The immune system is crucial for defense against external pathogens and a fine tuned balance of its functions is necessary for immune homeostasis. Inborn errors of the immune system result in primary immunodeficiency disorders (PIDs), characterized by a predisposition to infections, malignancies and autoimmune manifestations. Increasing identification and therefore prevalence of PIDs have encouraged intense investigation in this field in the past decades. With the help of modern genetic techniques, the study and molecular characterization of numerous PIDs have substantially contributed to recognition and understanding of important players in the immune system. The work presented here was carried out with the purpose of recognizing critical genes in the immune system by investigating the underlying genetic mutations in PID patients with recurrent infections and immune dysregulation. Additionally the significance of the specific findings in immune response and regulation was functionally assessed.
Three manuscripts describing one previously unknown mutation and two novel genes causing PID in humans resulted from the work accomplished during the course of this PhD. In the first manuscript we demonstrated the importance of the C345C domain of complement factor 3 (C3) in human immune response to encapsulated bacteria by discovering a previously unknown mutation within this domain (c. C4554G, p. Cys1518Trp) in a patient suffering from severe pneumococcal infections. The second publication discloses a novel PID marked by a CVID-like B-cell deficiency and severe autoimmunity as a result of mutation in the protein kinase C delta (PRKCD) gene encoding PKCδ (c.13521+1G>A). As a result, our study establishes direct implication of PKCδ in B-cell homeostasis and immune regulation in humans. The third paper of this thesis covers the detection of a hitherto unidentified disorder caused by homozygous mutation of the MAP3K14 gene encoding NF-κB-inducing kinase (NIK) (c. C1694G, p. Pro565Arg) in patients affected by a pervasive combined immunodeficiency. This finding determines non-redundant functions for NIK in human lymphoid immunity.
Collectively, the investigations within this thesis reveal previously unknown pivotal roles for the implicated domains/molecules in immunity against foreign antigens, immune homeostasis and tolerance in humans, and therefore contribute to a broader comprehension of the genetic mechanisms involved in pathogenesis of PIDs with susceptibility to immune dysregulation.