A genetic disorder that causes immunodeficiency and susceptibility to opportunistic infections has been discovered

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

The discovery was reported Jan. 20 in the journal Nature Immunology, will help identify people who carry this innate immunity error (IEI). “Our findings will provide the basis for genetic diagnosis and preventive treatment for these groups of patients,” said Martinez-Parikart.

IEIs, also known as primary immunodeficiencies, are genetic defects characterized by an increased susceptibility to infectious diseases, autoimmune, anti-inflammatory disorders, allergies and, in some cases, cancer.

To date, 485 different IEIs have been identified. It is now thought to occur in one in every 1,000 to 5,000 births, making it as prevalent as other genetic disorders, including cystic fibrosis and Duchenne muscular dystrophy.

Despite recent medical advances, about half of patients with IEIs still lack a genetic diagnosis that could help them avoid debilitating disease and death. This is why this research is important.

The fault in this case is a mutation in the IRF4 protein gene, which is a transcription factor pivotal for the development and function of B and T white blood cells, as well as other immune cells.

As a postdoctoral fellow at The Rockefeller University, Martínez-Barricarte was part of the international research team that, in 2018, identified an IRF4 mutation associated with Whipple disease, a rare bacterial infection of the intestine that causes diarrhea, weight loss, and abdominal and joint pain.

Martínez-Barricarte is now an Assistant Professor of Medicine in the Department of Genetic Medicine, Pathology, Microbiology and Immunology in the Department of Molecular Pathogenesis.

In 2020, after moving his lab to VUMC, he began collaborating with Aidé Tamara Staines-Boone, MD, and her colleagues in Monterrey, Mexico. They were caring for a young boy who had severe, frequent, recurrent fungal, viral and fungal infections.

Martínez-Barricarte and his team sequenced protein-coding regions in the boy’s genome and discovered the de novo IRF4 mutation, which originated in the patient and was not inherited from his parents.

After consulting with IRF4 experts at the Imagine Institute for the Study and Treatment of Hereditary Diseases in Paris, they were told that seven other groups had independently characterized the same mutation. They now cooperate as the International Federation IRF4.

In the current study, the consortium identified seven patients from six unrelated families across four continents with profound combined immunodeficiency who presented with frequent and severe infections, including pneumonia caused by fungi. Pneumocystis gerovici. Each patient had the same mutation in the DNA-binding domain of IRF4.

Extensive phenotyping of patients’ blood cells revealed abnormalities in immune cells associated with the disease, including impaired maturation of antibody-producing B cells, and decreased production of infection-fighting cytokines by T cells.

Two mouse models, in which the mutation was introduced into the mouse genome, showed a severe defect in antibody production consistent with the combined immunodeficiency observed in the patients.

The researchers also discovered that the mutation has a “polymorphic” effect that is detrimental to the activation and differentiation of immune cells.

While mutant IRF4 binds to DNA with higher affinity than the original form of the protein (in a hypermorphic manner), its combined transcriptional activity, canonical genes are decreased (hypomorphic), binds to other DNA sites (in a neomorphic manner), and its expression profile is altered. normal protein genotype.

This polymorphic activity is a novel mechanism of human disease. “We expect variants with polymorphic activity to be more prevalent in health and disease,” the authors concluded.

Co-authors from the Martínez-Barricarte lab included graduate students Garp Perez-Caraballo and Shane Zin, and research assistant Linh Tran. His research was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Grant #AI171466).