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Metabolic pressure and the breach of immunological self-tolerance

Abstract

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.

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Figure 1: Increased incidence of autoimmunity in affluent countries according to the hygiene hypothesis and the concept of early metabolic pressure and overload.
Figure 2: Metabolic pressure and immunotolerance to self.
Figure 3: Metabolic differences between Treg cells and Tconv cells, and Treg cells as metabolic sensors.

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Acknowledgements

We thank S. Bruzzaniti for manuscript editing. This work is dedicated to the memory of Eugenia Papa and Serafino Zappacosta. Supported by the European Research Council (“menTORingTregs” grant 310496 to G.M.), the Fondazione Italiana Sclerosi Multipla (2016/R/18 to G.M. and 2014/R/21 to V.D.R.), Telethon (GGP17086 to G.M.), Associazione Italiana per la Ricerca sul Cancro-Cariplo TRansforming IDEas in Oncological Research (17447 to V.D.R.) and the US National Institutes of Health (AI109677 to A.L.C.).

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Correspondence to Veronica De Rosa or Giuseppe Matarese.

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De Rosa, V., La Cava, A. & Matarese, G. Metabolic pressure and the breach of immunological self-tolerance. Nat Immunol 18, 1190–1196 (2017). https://doi.org/10.1038/ni.3851

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