-linking of surface-bound allergen-specific IgE antibodies, leading to degranulation and systemic release of inflammatory mediators. This can result in a potentially life-threatening rapid-onset clinical syndrome affecting the mucocutaneous tissues, airways, gastro-intestinal and cardiovascular systems called anaphylaxis. In addition to IgE cross-linking, effector cells can also be activated through so-called pseudo-allergic pathways involving non-IgE-dependent mechanisms (e.g. complement, MRGPRX2, IgG receptors etc.). The apparent complexity and diversity of hypersensitivity reactions has resulted in an increasing focus on personalized medicine in allergology. Effector cell assays such as the basophil and mast cell activation test are versatile instruments that could aid allergists in this endeavour. In addition, these tests can help gain insights in the pathophysiology of (non)-IgE-mediated hypersensitivity reactions. The global objective of this PhD project is the exploration of the clinical and translational applications of effector cell assays (BAT and MAT) and other diagnostic tests and biomarkers in diagnosis, endotyping and prognostication of selected rare and/or unusual hypersensitivity disorders including 1) hypersensitivity reactions to COVID-19 vaccines and the ubiquitously used drug excipients polyethylene glycol (PEG) and polysorbate 80, and 2) severe hymenoptera venom allergy in patients with and without underlying genetic risk modifiers such as clonal mast cell disease and hereditary alpha-tryptasemia.