Published on 30.01.2023
Research Acceleration
There are nearly 500 genetic defects responsible for different inherited immune deficiencies. Among them, the combined immune deficiencies are characterized by an alteration of the two main foot soldiers of the immune system: the T lymphocytes (for killers) and the B lymphocytes, whose role is to produce the antibodies in charge of detecting and neutralizing pathogens. Children born with these diseases have a weakened immune system, which can lead to severe infections.
By conducting a genetic and molecular analysis on a cohort of 7 patients from 6 families around the world, an international consortium including the Human Lymphohematopoiesis Laboratory, directed by Isabelle André, has discovered and characterized a completely new type of mutation responsible for a combined immune deficiency. The results are published in the journal Science Immunology.
A defect in antibody production...
"In addition to their immune deficiency, the patients in our cohort had atypical agammaglobulinemia. Unlike classical agammaglobulinemia, characterized by an absence of both antibodies and B cells in the bloodstream, our patients had B cells. However, these remained blocked at a stage of differentiation that prevented them from producing antibodies," explains Sven Kracker, researcher and theme leader in the laboratory.
"This explains why the patients' immune system is not able to control infections by even benign pathogens," adds Romane Thouenon, PhD and first co-author of the publication.
... linked to a genetic mutation never observed before
The researchers were able to find the cause: a new type of mutation never observed before in the IRF4 gene, which codes for a protein involved in regulating the expression of key genes in the differentiation of immune cells, particularly B and T lymphocytes. This new mutation - known as multimorphic - does not fit into a classic classification. "When we talk about a mutation, it is often a loss of function (the protein is no longer functional) or a gain of function (the protein gains a new function), says Sven Kracker. Our work shows that there is a gain of function associated with a loss of function of the IRF4 protein.
Indeed, the mutation characterized by the researchers does not prevent IRF4 from binding to DNA but induces a modification of its activity, blocking the maturation of B lymphocytes and thus the production of antibodies. This discovery highlights a completely new type of mutation and sheds light on the molecular immunological mechanisms involved in these immune deficiencies.