There is no doubt that the immune system is a complex system. Its functional complexity stems from 1) the high number of interactions (usually non-linear) among cells and molecules that take place during - and sustain - an immune response; 2) the interconnections that the immune system has with other systems like e.g. the neuroendocrine one; 3) the yet obscure relationships between the immune system and the environment in which several modulatory stimuli are embedded (e.g. antigens, molecules of various origin, physical stimuli, stress stimuli). The various signals that can interfere with the immune response define the environment into which the immune system operates: this environment is noisy because of the great amount of such signals. The immune noise has therefore at least two components: 1) the internal noise, due to the exchange of a network of molecular and cellular signals belonging to the immune system during an immune response or in the homeostasis of the immune system. The concept of the internal noise might be viewed in biological terms as a status of “sub-inflammation required by the immune response to occur; 2) the external noise, the set of external signals that target the immune system (and hence that add noise to the internal one) during the whole life of an organism.
The current paradigm for the physiology of natural complex systems is that a complex system can exploit the energy of the noisy environment to optimise its response to specific signals (1). In other words, a non zero level of noise is required to allow the system to better operate: too low or too high amount of noise would degrade the system’s response to specific stimuli (1). This paradigm was found to be valid for several systems either physical (laser, particles, stars) or biological (neural and sensorial system) (1). The mechanisms through which noise is able to optimise the system’s response to specific signals have been studied and revealed in biology at the molecular level, at the single cell level and for networks of cells, and hence these mechanisms appear to be scale-independent. For example, the response of neurons to stimuli is optimised for non-zero levels of added noise through a mechanism known as stochastic resonance (1). Communication among neurons generates internal noise by itself. This noise plays a key role to maintain neurons in an active state (2).
With this proposal we aim at clarifying the role of the noise in the immune system. The immune system, as any other natural complex system, operates and evolves in a noisy environment. It is tempting to speculate that a certain amount of noise is required by the immune system to optimise its response; by tuning noise might result in the modulation of an immune response. At least two experimental evidences suggest that both internal and environmental noise might show a regulatory role for the immune response: infectious diseases (environmental noise) protect NOD mice (non-obese diabetic) from spontaneous onset of diabetes (3); the response of mice to antigenic stimuli is increased by co-injection of syngeneic non-antigen-specific IgM (according to our hypothesis by tuning the internal noise of the immune system) (4).
The immune noise as defined above may vary in intensity over time. At a short time scale the noise intensity varies during an immune response to an antigen and, possibly, at different extents during the primary immune response with respect to the secondary one. At longer time scales, fluctuations of immune noise might characterize the state of chronic inflammation. At even longer time scales the environment might have a role in the shaping of the immune system during the life of an individual and in determining the exhaustion of immunological compartments. For example, it has been proposed that the continuous stimulation of the immune system by signals embedded in the environment could lead to the exhaustion of the virgin T cell compartment and that the decay of virgin T cells might correlate with the reduced variability of the immune repertoire in aged individuals and with the life expectancy of humans (5). To understand the quantitative relationships between the efficacy and the efficiency of the immune response and the intensity of the internal and of the environmental immune noise at different scale levels might allow one to optimise the immune response to antigens, with obvious implications in the immune-therapy with vaccines, and to forecast the evolution of the immune system during the life of an individual. A study of this kind has to be conducted in collaboration with experts of different fields under the spirit of a multidisciplinary approach in order to integrate the scientific knowledge developed in disciplines as different as physics, mathematics, biology and medicine.