Inborn Immunodeficiency Cause Discovered

A T95R mutation discovered in the gene for interferon regulatory factor 4 was found to affect the immune system in kids with profound immunodeficiency also known as an inborn combined immunodeficiency. The findings of the study are published in Science Immunology.

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

What are Inborn Immunodeficiencies

Inborn immunodeficiencies are rare and often vary in severity. “Immunodeficient children frequently contract infections of the upper airways,” says Mathas, who specializes in the molecular biology of transcription factors and leads the Biology of Malignant Lymphomas Lab at the ECRC. 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 Mathas. Alongside B cells and antibodies, T cells are an important pillar of the immune system.

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.

Susceptible to Upper Respiratory Infections
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 Mathas. 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 Mathas. 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.

More Genes for Diagnosing Deficiencies

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 Mathas.

Source: Eurekalert

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