The immune system as a regulator of normal physiology.

Concepts of how the immune system functions have evolved during the last half century. From widespread acceptance of Self-Nonself Discrimination to explain adaptive immunity, to increasing understanding of receptor-mediated activation of innate immunity through the Danger Model, understanding of the role of the immune response continues to grow with ever broader models such as the Damage Response Framework and the Discontinuity Model. The realisation that the majority of foreign antigens, such as those comprising the microbiome, are tolerated by the immune system, allows a re-appraisal of immune tolerance and how it relates to these conceptual shifts. Disease induced by both autoantigens and foreign antigens occurs most readily when the abundantly redundant immune system is defective, for genetic or other reasons, in one or more critical component. When fully competent, the primary role of the immune system is to "physiologically manage" both foreign and self-antigens by quietly engaging in activities such as waste disposal, autophagy, removal of apoptotic cell debris, tissue repair and metabolism. This is evidenced for foreign antigens by the limited incidence of clinical disease in pandemics despite widespread exposure of the population to the infectious agent: instead, many asymptomatic infected individuals harbour latent infections controlled by a healthy immune system, and are mainly at risk of developing overt disease when immune competency is impaired. In the case of autoantigens, by definition, exposure is 100% yet disease incidence is minimal and similarly requires a failure of immune competence, initiated by the same aberrant response to a coincident foreign antigen.