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In a new study published in the journal Science Immunology, Sylvain Latour and his team from the "Lymphocyte Activation and Susceptibility to Epstein-Barr Virus" laboratory at the Imagine Institute, in collaboration with doctors and researchers from the National Institutes of Health (NIH) in the United States, have discovered a new mutation in the IKAROS gene [1]. This gene - whose name is a reference to Icarus, son of Daedalus - is involved in the development of lymphocytes (guardians of our immunity), in the proliferation and differentiation of blood cells, and also plays a tumour suppressor role. In other words, it inhibits cell proliferation.
This gene was already known to researchers to have dominant-negative and loss-of-function mutations, leading to immune deficiencies in B cells associated with the development of B lymphoma (in the case of loss-of-function mutations), but also to combined immunodeficiencies affecting B cells, T cells and myeloid cells.
The symptoms and mechanisms altered by this new mutation are quite distinct from those seen in the other two types of mutations
In this new publication, the researchers carried out a complete genome sequencing of 8 undiagnosed patients with a set of symptoms typical of immune dysregulation, including inflammation, autoimmunity and allergic reactions. "We were thus able to describe for the first time a gain-of-function mutation of the IKAROS gene," explains Sylvain Latour, the last author of the publication.
The researchers also showed that this new mutation leads to a deregulation of several important players in the immune response : type 1 and type 2 T helper lymphocytes (Th1 & Th2), whose Th2 activity is increased, a low number of regulatory T lymphocytes, as well as an abnormal proliferation of antibody-secreting B lymphocytes. "The symptoms and mechanisms altered by this new mutation are quite distinct from those observed for the other two types of mutations. This tells us that we are dealing with a new disease" emphasises Sylvain Latour. The identification of new genetic mutations is crucial, not only to improve the understanding of the mechanisms of these rare diseases, but also to diagnose patients who do not yet have a name for their disease.