Metabolic pressure and the breach of immunological self-tolerance

The prevalence of autoimmune disorders in affluent countries has reached epidemic proportions. Over the past 50 years, a reverse trend between the frequency of infectious diseases and the incidence of autoimmune and allergic diseases led to the so-called 'hygiene hypothesis'. Given the epidemiological evidence and recent experimental data, we propose that this concept should also include metabolic pressure secondary to exposure to excessive daily caloric intake and overnutrition. We discuss how metabolic workload can modulate immunological tolerance and review the molecular mechanisms and the state of the art of the field. We also critically evaluate possibilities for restoring immunological homeostasis under conditions of metabolic pressure.