Excitability as a design principle in the immune system

Growing knowledge in immunology has outpaced the development of unifying concepts that explain how molecular circuits generate immune goals-strong response to pathogens, self-tolerance, and prevention of collateral damage. Here, we propose that excitability, a concept from dynamical systems, provides these goals in diverse contexts. An excitable system produces a large response pulse when stimulus crosses a threshold and then shuts itself down, followed by a refractory period. We mathematically screen thousands of cytokine and cell circuits to identify the handful that can show excitability. Of these, a single robust circuit is Pareto optimal for speed and strength-an effector that induces itself and induces its inhibitor. This circuit appears dozens of times in the human immune network, whereas the suboptimal circuits do not. It explains data on severe acute respiratory syndrome coronavirus 2, autoimmune flares, and tumor immunity and suggests therapeutic targets. Excitability may unite our understanding of immune circuits.