Tumor necrosis factor Receptor-Associated Factors in signal transduction and susceptibility to infection.

Inborn errors of immunity consist of a heterogeneous group of disorders caused by an equally heterogeneous group of causative factors. TRAFs, or tumor necrosis factor receptor-associated factors, are signal-transducing proteins with an important part in a variety of biological functions, including the innate and adaptive immune system, embryonal development and tissue homeostasis. Mutations and functional changes in the TRAF proteins have been associated with autoimmune disorders, cancer and neurodegenerative diseases. An in silico prediction model has identified TRAF genes and mutations therein as possible inducers of immune deficiency. Furthermore, in UZ Leuven immune-deficient patients with TRAF mutations, but no other known PID gene mutation, have been identified. After further genetic characterization of immune-deficient patients, 12 mutations with a high likelihood of pathogenicity were selected for research. This doctoral research project aims to explore the connection between TRAF proteins, their mutations, and susceptibility to infection. The susceptibility to infection will be assessed by the functional evaluation of a selected set of TRAF variants in 1) immune-associated in vitro cell cultures and 2) in patient-derived cells. Additionally (3), the clinical history of patients with functional variants will be documented and family members will be genetically profiled in order to further characterize the mutations (pending informed consent of all relevant parties).