Study reveals new genetic disorder causes susceptibility to opportunistic infections

Study reveals new genetic disorder causes susceptibility to opportunistic infections

Identification of a single heterozygous mutation in the IRF4 gene in seven CID patients. Credit: Immunology (2023). DOI: 10.1126/sciimmunol.ade7953

An international consortium led by immunologist Rubén Martínez-Barricarte, Ph.D., of the Vanderbilt University Medical Center, has discovered a new genetic disorder that impairs immunity epidemics and are highly susceptible to opportunistic infections including life-threatening fungal pneumonia.

This finding, reported January 20 in the journal Immunology, will help identify carriers of this innate immunity error (IEI). “Our findings will provide the basis for genetic diagnosis and prophylactic treatment for these groups of patients,” said Martínez-Barricarte.

IEI, also known as primary immunodeficiency, is Genetic defects is characterized by increased sensitivity to infectious diseasesautoimmune, anti-inflammatory disorders, allergies and in some cases cancer.

To date, 485 different IEIs have been identified. They are now thought to occur in one in every 1,000 to 5,000 births, making them as common as other genetic disorders, including cystic fibrosis and Duchene muscular dystrophy.

Despite recent medical advances, about half of patients with IEI still have not received a genetic diagnosis that could save them from debilitating illness and death. That’s why this study is so important.

The error in this case was caused by a genetic mutation of the IRF4 protein, a transcription factor that is critical to the development and function of B and T. White blood cellsand other immune cells.

A postdoctoral fellow at Rockefeller University, Martínez-Barricarte was part of an international team that, in 2018, identified an IRF4 mutation associated with Whipple disease, a rare intestinal infection causes diarrhea, weight loss, and abdominal pain. athritis.

Martínez-Barricarte is currently an assistant professor of Medicine in the Department of Genetic Medicine and Pathology, Microbiology & 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 are caring for a boy with 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.

After consulting with 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 describing the same mutation. Now they cooperate as the International Association IRF4.

In the current study, the consortium identified 7 patients from 6 unrelated families across 4 continents with severe combined immunodeficiency who developed recurrent and severe infections, including: including fungal pneumonia. Pneumocystis jirovecii. Each patient had the same mutation in the DNA-binding domain of IRF4.

Extensive phenotype of the patient’s blood cells reveals immune cell abnormalities associated with the disease, including impaired maturation of antibody-producing B cells and decreased production. T cells of anti-infective cytokines.

Two experimental mouse models, in which the mutation was inserted into the mouse genome, exhibited severe defects in antibody production consistent with the combined immunodeficiency observed in the patient. .

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

While mutant IRF4 binds to DNA with higher affinity than the natural form of the protein (in a metaphysical manner), its transcriptional activity in general, canonical genes is reduced (hypomorphic), and it is associated binds to other DNA sites (in the new structure). way), altering the protein’s normal gene expression profile.

This diverse activity is a novel mechanism of human disease. “We predict that variants with polymorphic activity may be more widespread in health and disease,” the researchers concluded.

Co-authors from Martínez-Barricarte’s lab include graduate students Jareb Pérez Caraballo and Xin Zhen, and research assistant Linh Tran.

More information:
A polymorphic mutation in IRF4 causes autosomal recessive immunodeficiency in humans, Immunology (2023). DOI: 10.1126/sciimmunol.ade7953

quote: Study showing a new genetic disorder that causes susceptibility to opportunistic infections (2023, January 21) retrieved January 21, 2023 from 2023-01-reveals-genetic-disorder-susceptibility-opportunistic.html

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