New genetic condition that raises vulnerability to opportunistic infections

An international consortium co-led by Vanderbilt University Medical Center immunogeneticist Rubén Martínez-Barricarte, PhD, has discovered a new genetic disorder that causes immunodeficiency and profound susceptibility to opportunistic infections including life-threatening fungal pneumonia.

The discovery, which was published on January 20^th, 2023 in the journal Science Immunology, will aid in identifying those who have this inborn error of immunity (IEI).

Our findings will provide the basis for genetic diagnosis and preventive treatment for these groups of patients.”

Rubén Martínez-Barricarte, PhD, Assistant Professor of Medicine, Division of Genetic Medicine, Vanderbilt University

IEIs, also called primary immunodeficiencies, are genetic defects that are more prone to allergies, autoimmunity, anti-inflammatory disorders, cancer, and infectious diseases.

There have been 485 different IEIs found so far. As common as other genetic diseases like cystic fibrosis and Duchene’s muscular dystrophy, they are now estimated to occur in one out of every 1,000 to 5,000 births.

Despite recent medical advancements, about 50% of IEI patients still do not have a genetic diagnosis, which could prevent them from developing life-threatening conditions and death. This is the reason why the research is so crucial.

In this instance, a mutation in the gene encoding the protein IRF4—a transcription factor essential for the growth and development and operation of B and T white blood cells along with other immune cells—has caused the error.

In 2018, an international research team led by Martnez-Barricarte, a postdoctoral fellow at Rockefeller University, discovered an IRF4 mutation linked to Whipple’s disease, a rare bacterial infection of the intestine that causes diarrhea, weight loss, abdominal pain, and joint pain.

Martnez-Barricarte is currently an Assistant Professor of Medicine in the Division of Genetic Medicine, and of Pathology, Microbiology, and Immunology in the Division of Molecular Pathogenesis.

He started working with Aidé Tamara Staines-Boone, MD, and her associates in Monterrey, Mexico, in 2020 after relocating his lab to Vanderbilt University Medical Center. They were taking care of a young boy who had severe and recurrent bacterial, viral, fungal, and mycobacterial infections.

When Martnez-Barricarte and his group sequenced the boy’s protein-coding regions of the genome, they found a de novo IRF4 mutation that was unique to the patient and was not passed down from his parents.

They were informed by IRF4 specialists at the Imagine Institute in Paris, which studies and treats genetic diseases, that the same mutation was being characterized independently by seven other groups. They are now working together as the International IRF4 Consortium.

In the current study, the consortium identified seven patients with profound combination immunodeficiency who had pneumonia brought on by the fungus Pneumocystis jirovecii from six unrelated families living on four continents. These patients also had recurrent and severe infections. Each patient had the same mutation in the DNA-binding domain of IRF4.

A thorough phenotyping of the blood cells of the patients revealed immune cell abnormalities linked to the disease, such as impaired B cell maturation that results in the production of antibodies and decreased T cell production of cytokines that fight infections.

The combined immune deficiency seen in the patients was replicated in two knock-in mouse models, in which the mutation was inserted into the mouse genome. These models showed a severe defect in antibody production.

The “multimorphic” effect of the mutation, the researchers found, was harmful to the activation and differentiation of immune cells.

While the mutant IRF4 binds to DNA with greater affinity than the native form (in a hypermorphic way), its transcriptional activity in common, canonical genes is reduced (hypomorphic), and it binds to other DNA sites (in a neomorphic way), altering the protein's normal gene expression profile.

This multimorphic activity is a new disease-causing mechanism in humans.

The researchers concluded, “We anticipate that variants with multimorphic activity may be more widespread in health and disease.”