Our research group studies the genetic causes of primary immunodeficiencies, with a particular focus on diseases that affect B cell development and function and therefore compromise antibody production. By identifying novel disease-causing variants in patients and families, we aim to uncover the biological pathways that are essential for normal immune function and to understand how disruption of these pathways leads to human disease. Primary immunodeficiencies are rare, but they often reveal fundamental principles of immunology that are relevant far beyond the individual disorders themselves.

A major area of our work centres on mutations in transcription factors, which control how immune cells develop and which genes they switch on or off. Even a single change in one of these regulators can profoundly alter the behaviour of B cells and other lymphocytes. An important example is our work on IRF4. In 2023, we showed together with colleagues from around the world that the heterozygous IRF4-T95R mutation causes an autosomal dominant combined immunodeficiency with severe defects in humoral immunity and that mouse knock-in models recapitulate key features of the human disease. This study helped establish how altered DNA binding by a transcription factor can drive a highly specific immune phenotype (IRF4 consortium, Science Immunology 2023).

To understand disease mechanisms in depth, we use mouse models carrying patient-derived mutations. These models allow us to investigate how genetic variants affect immune-cell development, differentiation, and function in vivo, and why particular mutations lead to distinct clinical presentations. We are especially interested in the idea that lessons from rare inherited immune disorders can illuminate broader mechanisms of human disease.  

This is particularly relevant for transcription factors, because similar or related mutations that cause immunodeficiency in the germline are also found as somatic mutations in cancer. Studying these mutations in the context of primary immunodeficiency therefore provides a powerful way to understand how altered gene regulation can contribute not only to immune failure but also to malignant transformation. 

In parallel, our group also investigates immunodeficiencies linked to the actin cytoskeleton. Recent work identified how mutations in LCP1, affecting the actin-bundling protein L-plastin, cause immune deficiency and haematological abnormalities (Hernandez et al., JACI 2024), further highlighting the importance of cytoskeletal regulation for immune-cell organisation, migration, and function.