PhD defence J. (Jill) de Wit

Recent identification of many novel causative genes has broadened the spectrum of clinical features associated with primary immunodeficiency diseases (PIDs). Patients with a PID and noninfectious complications are increasingly recognized with features of immune dysregulation, including autoimmunity, autoinflammation, lymphoproliferation and malignancy. Therefore, we suggest to consider PIDs as immune dysregulation syndromes rather than immune deficiency syndromes. Depending on the pathways, genetic variants and number and functionality of immune cells involved, the clinical picture could be dominated by a higher susceptibility to infections or an increased risk of autoimmune or autoinflammatory manifestations. In this thesis immune dysregulation is therefore visualized as a spectrum with infections on one end and autoimmunity on the other end. Patients with PIDs typically show various symptoms within this spectrum, but predominance of specific manifestations can be PID specific. Moreover, results of our studies support the hypothesis that immune dysregulation also plays a role in the multifactorial pathogenesis of skin disorders and atopy. In both atopic dermatitis and other atopic diseases, patients can be characterized by having either a predominant infectious phenotype or an autoimmune phenotype. As immune dysregulation may result in a diversity of clinical manifestations within the same patient, a model that assumes overlap between immune dysregulation disorders (PID, skin disorders and atopy) is proposed in this thesis. Our assumption emphasizes that more attention should be paid to the concurrent presence of various symptoms related to immune dysregulation in clinical care. For example, in order to further consider (specific) skin disorders as a potential warning sign for an underlying PID. In addition, gene-targeted and/or pathway-targeted treatment strategies registered for specific immune dysregulation disorders could be effective in other diseases with clinically overlapping symptoms in which immune dysregulation is involved.

Due to corona, the PhD defences do not take place publicly in the usual way in the Senate Hall or in the Professor Andries Querido Room. The candidates will defend their dissertation either in a small group or online.