Identification of a new mutation affecting the IRF4 gene associated with a primary immunodeficiency

By identifying a new variant of IRF4 (Interferon Regulatory Factor 4) in a multigenerational family in which several members suffered from an immunodeficiency associated with a defect in the production of antibodies, researchers from the "Human Lymphohematopoiesis Laboratory" team at Institut Imagine (INSERM, AP-HP, Université Paris Cité) have just put forward a new pathophysiological mechanism at the origin of Primary Immunodeficiency (PID). Their work was published last March in Journal of Experimental Medicine.

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Primary Immunodeficiencies (PIDs) are a group of different monogenetic diseases whose most common clinical manifestation is a defect in antibody production. Dr. Sven Kracker's team, in the laboratory headed by Dr. Isabelle André, was able to identify a mutation affecting the IRF4 gene in a family of patients suffering from PID. This gene codes for a transcription factor of the same name which plays an essential role in the secretion of antibodies and in the differentiation of B lymphocytes into germinal centre B cells or, later, into plasma cells.

Previous studies have shown that the level of expression of IRF4 influences its transcriptional activity, thereby modulating the differentiation of B and T lymphocytes. It has also been shown that its transcriptional activity is regulated by its interaction, at the DNA level, with its various protein partners.

In collaboration with teams from the Necker Enfants Malades Hospital and the Saint-Louis Hospital, the team was able to identify a mutation affecting the IRF4 protein in the interferon association domain, which is essential for the interaction of IRF4 with its protein partners. Although the expression of the mutated protein remains similar to that of the wild-type protein, the researchers showed that its activity was affected. Indeed, the mutation alters the binding of IRF4 to different protein partners on the DNA, affecting its activity for the transcription of genes involved in lymphocyte differentiation programmes.

This work also highlights a new mode of regulation of transcription factor activity. While most gene mutations can be defined at the functional level as a loss or gain of function, a more complex mechanism associating the formation of new protein complexes with a functional defect in transcriptional activity is identified here.

The description of these new pathophysiological mechanisms allows a better understanding of the development of diseases involving, as here, complex mechanisms. Understanding and characterising them may allow, in the longer term, the development of treatments for these genetic diseases.

DOI: 10.1084/jem.20221292