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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
McFarlane, H. Cell-mediated immunity in protein-calorie malnutrition. Lancet 2, 1146–1147 (1971).
Bhargava, A. Undernutrition, nutritionally acquired immunodeficiency, and tuberculosis control. Br. Med. J. 355, i5407 (2016).
Lord, G.M. et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897–901 (1998).
Bach, J.F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002).
Ehlers, S. & Kaufmann, S.H. Infection, inflammation, and chronic diseases: consequences of a modern lifestyle. Trends Immunol. 31, 184–190 (2010).
Matarese, G. & La Cava, A. The intricate interface between immune system and metabolism. Trends Immunol. 25, 193–200 (2004).
Procaccini, C., Galgani, M., De Rosa, V. & Matarese, G. Intracellular metabolic pathways control immune tolerance. Trends Immunol. 33, 1–7 (2012).
Cooper, G.S., Bynum, M.L. & Somers, E.C. Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. J. Autoimmun. 33, 197–207 (2009).
Lerner, A., Jeremias, P. & Matthias, T. The world incidence and prevalence of autoimmune diseases is increasing. Int. J. Celiac. Dis. 3, 151–155 (2015).
Theofilopoulos, A.N., Kono, D.H. & Baccala, R. The multiple pathways to autoimmunity. Nat. Immunol. 18, 716–724 (2017).
United States Department of Agriculture (USDA)–Economic Research Service. Food availability (per capita) data system https://www.ers.usda.gov/data-products/food-availability-per-capita-data-system/ (2016).
Selmi, C. The worldwide gradient of autoimmune conditions. Autoimmun. Rev. 9, A247–A250 (2010).
Manzel, A. et al. Role of “Western diet” in inflammatory autoimmune diseases. Curr. Allergy Asthma Rep. 14, 404 (2014).
Odegaard, J.I. & Chawla, A. Connecting type 1 and type 2 diabetes through innate immunity. Cold Spring Harb. Perspect. Med. 2, a007724 (2012).
Harpsøe, M.C. et al. Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort. Int. J. Epidemiol. 43, 843–855 (2014).
Williams, E.P., Mesidor, M., Winters, K., Dubbert, P.M. & Wyatt, S.B. Overweight and obesity: prevalence, consequences, and causes of a growing public health problem. Curr. Obes. Rep. 4, 363–370 (2015).
Darmawan, J., Muirden, K.D., Valkenburg, H.A. & Wigley, R.D. The epidemiology of rheumatoid arthritis in Indonesia. Br. J. Rheumatol. 32, 537–540 (1993).
Friedman, J.M. The alphabet of weight control. Nature 385, 119–120 (1997).
Hill, J.O. Understanding and addressing the epidemic of obesity: an energy balance perspective. Endocr. Rev. 27, 750–761 (2006).
Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015).
Prentice, A.M. The thymus: a barometer of malnutrition. Br. J. Nutr. 81, 345–347 (1999).
Howard, J.K. et al. Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J. Clin. Invest. 104, 1051–1059 (1999).
Di Rosa, F. & Gebhardt, T. Bone marrow T cells and the integrated functions of recirculating and tissue-resident memory T cells. Front. Immunol. 7, 51 (2016).
Versini, M., Jeandel, P.Y., Rosenthal, E. & Shoenfeld, Y. Obesity in autoimmune diseases: not a passive bystander. Autoimmun. Rev. 13, 981–1000 (2014).
Ferrara, C.T. et al. Type 1 Diabetes TrialNet Study Group. Excess BMI in childhood: a modifiable risk factor for type 1 diabetes development? Diabetes Care 40, 698–701 (2017).
Fourlanos, S., Harrison, L.C. & Colman, P.G. The accelerator hypothesis and increasing incidence of type 1 diabetes. Curr. Opin. Endocrinol. Diabetes Obes. 15, 321–325 (2008).
Fourlanos, S. et al. The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care 31, 1546–1549 (2008).
Mokry, L.E. et al. Obesity and multiple sclerosis: A mendelian randomization study. PLoS Med. 13, e1002053 (2016).
Sterry, W., Strober, B.E. & Menter, A. Obesity in psoriasis: the metabolic, clinical and therapeutic implications. Report of an interdisciplinary conference and review. Br. J. Dermatol. 157, 649–655 (2007).
Procaccini, C. et al. Obesity and susceptibility to autoimmune diseases. Expert Rev. Clin. Immunol. 7, 287–294 (2011).
Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).
Winer, S. et al. Obesity predisposes to Th17 bias. Eur. J. Immunol. 39, 2629–2635 (2009).
Galgani, M. & Matarese, G. Editorial: acute inflammation in obesity: IL-17A in the middle of the battle. J. Leukoc. Biol. 87, 17–18 (2010).
Kono, D.H. & Theofilopoulos, A.N. Autoimmunity. In:. Kelley and Firestein's Textbook of Rheumatology 10th edn. (eds. Firestein, G.S., Budd, R.C., Gabriel, S.E., McInnes, I.B. & O'Dell, J.R.) 2, 301–317 (Elsevier, Philadelphia, 2017).
Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).
Winer, D.A. et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 17, 610–617 (2011).
Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).
Arai, S. et al. Obesity-associated autoantibody production requires AIM to retain the immunoglobulin M immune complex on follicular dendritic cells. Cell Reports 3, 1187–1198 (2013).
Kurien, B.T., Hensley, K., Bachmann, M. & Scofield, R.H. Oxidatively modified autoantigens in autoimmune diseases. Free Radic. Biol. Med. 41, 549–556 (2006).
Saxton, R.A. & Sabatini, D.M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).
Efeyan, A., Comb, W.C. & Sabatini, D.M. Nutrient-sensing mechanisms and pathways. Nature 517, 302–310 (2015).
Delgoffe, G.M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).
Procaccini, C. et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33, 929–941 (2010).
Kim, J.S. et al. Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways. Nat. Immunol. 14, 611–618 (2013).
Park, Y. et al. TSC1 regulates the balance between effector and regulatory T cells. J. Clin. Invest. 123, 5165–5178 (2013).
Zeng, H. et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499, 485–490 (2013).
Huynh, A. et al. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat. Immunol. 16, 188–196 (2015).
Gerriets, V.A. et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 17, 1459–1466 (2016).
De Rosa, V. et al. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat. Immunol. 16, 1174–1184 (2015).
Hawse, W.F., Boggess, W.C. & Morel, P.A. TCR signal strength regulates Akt substrate specificity to induce alternate murine Th and T regulatory cell differentiation programs. J. Immunol. 199, 589–597 (2017).
Turner, M.S., Kane, L.P. & Morel, P.A. Dominant role of antigen dose in CD4+Foxp3+ regulatory T cell induction and expansion. J. Immunol. 183, 4895–4903 (2009).
Turner, M.S., Isse, K., Fischer, D.K., Turnquist, H.R. & Morel, P.A. Low TCR signal strength induces combined expansion of Th2 and regulatory T cell populations that protect mice from the development of type 1 diabetes. Diabetologia 57, 1428–1436 (2014).
Miskov-Zivanov, N., Turner, M.S., Kane, L.P., Morel, P.A. & Faeder, J.R. The duration of T cell stimulation is a critical determinant of cell fate and plasticity. Sci. Signal. 6, ra97 (2013).
He, X. et al. Single CD28 stimulation induces stable and polyclonal expansion of human regulatory T cells. Sci. Rep. 7, 43003 (2017).
Sabbatini, M. et al. Oscillatory mTOR inhibition and Treg increase in kidney transplantation. Clin. Exp. Immunol. 182, 230–240 (2015).
Ersching, J. et al. Germinal center selection and affinity maturation require dynamic regulation of mTORC1 kinase. Immunity 46, 1045–1058 (2017).
Endo, Y. et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase ACC1. Cell Reports 12, 1042–1055 (2015).
Reis, B.S. et al. Leptin receptor signaling in T cells is required for Th17 differentiation. J. Immunol. 194, 5253–5260 (2015).
Stelzner, K. et al. Free fatty acids sensitize dendritic cells to amplify TH1/TH17-immune responses. Eur. J. Immunol. 46, 2043–2053 (2016).
Daley, S.R. et al. Rasgrp1 mutation increases naive T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies. eLife 2, e01020 (2013).
Ohkura, N., Kitagawa, Y. & Sakaguchi, S. Development and maintenance of regulatory T cells. Immunity 38, 414–423 (2013).
Shevach, E.M. & Thornton, A.M. tTregs, pTregs, and iTregs: similarities and differences. Immunol. Rev. 259, 88–102 (2014).
Kaur, G., Goodall, J.C., Jarvis, L.B. & Hill Gaston, J.S. Characterisation of Foxp3 splice variants in human CD4+ and CD8+ T cells–identification of Foxp3Δ7 in human regulatory T cells. Mol. Immunol. 48, 321–332 (2010).
Smith, E.L., Finney, H.M., Nesbitt, A.M., Ramsdell, F. & Robinson, M.K. Splice variants of human FOXP3 are functional inhibitors of human CD4+ T-cell activation. Immunology 119, 203–211 (2006).
Allan, S.E. et al. The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J. Clin. Invest. 115, 3276–3284 (2005).
Vukmanovic-Stejic, M. et al. Human CD4+CD2hiFoxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J. Clin. Invest. 116, 2423–2433 (2006).
Vukmanovic-Stejic, M. et al. The kinetics of CD4+Foxp3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo. J. Clin. Invest. 118, 3639–3650 (2008).
Zhu, J. & Shevach, E.M. TCR signaling fuels Treg cell suppressor function. Nat. Immunol. 15, 1002–1003 (2014).
Procaccini, C. et al. The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity 44, 406–421 (2016).
De Rosa, V. et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity 26, 241–255 (2007).
Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 25, 1282–1293 (2017).
Cipolletta, D. et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012).
Naito, M. et al. Therapeutic impact of leptin on diabetes, diabetic complications, and longevity in insulin-deficient diabetic mice. Diabetes 60, 2265–2273 (2011).
Perry, R.J., Petersen, K.F. & Shulman, G.I. Pleotropic effects of leptin to reverse insulin resistance and diabetic ketoacidosis. Diabetologia 59, 933–937 (2016).
Scudellari, M. News Feature: Cleaning up the hygiene hypothesis. Proc. Natl. Acad. Sci. USA 114, 1433–1436 (2017).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).
Netea, M.G. et al. Trained immunity: A program of innate immune memory in health and disease. Science 352, aaf1098 (2016).
Vatanen, T. et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 165, 1551 (2016).
Pross, H.F. & Eidinger, D. Antigenic competition: a review of nonspecific antigen-induced suppression. Adv. Immunol. 18, 133–168 (1974).
Serreze, D.V. & Leiter, E.H. Genetic and pathogenic basis of autoimmune diabetes in NOD mice. Curr. Opin. Immunol. 6, 900–906 (1994).
Delovitch, T.L. & Singh, B. The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7, 727–738 (1997).
Candon, S. et al. Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin-dependent diabetes. PLoS One 10, e0125448 (2015).
Brown, K. et al. Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice. ISME J. 10, 321–332 (2016).
Kostic, A.D. et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 17, 260–273 (2015).
Alam, C. et al. Effects of a germ-free environment on gut immune regulation and diabetes progression in non-obese diabetic (NOD) mice. Diabetologia 54, 1398–1406 (2011).
Sadelain, M.W., Qin, H.Y., Lauzon, J. & Singh, B. Prevention of type I diabetes in NOD mice by adjuvant immunotherapy. Diabetes 39, 583–589 (1990).
Qin, H.Y. & Singh, B. BCG vaccination prevents insulin-dependent diabetes mellitus (IDDM) in NOD mice after disease acceleration with cyclophosphamide. J. Autoimmun. 10, 271–278 (1997).
Lehmann, D. & Ben-Nun, A. Bacterial agents protect against autoimmune disease. I. Mice pre-exposed to Bordetella pertussis or Mycobacterium tuberculosis are highly refractory to induction of experimental autoimmune encephalomyelitis. J. Autoimmun. 5, 675–690 (1992).
Ben-Nun, A., Yossefi, S. & Lehmann, D. Protection against autoimmune disease by bacterial agents. II. PPD and pertussis toxin as proteins active in protecting mice against experimental autoimmune encephalomyelitis. Eur. J. Immunol. 23, 689–696 (1993).
Ben-Nun, A., Mendel, I., Sappler, G. & Kerlero de Rosbo, N. A 12-kDa protein of Mycobacterium tuberculosis protects mice against experimental autoimmune encephalomyelitis. Protection in the absence of shared T cell epitopes with encephalitogenic proteins. J. Immunol. 154, 2939–2948 (1995).
Carbone, F. et al. Regulatory T cell proliferative potential is impaired in human autoimmune disease. Nat. Med. 20, 69–74 (2014).
Kim, J.W. & Dang, C.V. Multifaceted roles of glycolytic enzymes. Trends Biochem. Sci. 30, 142–150 (2005).
Yang, Z., Fujii, H., Mohan, S.V., Goronzy, J.J. & Weyand, C.M. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J. Exp. Med. 210, 2119–2134 (2013).
Melis, D. et al. Cutting edge: increased autoimmunity risk in glycogen storage disease type 1b is associated with a reduced engagement of glycolysis in T cells and an impaired regulatory T cell function. J. Immunol. 198, 3803–3808 (2017).
Kim, J.G. et al. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat. Neurosci. 17, 908–910 (2014).
Matarese, G. et al. Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses. Proc. Natl. Acad. Sci. USA 110, 6193–6198 (2013).
Kuchroo, V.K. & Nicholson, L.B. Immunology: Fast and feel good? Nature 422, 27–28 (2003).
Sanna, V. et al. Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J. Clin. Invest. 111, 241–250 (2003).
Choi, I.Y. et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Reports 15, 2136–2146 (2016).
O'Neill, L.A. & Hardie, D.G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013).
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.).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni.3851
This article is cited by
-
PMI-controlled mannose metabolism and glycosylation determines tissue tolerance and virus fitness
Nature Communications (2024)
-
Reimagining an immunological dogma
Nature Immunology (2021)
-
Autoimmune Inflammation and Insulin Resistance: Hallmarks So Far and Yet So Close to Explain Diabetes Endotypes
Current Diabetes Reports (2021)
-
Divide and hide: proliferating β-cells control immune tolerance in autoimmune diabetes
Nature Metabolism (2019)