Mitochondrial Disorders Weaken Immunity in Children

Researchers from the National Institutes of Health (NIH) discovered that altered B cell function in children with mitochondrial abnormalities resulted in a weaker and less diversified antibody response to viral infections in a recent study. Researchers at the National Human Genome Research Institute (NHGRI) led the study, which was published in Frontiers in Immunology. They analyzed gene activity of immune cells in children with mitochondrial disorders and discovered that B cells, which produce antibodies to fight viral infections, are less able to survive cellular stress.

Our work is one of the first examples to study how B cells are affected in mitochondrial disease by looking at human patients,” said Eliza Gordon-Lipkin, M.D., assistant research physician in NHGRI’s Metabolism, Infection and Immunity Section and co-first author of the paper.

Mitochondria are essential parts of practically every cell in the body because they turn food and oxygen into energy. More than 350 genes have been related to mitochondrial diseases, which manifest differently depending on which cells are damaged.

“For children with mitochondrial disorders, infections can be life threatening or they can worsen the progression of their disorder,” said Peter McGuire, M.B.B.Ch., NHGRI investigator, head of the Metabolism, Infection and Immunity Section and senior author of the study. “We wanted to understand how immune cells differ in these patients and how that influences their response to infections.”

A mitochondrial disease affects around one in every 5,000 persons worldwide. Leigh’s syndrome, which predominantly affects the nervous system, and Kearns-Sayre syndrome, which mostly affects the eyes and heart, are two mitochondrial illnesses.

While mitochondrial abnormalities are known to affect organs like the heart, liver, and brain, it is less clear how they affect the immune system.

Researchers analyzed immune cells detected in blood using a genomic approach called single-cell RNA sequencing, which evaluates gene activity in distinct cell types. These cells comprise many types of white blood cells that assist the body in fighting illnesses. During times of stress, these cells release a microRNA known as mir4485. MicroRNAs are short RNA strings that assist control when and where genes are activated and deactivated. Mir4485 regulates biological pathways that aid in cell survival.

“We think that B cells in these patients undergo cellular stress when they turn into plasma cells and produce antibodies, and these B cells then try to survive by producing the microRNA to cope,” said Dr. McGuire. “But the B cells are too fragile due to their limited energy, so they are unable to survive the stressful conditions.”

Researchers utilized the VirScan technique to examine all previous viral infections, assess how well the immune system battled those infections, and examine the effects of B cells and plasma cells on antibody production. Immune systems in children with mitochondrial abnormalities are less able to recognize and kill invading viruses and clear infections due to a weaker antibody response.

The researchers hope to use the findings of this study to guide future treatment of individuals with mitochondrial diseases, adding that more translational research in this area is needed.

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