Dechipering the mechanism of immune dysfunction in Vici syndrome

Vici Syndrome is a complex disease characterized by congenital malformations of the brain, cataract, skin hypopigmentation, progressive damage of the heart and muscle function, and immune deficiency. Affected children do not respond to vaccination, have a low level of antibodies in the blood and suffer from frequent and severe infections. The disease is due to mutations in EPG5 gene, encoding a protein that regulates trafficking and function of vesicles within cells. Vesicles are used by the cell to eliminate its damaged components and dead cellular bodies. The cell isolates the unwanted material into a vesicle that is then fused to the lysosome, another type of vesicle containing proteins that destroy the captured cargo. This system is indispensable in embryogenesis and throughout life, thus explaining the complexity of the disease. As infections are frequent and life-threatening in patients, EPG5 may also be important for the immune system. We will investigate whether EPG5 plays a role in the mechanism(s) by which the immune system captures and degrades microorganisms and foreign particles and then use the digested remnants to trigger the immune response. We will use cell lines from patients and controls to study with fluorescent molecules the uptake and trafficking of vesicles and particles. In cells of the immune system the downstream events will be evaluated by measuring antibody and cytokine production and cellular activation. Several other rare diseases including metabolic disorders and multiorgan dysfunctions are due to mutation of genes involved in the formation, trafficking, fusion or release of vesicles inside the cell. Many of these diseases are associated to immune deficiency. Our study may represent a prototype deciphering the molecular mechanism of specific immune defects in a complex disease. Only after understanding all the aspects of a disease it is possible to develop adequate therapies able to eliminate at least part of the symptoms and risks of patients with genetic multi-systemic syndromes.