Molecular mechanisms of immunodeficiency A large number of immunodeficiency syndromes (IS) present clinical manifestations of autoimmunity. The decreased ability to clear infections may be responsible for causing autoimmunity through perpetual immune system activation. Health © Shutterstock A number of rare diseases are characterised by a heightened susceptibility to infections from childhood onward. These primary ISs are usually hereditary and are also known as congenital immunodeficiencies. The study of the ISs – familial haemophagocytic lymphohistiocytosis and Griscelli syndrome, revealed the crucial role of the members of protein families that regulate vesicle trafficking and membrane fusion. Loss-of-function mutations in these proteins rendered natural killer (NK) cells and CD8+ T cells unable to clear infection, resulting in a life-threatening sepsis-like condition. The precise functioning of these proteins in granule release remains incompletely understood. The goal of the EU-funded MOLMECHSNKTOX (Molecular mechanisms of natural killer cell cytotoxicity) project was to study presynaptic signalling cascades leading to NK cell exocytosis, and sub-cellular events leading to granule release. Investigators employed a cross-disciplinary approach in this study using cutting-edge skills in cell biology, immunology and proteomics. To date, only some causative genes of IS have been identified and a majority of clinical cases remain unexplained. The knowledge obtained in the current study significantly contributed to the understanding of the complex molecular mechanisms involved in NK cell lytic granule exocytosis. These findings facilitate the diagnosis and treatment of patients suffering from various IS. Keywords Immunodeficiency syndromes, autoimmunity, natural killer, MOLMECHSNKTOX, cell exocytosis
