We recently described a mutation in the DNA-binding domain of IRF4 found in multiple patients with combined immunodeficiency disease. Interestingly, the mutation does not fit into the standard paradigm of gain- or loss-of-function effects and instead combines features of gain-, loss- and neomorphic activities. Through detailed investigation in mouse models, we could show that the mutation leads to a complex dysregulation of the germinal centre with an increased size of germinal centres but a failure to properly select for high-affinity B cells. The dysregulation of the germinal centre is driven by a T-cell intrinsic overproduction of Th2-associated cytokines.
In further studies we showed that many mutations in the DNA-binding domain of IRF4 recurrently found in germinal-centre derived lymphoid malignancies have similar multimorphic properties with each of the mutation leading to a unique dysregulation of the germinal centre.
