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May 26, 2014

Discovery of an on-off switch for the immune response

Schematic diagram showing how immune response is turned on

NF-kappa-B, a protein complex that activates DNA transcription in cells under certain special conditions, such as oxidative stress and heat shock, is a key element of the body’s response to stress. However, it needs to be tightly regulated. An inadequate response can lead to a compromised immune system and susceptibility to infection, whereas prolonged activation of the complex is associated with cancer. It has been widely assumed, thus, that there must be a “threshold” mechanism, so that expression of NF-kappa-B can be turned on and off like a light switch. However, though great advances have been made in recent years to understand the complex cascade of events that regulates how the activation of NF-kappa-B is turned on and off remains poorly understood.

Now, in a significant study published in Science, researchers from the RIKEN Center for Integrative Medical Science and the RIKEN Quantitative Biology Center, along with colleagues from other institutes, used experiments with immune B-cells, along with computer modelling, to show that an epigenetic mechanism, involving a complex dance among a series of proteins including CARMA1, TAK1, and IKK, create a positive feedback mechanism that serves as a threshold allowing NF-kappa-B to activate. To test the results, they compared normal B cells with cells with mutated CARMA1, and found indeed that the CARMA1 feedback-deficient cells showed a graded immune response while the wild-type cells showed a switch-like behavior, showing that there is a switching mechanism that involves the CARMA1 protein complex.

This interesting finding helps to explain how nature transforms analog information into the "digital" form of on and off. It also has the potential to lead to advances in therapeutics. According to Hisaaki Shinohara of IMS, the first author of the paper, "Since 20-50% of B cell receptors potentially bind to the self, the threshold mechanism may contribute to distinguishing dangerous pathogens from self, and so elucidating the interplay between these molecules could give insights for new ways to treat not only cancer but also autoimmune diseases."