This project is aimed at exploiting fundamental knowledge on the signal transduction machinery that exists in lymphocytes for a better understanding of autoimmune disease. The molecular work by Prof. Beyaert has led to the functional characterization of a signaling molecule (CYLD) that acts downstream of the antigen receptor expressed by lymphocytes, a critical cell type of our immune system. Under normal conditions, CYLD acts as a repressor of inflammatory responses.
After initiation of immune responses, however, lymphocytes become activated and the CYLD
molecule is cleaved which results in a loss of its repressor function. The logical next step now is to investigate how this mechanism translates to the immune system’s functionality in living organisms.
The same lymphocytes are key mediators in most forms of autoimmunity, including rheumatoid
arthritis and type 1 diabetes. Although it is unknown what causes these diseases, it has become clear that the lymphocytes somehow become chronically activated and start attacking the body’s own cells. We therefore wish to investigate the role of CYLD cleavage in animal models of autoimmunity to assess whether aberrations in this pathway contribute to disease. This will be achieved by the generation of a transgenic mouse strain in which CYLD cleavage is impossible.
Finally, samples from patients suffering from autoimmunity will be analyzed for defects in
CYLD cleavage in order to evaluate the process’ clinical relevance.