Abstract

Research in immunology has been a rapidly evolving field in recent years, largely facilitated by the advent of next-generation sequencing techniques. The opportunity to study the entire coding sequence of the genome has resulted in the discovery of more than 400 well-characterized, monogenic inborn errors of immunity. Research on these rare patients, who mostly present early in life to pediatric hospitals, has informed our understanding of human immunity since it allows to study the function of a mutated gene product in the context of human disease. Whilst the power of the immune system has evolved to fight infection, fine-tuned regulatory mechanisms gained importance. Keeping the balance between tolerance and protection involves close communication between immune cells and their environment. Such interactions are often mediated by soluble factors, i.e. cytokines. The work presented in this thesis is centered around two important signalling pathways: Interleukin-2 signalling has long been recognized pivotal for T cell immunity. The discovery of homozygous loss-of-function variants in IL2RB underscores its non-redundant role in preventing autoimmunity by promoting regulatory T cell survival and function. Additionally, a terminal differentiation defect of cytotoxic lymphocytes renders affected patients specifically susceptible to Cytomegalo-virus disease. Additional work on patients with loss- and gain-of-functions in the downstream signalling molecule STAT5B expands the phenotypic spectrum and explores potential treatment op-tions using Janus tyrosine kinase inhibitors. The second pathway under study is type I interferon signalling. Functional validation of a new biallelic IFNAR1 variant abrogating responses to type I interferon was undertaken in an individual presenting with haemophagocytic lymphohistiocytosis following receipt of live-viral vaccine. Lethal autoinflammation was also seen in patients where homozygous STAT2 variants were found to hamper negative feedback regulation and thus causing unrestrained type I interferon activity. Mechanistic studies on the inflammatory consequences of dysregulated type I interferon responses in STAT2- and IRF9-deficient primary cells and induced pluripotent stem cell derived macrophages offer a molecular explanation for the clinically observed inflammation in these individuals. By dissecting the molecular mechanisms underlying immune dysregulation in these rare patients with monogenic errors of immunity I am hoping to contribute to improved diagnostic rates and to help pave the way for personalized treatment options in these ‘orphan’ diseases.