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University of Basel

16 September 2019

Too much of a good thing: overactive immune cells trigger inflammation

Scientists describe a previously unknown disorder of the immune system: in a distinct subset of immune cells from patients with primary immunodeficiency, cellular respiration is significantly increased. This cellular metabolic overactivity leads to inflammation, as an international research team led by the University of Basel and University Hospital Basel report in the journal Nature Immunology.

Molecular model: A typical interaction between the A45T mutated SDHA gene (green) and the SDHB gene (blue) – it increases the functioning of the whole complex and thereby triggers inflammation signals in the affected immune cells. (Image: DBM)
Molecular model: A typical interaction between the A45T mutated SDHA gene (green) and the SDHB gene (blue) – it increases the functioning of the whole complex and thereby triggers inflammation signals in the affected immune cells.
© DBM

The immune system protects us from infections and tumors – a challenging task, not least because harming the body’s own healthy tissue must be avoided at the same time. However, rare genetic diseases lead to defects in the immune system known as primary immunodeficiency disorders (PID). One consequence of such disorders is susceptibility to infections, yet certain tumors and non-infectious inflammation (autoimmune diseases) can also occur more frequently.

The researchers tested the hypothesis that the metabolic activity in the immune cells of PID patients can serve as a biomarker. They based this on the fact that cellular metabolism is a key regulator of the functioning of immune cells. In the immune cells of a subset of the examined PID patients, a key metabolic process – cellular respiration – was indeed significantly increased. During cellular respiration, energy is generated in the mitochondria, the “powerhouses of the cell”.

Increased cellular respiration

On the basis of this discovery, the researchers were able to decode a new kind of disease mechanism, from the genetic defect via mitochondria and back to signal transduction to the nucleus. The increased cellular respiration was triggered by the hyperactivity of a protein in the respiratory chain. This then signaled the cells to produce inflammatory mediators. With these findings, the researchers were able to successfully administer a targeted treatment approved for another indication.

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