Patient-tailored approach for diagnostics and treatment of inborn errors of immunity

The thesis explores Inborn Errors of Immunity (IEIs), previously known as Primary Immunodeficiencies (PIDs), which are genetic disorders disrupting the immune system's development and function. Beyond infection susceptibility, IEIs encompass autoimmunity, autoinflammation, malignancy, and atopic conditions. The Goldilocks principle, emphasizing the importance of maintaining balance, is applied to immune signaling pathways, specifically in B cell differentiation and type I interferon (IFN) production.
Part I focuses on B cell differentiation and the NF-κB signaling pathways. TRAF3 mutations disrupt the non-canonical NF-κB pathway, leading to immune dysregulation. Therapeutic strategies, like daratumumab, show promise in restoring balance by reducing B cell activation. Standardized in vitro assays for B cell differentiation are developed, facilitating research and diagnosis.
Part II delves into the Goldilocks principle in type I IFN production and signaling during infection. Insufficient or excessive type I IFN leads to susceptibility or autoinflammation, respectively. A novel TICAM1 mutation impairs antiviral responses, highlighting the importance of specific signaling cascades. Type I interferonopathies, like Aicardi-Goutières syndrome (AGS), are explored, with JAK-inhibitors showing potential in restoring immune balance. Hematopoietic stem cell transplantation (HSCT) is considered for treatment-resistant interferonopathies.
Part III focuses on patient-tailored diagnostics and novel technologies, including Cytometry by Time-Of-Flight (CyTOF), revealing potential markers for diagnostic settings. The discussion emphasizes the Goldilocks principle's role in immune homeostasis and the potential of targeted therapeutic interventions to manage immunological disorders effectively. Overall, the thesis underscores the intricate balance required for immune system functioning and the implications of disruptions in IEIs.