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B-cell responses belittled in mitochondrial disorders

B-cell responses belittled in mitochondrial disorders‘ – Written by Charlotte Harrison, Science Writer 

Mitochondrial diseases are a group of genetic disorders characterized by defects in oxidative phosphorylation. People with mitochondrial diseases are particularly vulnerable to infections, which can worsen disease progression or be life-threatening.

A study in Frontiers in Immunology offers a mechanistic explanation for the heightened infection risk; altered B cell function in children with mitochondrial disorders causes a weaker and less diverse antibody response to viral infections. The paper was also one of the first to explore how impaired oxidative phosphorylation impacts B cells using patient samples. 

B-cell fragility

The researchers used scRNAseq analysis of peripheral blood mononuclear cells to study the levels of different immune cells. In children with mitochondrial diseases, there was a large reduction in the level of specific cell types involved in the humoral immune response. The altered cells included antigen-presenting cells, B cells and plasma cells, whereas T cell levels were unaffected. 

The authors discovered that MTRNR2L8, a marker of bioenergetic stress, was increased in the cell types that were most depleted. Moreover, mir4485, a miRNA contained in the intron of MTRNR2L8, was co-expressed.

Knockdown studies of mir4485 in cultured B cells showed that this miRNA promoted cell survival by modulating apoptosis.

The authors commented on the implications of these findings in a press release:

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

Limited repertoire

To determine the functional consequences of their findings about B cells, the authors next studied the repertoire of antiviral antibodies in children with mitochondrial disorders using phage display and immunoprecipitation sequencing.

Here, patients had a similar number of viral infections to controls, and patients and controls had antibodies against the same species of viruses. However, children with mitochondrial disorders had a weaker antibody response and the repertoire of antibodies produced to a specific viral protein was less diverse. This finding provides a rationale for why children with mitochondrial disorders are less able to clear viral infections.

Moving forward, the authors advocate that more studies should follow their lead and investigate patient samples to help boost the translation of immune-metabolic studies.

Image Credit: Canva