Congenital immunodeficiency discovered – and elucidated

Berlin, 23 January 2023

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An international research team has now reported in the journal Science Immunology* how the exchange of a single building block in the genome triggers a previously unknown immune defect in humans. Scientists from the Experimental and Clinical Research Center (ECRC), a joint institution of the Charité – Universitätsmedizin Berlin and the Max Delbrück Center, were significantly involved. They discovered a specific mutation in the gene regulator IRF4.

In seven children with marked immunodeficiency, an international consortium of researchers discovered a matching mutation in the gene for interferon regulatory factor 4 (IRF4). IRF4 is a so-called transcription factor, i.e. it regulates the activity of certain genes. It is also important during the development and activation of immune cells. The patients come from six unrelated families living on four different continents.

As the team, which includes the group of Prof. Dr. Stephan Mathas and Dr. Martin Janz from the ECRC, was able to prove, a single building block in the IRF4 gene is exchanged in the affected individuals. This specific genetic change is called a T95R mutation. The researchers were also able to clarify how the mutation affects the immune system: a previously undescribed mechanism leads to a congenital immunodeficiency.

Congenital immunodeficiencies are rare and often vary in severity. “Immunodeficient children repeatedly suffer from upper respiratory tract infections,” explains Prof. Mathas. These are often infections with the Epstein-Barr or cytomegalovirus or with Pneumocystis jirovecii, a pathogen that triggers pneumonia; all infections that physicians:in know well from people with immune deficiencies.

The seven patients also suffer from these infections. On closer examination, their immune systems also have similarities: “It was noticeable that all the children have too few antibodies in their blood and very few B cells, which normally produce these antibodies. In addition, the number of their T cells and their function is reduced compared to healthy people,” says Prof. Mathas. T cells, along with B cells and antibodies, are an important arm of the immune system.

In many children with congenital immune deficiency, the cause of the defect is unknown, but nowadays it can be determined by decoding the genetic information. In this way, the IRF4 mutation T95R also came to light. Through close exchange among colleagues in international networks, it became clear that the genetic cause of the disease in these children, whose families are not related, is the same mutation. They are the index patients in whom the defect is now described for the first time. The international consortium has also succeeded in creating the same clinical picture by targeted mutation of IRF4 in mice, which has made it possible to better understand in detail the immune system dysfunctions triggered by IRF4.

The T95R mutation is always located on only one of the two copies of the genetic material. And although patients always make the healthy form of IRF4, all affected individuals develop this immune deficiency. “The biology of the mutation virtually beats that of the healthy form,” says Prof. Mathas. As genetic analyses of the families revealed, the index patients did not inherit the gene alteration from their parents, but it occurred spontaneously in the germline or early embryonic development.

The mutation is located at the exact site of IRF4 that the gene regulator uses to bind to DNA. “The mutation, in interaction with other factors, alters the affinity of IRF4 for DNA,” explains Prof. Mathas. The mutated IRF4 protein therefore not only binds more strongly or more weakly to known DNA binding sites, depending on the context, but moreover also binds to sites of the genetic material where it should not bind at all; i.e. sites to which the normal variant of the protein would never adhere. Through bioinformatic analysis, the researchers were able to identify these new binding sites. In their publication, the researchers describe the mutation as “multimorphic” because not only are certain genes blocked, but others and even new ones are activated.

Depending on the type and severity of a congenital immunodeficiency, affected individuals receive, for example, stem cell transplants or lifelong, regular injections with antibodies. “The work now published suggests that one could change the binding sites of mutant transcription factors without affecting the healthy variant,” says Prof. Mathas.

In any case, the IRF4 mutation T95R will now be added to the catalog of genes included in the diagnosis of congenital immunodeficiency. Interestingly, IRF4 also plays an important role in the development of certain blood cancers, which Prof. Mathas and his team are researching.

*Fornes O et al. A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency. Sci Immunol 2023 Jan 20. doi: 10.1126/sciimmunol.ade7953

About the study

In addition to two German research groups – from Charité / MDC and the University of Ulm – the research consortium includes researchers from children’s hospitals and universities in Canberra (Australia), Shanghai (China), Vancouver (Canada), Paris (France), Nashville (USA) and the National Institutes of Health in Betheseda (USA).

Caption: Analysis of IRF4 (stained brown) in a form of lymphoma. © Pathology University Hospital Würzburg | Prof. I. Anagnostopoulos


 IRF4 in lymph node cancer. © Pathology University Hospital Würzburg | Prof. I. Anagnostopoulos (2.20 MB).


Original publication

AG Janz/Mathas at the ECRC