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. life.
The discovery, reported January 20 in the journal Science Immunology, will help identify people who carry this immune error (IEI). “Our results 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 thought to occur in one in 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 IEIs do not have a genetic diagnosis that could help them avoid debilitating illness and death. That’s why this research is so important.
The error in this case is a mutation in the gene for the IRF4 protein, a transcription factor critical to the development and function of white blood cells B and T, as well as other immune cells.
As a postdoctoral fellow at Rockefeller University, Martínez-Barricarte was part of an international research team that identified, in 2018, an IRF4 mutation associated with Whipple’s disease, a rare bacterial infection of the intestine that causes diarrhea, weight loss, and abdominal pain and joint pain.
Martínez-Barricarte is now assistant professor of Medicine in the Department of Genetic Medicine, and Pathology, Microbiology & Immunology in the Division of Molecular Pathogenesis.
In 2020, after moving his laboratory 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 came from 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 expressing the same mutation. They now collaborate as the IRF4 International Consortium.
In the current study, the consortium identified seven patients from six unrelated families across four continents with profound combined immunodeficiency who experienced recurrent and severe infections, including pneumonia caused by the fungus. Pneumocystis jirovecii. All patients had the same mutation in the DNA binding domain of IRF4.
Extensive phenotyping of the patients’ blood cells revealed immune cell abnormalities associated with the disease, including impaired maturation of antibody-producing B cells, and decreased T-cell production of infection-fighting cytokines.
Two knock-in mouse models, in which the mutation was inserted into the mouse genome, showed a major defect in antibody production consistent with the combined immunodeficiency observed in the patients.
The researchers also found that the mutation had a “multimorphic” effect that would impair the activation and differentiation of immune cells.
Although the mutant IRF4 binds to DNA with a higher affinity than the native form of the protein (in a hypermorphic manner), its transcriptional activity is reduced in common, canonical genes (hypomorphic), and it binds to other DNA sites (in a neomorphic). way), altering the protein’s normal gene expression profile.
This polymorphic activity is a novel mechanism for human disease. “We expect that variations with polymorphic activity may be more prevalent in health and disease,” the researchers said.
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).