An international consortium co-led by immunogeneticist Rubén Martínez-Barricarte, Ph.D., at Vanderbilt University Medical Center has discovered a new genetic disorder that causes immune deficiency and risk for opportunistic diseases, including life-threatening fungal pneumonia Extreme susceptibility to infection.
The findings were reported Jan. 20 in the journal Science Immunology, will help identify people who carry this Innate Immunity Error (IEI). “Our findings will inform genetic diagnosis and preventive treatment in these patient populations,” says Martínez-Barricarte.
IEI, also known as primary immunodeficiency, is a genetic defect characterized by increased susceptibility to infectious diseases, autoimmunity, anti-inflammatory diseases, allergies and, in some cases, cancer.
To date, 485 different IEIs have been identified. These disorders are now thought to affect one in every 1,000 to 5,000 births, making them as common as other genetic disorders, including cystic fibrosis and Duchenne muscular dystrophy.
Despite recent medical advances, about half of IEI patients still lack the genetic diagnosis that could help them avoid debilitating disease and death. That’s why this research is so important.
In this case, the error was a genetic mutation for the protein IRF4, a transcription factor critical for the development and function of B and T white blood cells, as well as other immune cells.
A postdoctoral fellow at The Rockefeller University, Martínez-Barricarte was part of an international team of researchers that in 2018 identified IRF4 mutations associated with Whipple disease, a rare bacterial infection of the gut that causes diarrhea, weight Relieves and tummy and abdominal discomfort. joint pain.
Martínez-Barricarte is now an Assistant Professor of Medicine in the Department of Genetic Medicine and Assistant Professor of Pathology, Microbiology and Immunology in the Department of Molecular Pathogenesis.
In 2020, after moving his lab to VUMC, he began collaborating with Aide Tamara Staines-Boone, MD, and his colleagues in Monterrey, Mexico. They were caring for a young boy with severe and recurrent fungal, viral, mycobacterial and other infections.
Martínez-Barricarte and his team sequenced the protein-coding region of the boy’s genome and found a de novo mutation in IRF4 that originated in the patient and was not inherited from his parents.
After consulting with IRF4 experts at the Institute for Research in Genetic Diseases and Therapeutic Imagination in Paris, they were told that seven other groups were independently characterizing the same mutation. They are now collaborating as the IRF4 International Consortium.
In the current study, the consortium identified seven patients with severe combined immunodeficiency from six unrelated families on four continents who experienced recurrent and severe infections, including pneumonia caused by the fungus Pneumocystis jirovecii. Each patient had the same mutation in the DNA-binding domain of IRF4.
Extensive phenotyping of the patients’ blood cells revealed abnormalities in immune cells associated with the disease, including impaired maturation of antibody-producing B cells and reduced production of infection-fighting T cells by T cells.
Two knock-in mouse models, in which mutations were inserted into the mouse genome, exhibited severe defects in antibody production, consistent with the combined immunodeficiency observed in patients.
The researchers also found that the mutation has a “polymorphic” effect that is detrimental to the activation and differentiation of immune cells.
Although mutant IRF4 binds DNA with higher affinity than the native form of the protein (in a hypermorphic manner), its common canonical gene has reduced transcriptional activity (hypomorphic), and it binds to other DNA sites (in a novel state mode) mode), altering the normal gene expression profile of the protein.
This polymorphic activity is a novel mechanism of human disease. “We anticipate that variants with polymorphic activity may be more prevalent in health and disease,” the researchers concluded.
Co-authors in Martínez-Barricarte’s lab include 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).