Balancing sensitivity, risk, and immunopathology in immune regulation

Abstract

Activation of an immune response is energetically costly and excessive immune system activity can result in immunopathology, yet a slow or insufficient immune response carries the risk of pathogen establishment with consequent pathology arising from the infection. Mathematical theory and empirical data demonstrate that hosts balance the costs of immunity against the risk of infection by closely regulating immunological dynamics. An optimal immune system is rapidly and robustly deployed against a true infectious threat and rapidly deactivated once the threat has been controlled. Genetic variation in the sensitivity of an immune system, as well as in the activation and shutdown kinetics of host immune responses, can contribute to the evolution of pathogen virulence and host tolerance of infection. Improved understanding of the adaptive forces that operate on immune regulatory dynamics will clarify fundamental principles governing the evolution and maintenance of innate immune systems.

Figure 1.

Regulation of immune signaling during infection. Negative regulators of immune responses (A) can degrade MAMPs and DAMPs to prevent signal transduction from immune receptors (1, e.g. peptidoglycan-recognition proteins with amidase activity), they can inhibit or degrade signaling proteins and transcription factors that propagate those signals (2, e.g. the proteins Cactus and PIRK), or they can modify the activity of the resulting effector response (3, e.g. antioxidants that detoxify immune-generated ROS). The net effect of these regulators is to slow the induction of an immune response and to accelerate its decay. Lower activity of a negative regulator can result in a prolonged immune response (B, gray line) relative to a response that returns more quickly to baseline (black line). While reducing negative regulation on the system could potentially result in faster activation and/or more complete clearance of microbes compared to a dampened reaction that might allow chronic persistence of an infection (C), a host with more aggressive immunity could suffer a net higher damage (D, gray dashed line, where immunopathology exceeds the damaged done by infection) compared to a host whose immune system is under moderate negative regulation (D, black line, where immunopathology is reduced but damage due to chronic infection continues to accumulate) or one whose immune system is strongly regulated so that immunopathological damage is lower than direct damage from the infection (D, dotted gray line).