A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Interferon regulatory factor 4 (IRF4) is a crucial transcription factor for immune cell development and function.
• Combined immunodeficiency (CID) encompasses a group of genetic disorders impairing adaptive immunity.

Purpose of the Study:

• To investigate the genetic basis and functional consequences of a recurrent IRF4 mutation identified in patients with CID.
• To elucidate the molecular mechanisms by which the IRF4 variant leads to immune dysregulation.

Main Methods:

• Genetic sequencing to identify IRF4 mutations in affected individuals.
• In vitro studies on patient-derived immune cells to assess B and T cell function.
• Development and analysis of a knock-in mouse model expressing the IRF4 variant.
• Biochemical assays to characterize the DNA binding and transcriptional activity of the mutant IRF4 protein.

Main Results:

• A recurrent heterozygous mutation, IRF4 p.T95R, was identified in seven patients from six families, causing autosomal dominant CID.
• Patients presented with susceptibility to opportunistic infections (e.g., Pneumocystis jirovecii) and agammaglobulinemia, with impaired B cell maturation and T cell populations (T_H17, T_FH).
• The IRF4^T95R variant exhibits a complex multimorphic pathophysiology, acting as a hypermorph (increased DNA binding affinity), hypomorph (reduced canonical transcriptional activity), and neomorph (binding noncanonical sites and altering gene expression).

Conclusions:

• The IRF4^T95R mutation represents a novel cause of human CID with a unique multimorphic mechanism.
• This pathophysiology disrupts lymphocyte development and function, leading to severe immune deficiency.
• Understanding this IRF4 variant's function provides insights into immune system regulation and potential therapeutic targets.