New genetic disease that causes susceptibility to opportunistic infections – ScienceDaily

New genetic disease that causes susceptibility to opportunistic infections – ScienceDaily

New genetic disease that causes susceptibility to opportunistic infections – ScienceDaily

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

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

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

To date, 485 different IEIs have been identified. They are now believed to occur in one in every 1,000 to 5,000 births, making them 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 illness and death. This is why this research is so important.

The error, in this case, is a mutation in the IRF4 protein gene, a transcription factor that is essential for the development and functioning of white blood cells B and T, as well as other cells of the immune system.

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

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

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

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

When consulting IRF4 experts at the Imagine Institute for the Study and Treatment of Genetic Diseases in Paris, they were told that seven other groups were independently characterizing the same mutation. They now collaborate as the IRF4 International Consortium.

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

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

Two knock-in mouse models, in which the mutation was inserted into the mouse genome, exhibited a severe defect in antibody production consistent with the combined immune deficiency seen in the patients.

The researchers also found that the mutation had a “multimorphic” effect detrimental to immune cell activation and differentiation.

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

This multimorphic activity is a new mechanism for human disease. “We anticipate that variants with multimorphic activity may be more widespread in health and disease,” the researchers concluded.

Co-authors from the Martínez-Barricarte lab included graduate students Jareb Pérez Caraballo and Xin Zhen, 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).

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