Inborn immunodeficiency discovered - and explained

In a study of seven children with profound immunodeficiency, an international consortium of researchers has discovered a T95R mutation in the gene for interferon regulatory factor 4. IRF4 is a transcription factor that controls proteins, which means it regulates how much messenger RNA a cell produces. But it also plays a key role in the development and activation of immune cells. The seven patients came from six unrelated families living on four different continents. The research team were also able to identify how the mutation affects the immune system. A previously undescribed mechanism causes an inborn combined immunodeficiency. The consortium has now published its findings in Science Immunology.

Inborn immunodeficiencies are rare and often vary in severity. “Immunodeficient children frequently contract infections of the upper airways,” says an author. The illnesses are often caused by Epstein-Barr virus, cytomegalovirus, or Pneumocystis jirovecii, a pathogen that causes pneumonia. These are all infections that physicians regularly see in other patients with immunodeficiencies.

The seven patients in this study also suffer from these infections. When the researchers delved deeper, they found that the children’s immune systems shared some similarities: “All the children have too few antibodies in their blood and very few B cells, which normally produce the antibodies. They also have fewer T cells than healthy individuals, and the T cells they do have function less well,” says the author. Alongside B cells and antibodies, T cells are an important pillar of the immune system.

In many children who are born with an immunodeficiency, the cause of the condition is unknown. Today, though, genome sequencing can help shed light on it. This was how the study’s authors discovered the T95R mutation in IRF4. By collaborating closely in international networks, the researchers traced the genetic cause of the disease in these children from unrelated families to the same point mutation. This makes them the index patients – the first described cases – for this deficiency. The consortium was also able to produce the same syndrome in mice by specifically mutating the Irf4 gene. This allowed the researchers to gain a more detailed understanding of the errors of immunity caused by IRF4.

The T95R mutation is only ever found on one of the two copies of the genome. And although the patients also always produce healthy IRF4, they all develop the immunodeficiency. “The biology of the mutation effectively beats the biology of the healthy form,” says the author. Genome analysis of the families revealed that the index patients didn’t inherit the mutation from their parents. Rather, it occurred spontaneously (de novo) in the germline or during early embryonic development.

The mutation in transcription factor IRF4 occurs at the precise location where the protein binds to DNA. Usually, the amino acid threonine (T) is found here, but in the mutation it is replaced by arginine. “In conjunction with other factors, the mutation changes IRF4’s affinity for DNA,” says the author. This means that, as well as binding to known DNA binding sites with varying degrees of strength depending on the context, the mutated IRF4 protein also binds to parts of the genome that it shouldn’t be involved in at all – sites that the normal variant of the protein (the wild type) would never bind to. Bioinformatics analyses allowed the researchers to identify these new binding sites. They describe the mutation in their paper as “multimorphic” because as well as blocking certain genes, it also activates others – and even new ones.

Depending on the type and severity of an inborn immunodeficiency, patients might undergo stem cell transplants or receive regular antibody injections throughout their lives. “Now our study suggests that it would be possible to change a mutated transcription factor’s binding sites without affecting the healthy variant,” says the author.

The T95R mutation in IRF4 will now be added to the catalogue of genes used to diagnose inborn immunodeficiency. Interestingly, IRF4 also plays an important role in the development of certain types of blood cancer, which the lab is also investigating.