The initial application of the hygiene hypothesis for autoimmune diseases proposed in the early 2000s has been confirmed and consolidated by a wealth of published data in both animal models and human autoimmune conditions.
The hygiene hypothesis probably explains the uneven geographical distribution of autoimmune diseases in the world. Individuals migrating from countries with low incidence of autoimmune diseases to countries with high incidence develop the disease with the frequency of the host country, provided that migration occurred at a young age and under a threshold that varies according to the disease.
Pathogenic bacteria, viruses and parasites are often endowed with strong protective effects on autoimmunity even when infection occurs late after birth.
Gut commensal bacteria may also have a protective role in autoimmunity when administered early in life.
Pathogens, parasites and commensals essentially act by stimulating immune regulatory pathways, implicating the innate and the adaptive immune system. Importantly, the effect is seen with both living organisms and their derivatives or purified extracts.
Both pathogens and commensals stimulate pattern recognition receptors, including Toll-like receptors (TLRs) to protect against autoimmunity. This effect may be mimicked by TLR agonists acting through pharmacological stimulation or desensitization of the target receptor.
The incidence of autoimmune diseases has been steadily rising. Concomitantly, the incidence of most infectious diseases has declined. This observation gave rise to the hygiene hypothesis, which postulates that a reduction in the frequency of infections contributes directly to the increase in the frequency of autoimmune and allergic diseases. This hypothesis is supported by robust epidemiological data, but the underlying mechanisms are unclear. Pathogens are known to be important, as autoimmune disease is prevented in various experimental models by infection with different bacteria, viruses and parasites. Gut commensal bacteria also play an important role: dysbiosis of the gut flora is observed in patients with autoimmune diseases, although the causal relationship with the occurrence of autoimmune diseases has not been established. Both pathogens and commensals act by stimulating immunoregulatory pathways. Here, I discuss the importance of innate immune receptors, in particular Toll-like receptors, in mediating the protective effect of pathogens and commensals on autoimmunity.
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Strachan, D. P. Hay fever, hygiene, and household size. BMJ 299, 1259–1260 (1989). This is a visionary epidemiological study that paved the way for the hygiene hypothesis in atopic diseases.
Strachan, D. P. Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax 55 (Suppl. 1), S2–S10 (2000).
Ege, M. J. et al. Exposure to environmental microorganisms and childhood asthma. N. Engl. J. Med. 364, 701–709 (2011).
Greenwood, B. M., Herrick, E. M. & Voller, A. Suppression of autoimmune disease in NZB and (NZB x NZW) F1 hybrid mice by infection with malaria. Nature 226, 266–267 (1970).
Greenwood, B. M., Herrick, E. M. & Voller, A. Can parasitic infection suppress autoimmune disease? Proc. R. Soc. Med. 63, 19–20 (1970).
Rook, G. A. & Stanford, J. L. Give us this day our daily germs. Immunol. Today 19, 113–116 (1998).
Sewell, D. L., Reinke, E. K., Hogan, L. H., Sandor, M. & Fabry, Z. Immunoregulation of CNS autoimmunity by helminth and mycobacterial infections. Immunol. Lett. 82, 101–110 (2002).
Oldstone, M. B. Prevention of type I diabetes in nonobese diabetic mice by virus infection. Science 239, 500–502 (1988). This seminal study demonstrates the protective effect of a viral infection on the development of spontaneous autoimmune IDDM in NOD mice.
Oldstone, M. B., Ahmed, R. & Salvato, M. Viruses as therapeutic agents. II. Viral reassortants map prevention of insulin-dependent diabetes mellitus to the small RNA of lymphocytic choriomeningitis virus. J. Exp. Med. 171, 2091–2100 (1990).
Bach, J. F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002).
Bach, J. F. Protective role of infections and vaccinations on autoimmune diseases. J. Autoimmun. 16, 347–353 (2001).
Deckers, I. A. et al. Investigating international time trends in the incidence and prevalence of atopic eczema 1990-2010: a systematic review of epidemiological studies. PLoS ONE 7, e39803 (2012).
Kotz, D., Simpson, C. R. & Sheikh, A. Incidence, prevalence, and trends of general practitioner-recorded diagnosis of peanut allergy in England, 2001 to 2005. J. Allergy Clin. Immunol. 127, 623–630.e1 (2011).
Patterson, C. C. et al. Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase. Diabetologia 55, 2142–2147 (2012).
Karvonen, M., Pitkaniemi, J. & Tuomilehto, J. The onset age of type 1 diabetes in Finnish children has become younger. The Finnish Childhood Diabetes Registry Group. Diabetes Care 22, 1066–1070 (1999).
Koch-Henriksen, N. & Sorensen, P. S. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 9, 520–532 (2010).
Mackenzie, I. S., Morant, S. V., Bloomfield, G. A., MacDonald, T. M. & O'Riordan, J. Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the General Practice Research Database. J. Neurol. Neurosurg. Psychiatry 85, 76–84 (2014).
Grytten, N., Torkildsen, O. & Myhr, K. M. Time trends in the incidence and prevalence of multiple sclerosis in Norway during eight decades. Acta Neurol. Scand. 132, 29–36 (2015).
Houzen, H. et al. Increased prevalence, incidence, and female predominance of multiple sclerosis in northern Japan. J. Neurol. Sci. 323, 117–122 (2012).
Li, X. H. et al. A nine-year prospective study on the incidence of childhood type 1 diabetes mellitus in China. Biomed. Environ. Sci. 13, 263–270 (2000).
Handel, A. E., Handunnetthi, L., Ebers, G. C. & Ramagopalan, S. V. Type 1 diabetes mellitus and multiple sclerosis: common etiological features. Nat. Rev. Endocrinol. 5, 655–664 (2009).
Stewart, A. W., Mitchell, E. A., Pearce, N., Strachan, D. P. & Weiland, S. K. The relationship of per capita gross national product to the prevalence of symptoms of asthma and other atopic diseases in children (ISAAC). Int. J. Epidemiol. 30, 173–179 (2001).
Patterson, C. C., Carson, D. J. & Hadden, D. R. Epidemiology of childhood IDDM in Northern Ireland 1989-1994: low incidence in areas with highest population density and most household crowding. Diabetologia 39, 1063–1069 (1996).
Paalanen, L., Prattala, R., Palosuo, H., Helakorpi, S. & Laatikainen, T. Socio-economic differences in the use of dairy fat in Russian and Finnish Karelia, 1994–2004. Int. J. Publ. Health 55, 325–337 (2010).
Kondrashova, A. et al. A six-fold gradient in the incidence of type 1 diabetes at the eastern border of Finland. Ann. Med. 37, 67–72 (2005).
Laatikainen, T. et al. Allergy gap between Finnish and Russian Karelia on increase. Allergy 66, 886–892 (2011).
Kondrashova, A. et al. Signs of beta-cell autoimmunity in nondiabetic schoolchildren: a comparison between Russian Karelia with a low incidence of type 1 diabetes and Finland with a high incidence rate. Diabetes Care 30, 95–100 (2007).
Kuehni, C. E., Strippoli, M. P., Low, N. & Silverman, M. Asthma in young south Asian women living in the United Kingdom: the importance of early life. Clin. Exp. Allergy 37, 47–53 (2007).
Bodansky, H. J., Staines, A., Stephenson, C., Haigh, D. & Cartwright, R. Evidence for an environmental effect in the aetiology of insulin dependent diabetes in a transmigratory population. BMJ 304, 1020–1022 (1992).
Feltbower, R. G. et al. Trends in the incidence of childhood diabetes in south Asians and other children in Bradford. UK. Diabet. Med. 19, 162–166 (2002).
Dean, G. & Elian, M. Age at immigration to England of Asian and Caribbean immigrants and the risk of developing multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 63, 565–568 (1997).
Gale, C. R. & Martyn, C. N. Migrant studies in multiple sclerosis. Prog. Neurobiol. 47, 425–448 (1995).
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). This is a remarkable study reporting the detailed follow-up of the gut microbiota composition in children at risk of developing IDDM from birth to the onset of hyperglycaemia.
Ball, T. M. et al. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N. Engl. J. Med. 343, 538–543 (2000).
Cardwell, C. R. et al. Birth order and childhood type 1 diabetes risk: a pooled analysis of 31 observational studies. Int. J. Epidemiol. 40, 363–374 (2011).
Almeida, M. C. et al. The effect of antihelminthic treatment on subjects with asthma from an endemic area of schistosomiasis: a randomized, double-blinded, and placebo-controlled trial. J. Parasitol. Res. 2012, 296856 (2012).
Fleming, J. O. et al. Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study. Mult. Scler. 17, 743–754 (2011).
Larson, J. D. et al. Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity. Proc. Natl Acad. Sci. USA 109, E1092–E1100 (2012).
Alyanakian, M. A. et al. Transforming growth factor-beta and natural killer T-cells are involved in the protective effect of a bacterial extract on type 1 diabetes. Diabetes 55, 179–185 (2006).
Finlay, C. M., Walsh, K. P. & Mills, K. H. Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases. Immunol. Rev. 259, 206–230 (2014).
Gause, W. C. & Maizels, R. M. Macrobiota -— helminths as active participants and partners of the microbiota in host intestinal homeostasis. Curr. Opin. Microbiol. 32, 14–18 (2016). This study reports that the helminth H. polygyrus produces a TGFβ mimic that fully reproduces the effect of this immunoregulatory cytokine on the host immune system.
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).
De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl Acad. Sci. USA 107, 14691–14696 (2010).
Lin, A. et al. Distinct distal gut microbiome diversity and composition in healthy children from Bangladesh and the United States. PLoS ONE 8, e53838 (2013).
David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).
Schmidt, B. et al. Establishment of normal gut microbiota is compromised under excessive hygiene conditions. PLoS ONE 6, e28284 (2011). This study provides direct confirmation of the role of hygiene on gut microbiota composition in an original experimental model using piglets reared in conventional or clean conditions.
Vatanen, T. et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 165, 842–853 (2016). This is a comparative study of the gut microbiota composition in individuals from Finland and Karelia, two neighbouring countries with a substantial difference in the incidence of IDDM. The study demonstrates structural differences in LPS produced by 'non-protective' versus 'protective' commensals in the Finnish and the Karelian microbiota, respectively.
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).
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).
Yurkovetskiy, L. et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 39, 400–412 (2013).
Brown, K. et al. Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice. ISME J. 10, 321–332 (2016).
Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).
Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4615–4622 (2011).
Goverman, J. et al. Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72, 551–560 (1993).
Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).
Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).
Barclay, W. & Shinohara, M. L. Inflammasome activation in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Brain Pathol. 27, 213–219 (2017).
Dumas, A. et al. The inflammasome pyrin contributes to pertussis toxin-induced IL-1β synthesis, neutrophil intravascular crawling and autoimmune encephalomyelitis. PLoS Pathog. 10, e1004150 (2014).
Aumeunier, A. et al. Systemic Toll-like receptor stimulation suppresses experimental allergic asthma and autoimmune diabetes in NOD mice. PLoS ONE 5, e11484 (2010). This is the first systematic comparative study of the protective effect of different TLR agonists on autoimmunity and experimental asthma, which shows that distinct mechanisms underlie the therapeutic activity, depending on the TLR agonist used.
Calcinaro, F. et al. Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse. Diabetologia 48, 1565–1575 (2005).
Falcone, M. et al. Prevention of onset in an insulin-dependent diabetes mellitus model, NOD mice, by oral feeding of Lactobacillus casei. J. Diabetes Res. 105, 643–649 (1997).
Lavasani, S. et al. A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. PLoS ONE 5, e9009 (2010).
Markle, J. G. et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084–1088 (2013).
Wen, L. et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 455, 1109–1113 (2008).
Peng, J. et al. Long term effect of gut microbiota transfer on diabetes development. J. Autoimmun 53, 85–94 (2014).
Cardwell, C. R. et al. Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies. Diabetologia 51, 726–735 (2008).
Clausen, T. D. et al. Prelabor cesarean section and risk of childhood type 1 diabetes: a nationwide register-based cohort study. Epidemiology 27, 547–555 (2016).
Maghzi, A. H. et al. Cesarean delivery may increase the risk of multiple sclerosis. Mult. Scler. 18, 468–471 (2012).
Knights, D. et al. Use of antibiotics in childhood and risk of Type 1 diabetes: a population-based case-control study. Nat. Microbiol. 34, 272–277 (2017).
Boursi, B., Mamtani, R., Haynes, K. & Yang, Y. X. The effect of past antibiotic exposure on diabetes risk. Eur. J. Endocrinol. 172, 639–648 (2015).
Clausen, T. D. et al. Broad-spectrum antibiotic treatment and subsequent childhood type 1 diabetes: a nationwide Danish cohort study. PLoS ONE 11, e0161654 (2016).
Hviid, A. & Svanstrom, H. Antibiotic use and type 1 diabetes in childhood. Am. J. Epidemiol. 169, 1079–1084 (2009).
Livanos, A. E. et al. Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat. Microbiol. 1, 16140 (2016).
Alonso, A., Jick, S. S., Jick, H. & Hernan, M. A. Antibiotic use and risk of multiple sclerosis. Am. J. Epidemiol. 163, 997–1002 (2006).
Ljungberg, M., Korpela, R., Ilonen, J., Ludvigsson, J. & Vaarala, O. Probiotics for the prevention of beta cell autoimmunity in children at genetic risk of type 1 diabetes — the PRODIA study. Ann. NY Acad. Sci. 1079, 360–364 (2006).
Uusitalo, U. et al. Association of early exposure of probiotics and islet autoimmunity in the TEDDY study. JAMA Pediatr. 170, 20–28 (2016).
Pelucchi, C. et al. Probiotics supplementation during pregnancy or infancy for the prevention of atopic dermatitis: a meta-analysis. Epidemiology 23, 402–414 (2012).
Liacopoulos, P. & Ben-Efraim, S. Antigenic competition. Prog. Allergy 18, 97–204 (1975).
Pross, H. F. & Eidinger, D. Antigenic competition: a review of nonspecific antigen-induced suppression. Adv. Immunol. 18, 133–168 (1974).
Buus, S., Sette, A., Colon, S. M., Miles, C. & Grey, H. M. The relation between major histocompatibility complex (MHC) restriction and the capacity of Ia to bind immunogenic peptides. Science 235, 1353–1358 (1987).
Guillet, J. G. et al. Immunological self, nonself discrimination. Science 235, 865–870 (1987).
Almeida, A. R., Rocha, B., Freitas, A. A. & Tanchot, C. Homeostasis of T cell numbers: from thymus production to peripheral compartmentalization and the indexation of regulatory T cells. Semin. Immunol. 17, 239–249 (2005).
Surh, C. D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848–862 (2008).
Qin, H. Y., Sadelain, M. W., Hitchon, C., Lauzon, J. & Singh, B. Complete Freund's adjuvant-induced T cells prevent the development and adoptive transfer of diabetes in nonobese diabetic mice. J. Immunol. 150, 2072–2080 (1993).
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).
Lee, I. F., Qin, H., Trudeau, J., Dutz, J. & Tan, R. Regulation of autoimmune diabetes by complete Freund's adjuvant is mediated by NK cells. J. Immunol. 172, 937–942 (2004).
Tian, B. et al. Upregulating CD4+CD25+FOXP3+ regulatory T cells in pancreatic lymph nodes in diabetic NOD mice by adjuvant immunotherapy. Transplantation 87, 198–206 (2009).
Serreze, D. V. et al. Th1 to Th2 cytokine shifts in nonobese diabetic mice: sometimes an outcome, rather than the cause, of diabetes resistance elicited by immunostimulation. J. Immunol. 166, 1352–1359 (2001).
Mori, Y., Kodaka, T., Kato, T., Kanagawa, E. M. & Kanagawa, O. Critical role of IFN-γ in CFA-mediated protection of NOD mice from diabetes development. Int. Immunol. 21, 1291–1299 (2009).
Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).
Caramalho, I. et al. Regulatory T cells contribute to diabetes protection in lipopolysaccharide-treated non-obese diabetic mice. Scand. J. Immunol. 74, 585–595 (2011).
Tian, J. et al. Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. J. Immunol. 167, 1081–1089 (2001).
Fillatreau, S., Sweenie, C. H., McGeachy, M. J., Gray, D. & Anderton, S. M. B cells regulate autoimmunity by provision of IL-10. Nat. Immunol. 3, 944–950 (2002).
Mauri, C., Gray, D., Mushtaq, N. & Londei, M. Prevention of arthritis by interleukin 10-producing B cells. J. Exp. Med. 197, 489–501 (2003).
Mizoguchi, A., Mizoguchi, E., Takedatsu, H., Blumberg, R. S. & Bhan, A. K. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 16, 219–230 (2002).
Shen, P. & Fillatreau, S. Antibody-independent functions of B cells: a focus on cytokines. Nat. Rev. Immunol. 15, 441–451 (2015).
Shen, P. et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507, 366–370 (2014).
Shen, P. & Fillatreau, S. Suppressive functions of B cells in infectious diseases. Int. Immunol. 27, 513–519 (2015).
Filippi, C. M., Estes, E. A., Oldham, J. E. & von Herrath, M. G. Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice. J. Clin. Invest. 119, 1515–1523 (2009).
Cooke, A. et al. Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice. Parasite Immunol. 21, 169–176 (1999).
Zaccone, P. et al. Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes. Eur. J. Immunol. 33, 1439–1449 (2003).
Grainger, J. R. et al. Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway. J. Exp. Med. 207, 2331–2341 (2010).
Ince, M. N. et al. Role of T cell TGF-β signaling in intestinal cytokine responses and helminthic immune modulation. Eur. J. Immunol. 39, 1870–1878 (2009).
Liu, Q. et al. Helminth infection can reduce insulitis and type 1 diabetes through CD25- and IL-10-independent mechanisms. Infect. Immun. 77, 5347–5358 (2009).
Walk, S. T., Blum, A. M., Ewing, S. A., Weinstock, J. V. & Young, V. B. Alteration of the murine gut microbiota during infection with the parasitic helminth Heligmosomoides polygyrus. Inflamm. Bowel Dis. 16, 1841–1849 (2010).
Ramanan, D. et al. Helminth infection promotes colonization resistance via type 2 immunity. Science 352, 608–612 (2016).
Hubner, M. P., Stocker, J. T. & Mitre, E. Inhibition of type 1 diabetes in filaria-infected non-obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells. Immunology 127, 512–522 (2009).
Hubner, M. P. et al. Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-β. J. Immunol. 188, 559–568 (2012).
Lund, M. E. et al. Secreted proteins from the helminth Fasciola hepatica inhibit the initiation of autoreactive T cell responses and prevent diabetes in the NOD mouse. PLoS ONE 9, e86289 (2014).
Finlay, C. M. et al. Helminth products protect against autoimmunity via innate type 2 cytokines IL-5 and IL-33, which promote eosinophilia. J. Immunol. 196, 703–714 (2016).
Cording, S., Medvedovic, J., Aychek, T. & Eberl, G. Innate lymphoid cells in defense, immunopathology and immunotherapy. Nat. Immunol. 17, 755–757 (2016).
Dolpady, J. et al. Oral probiotic VSL#3 prevents autoimmune diabetes by modulating microbiota and promoting indoleamine 2,3-dioxygenase-enriched tolerogenic intestinal environment. J. Diabetes Res. 2016, 7569431 (2016).
Kobayashi, T. et al. Probiotic upregulation of peripheral IL-17 responses does not exacerbate neurological symptoms in experimental autoimmune encephalomyelitis mouse models. Immunopharmacol. Immunotoxicol. 34, 423–433 (2012).
Ochoa-Reparaz, J. et al. Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J. Immunol. 183, 6041–6050 (2009).
Ochoa-Reparaz, J. et al. A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol. 3, 487–495 (2010). This is an important study describing a constituent of the commensal organism B. fragilis (that is, PSA) with remarkable protective activity in models of EAE and colitis.
Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008).
Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).
Chinen, T., Volchkov, P. Y., Chervonsky, A. V. & Rudensky, A. Y. A critical role for regulatory T cell-mediated control of inflammation in the absence of commensal microbiota. J. Exp. Med. 207, 2323–2330 (2010).
Ivanov, I. I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337–349 (2008).
Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).
Nagano, Y., Itoh, K. & Honda, K. The induction of Treg cells by gut-indigenous Clostridium. Curr. Opin. Immunol. 24, 392–397 (2012).
Gagliani, N. et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat. Med. 19, 739–746 (2013).
Apetoh, L. et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Brain Pathol. 11, 854–861 (2010).
Weiner, H. L., da Cunha, A. P., Quintana, F. & Wu, H. Oral tolerance. Immunol. Rev. 241, 241–259 (2011).
Pistoia, V. & Raffaghello, L. Mesenchymal stromal cells and autoimmunity. Int. Immunol. 29, 49–58 (2017).
Uccelli, A., Moretta, L. & Pistoia, V. Mesenchymal stem cells in health and disease. Nat. Rev. Immunol. 8, 726–736 (2008).
Sica, A. & Massarotti, M. Myeloid suppressor cells in cancer and autoimmunity. J. Autoimmun. http://dx.doi.org/10.1016/j.jaut.2017.07.010 (2017).
Karumuthil-Melethil, S., Perez, N., Li, R. & Vasu, C. Induction of innate immune response through TLR2 and dectin 1 prevents type 1 diabetes. J. Immunol. 181, 8323–8334 (2008).
Karumuthil-Melethil, S. et al. TLR2- and Dectin 1-associated innate immune response modulates T-cell response to pancreatic β-cell antigen and prevents type 1 diabetes. Diabetes 64, 1341–1357 (2015).
Serreze, D. V., Hamaguchi, K. & Leiter, E. H. Immunostimulation circumvents diabetes in NOD/Lt mice. J. Autoimmun. 2, 759–776 (1989).
Quintana, F. J., Rotem, A., Carmi, P. & Cohen, I. R. Vaccination with empty plasmid DNA or CpG oligonucleotide inhibits diabetes in nonobese diabetic mice: modulation of spontaneous 60-kDa heat shock protein autoimmunity. J. Immunol. 165, 6148–6155 (2000).
Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).
Wang, Y. et al. An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling. Nat. Commun. 5, 4432 (2014).
Filippi, C. M. et al. TLR2 signaling improves immunoregulation to prevent type 1 diabetes. Eur. J. Immunol. 41, 1399–1409 (2011).
Xiong, Y. et al. Endotoxin tolerance inhibits Lyn and c-Src phosphorylation and association with Toll-like receptor 4 but increases expression and activity of protein phosphatases. J. Innate Immun. 8, 171–184 (2016).
Freudenberg, M. A. & Galanos, C. Induction of tolerance to lipopolysaccharide (LPS)-D-galactosamine lethality by pretreatment with LPS is mediated by macrophages. Infect. Immun. 56, 1352–1357 (1988).
Medvedev, A. E., Kopydlowski, K. M. & Vogel, S. N. Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: dysregulation of cytokine, chemokine, and Toll-like receptor 2 and 4 gene expression. J. Immunol. 164, 5564–5574 (2000). This is a comprehensive work on changes in intracellular signalling in macrophages that lead to LPS (endotoxin) tolerance, which highlights the fundamental role of the activation of various phosphatases.
Kim, D. H. et al. Inhibition of autoimmune diabetes by TLR2 tolerance. J. Immunol. 187, 5211–5220 (2011).
Anstadt, E. J., Fujiwara, M., Wasko, N., Nichols, F. & Clark, R. B. TLR tolerance as a treatment for central nervous system autoimmunity. J. Immunol. 197, 2110–2118 (2016). This is an interesting report demonstrating that low doses of two different TLR2 ligands attenuate adoptively transferred EAE through receptor desensitization. One of these TLR2 ligands is a human microbiome product, which has significantly decreased serum levels in patients with multiple sclerosis compared with unaffected controls.
Hayashi, T. et al. Treatment of autoimmune inflammation by a TLR7 ligand regulating the innate immune system. PLoS ONE 7, e45860 (2012).
Schuijs, M. J. et al. Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells. Science 349, 1106–1110 (2015). This is a study highlighting the potential in vivo relevance of TLR desensitization by LPS in humans. The novel finding is that the LPS-induced TLR4 desensitization targets the lung epithelium and requires the ubiquitin-modifying enzyme A20.
Siebeneicher, S. et al. Epicutaneous immune modulation with Bet v 1 plus R848 suppresses allergic asthma in a murine model. Allergy 69, 328–337 (2014).
Aryan, Z. & Rezaei, N. Toll-like receptors as targets for allergen immunotherapy. Curr. Opin. Allergy Clin. Immunol. 15, 568–574 (2015).
Burrows, M. P., Volchkov, P., Kobayashi, K. S. & Chervonsky, A. V. Microbiota regulates type 1 diabetes through Toll-like receptors. Proc. Natl Acad. Sci. USA 112, 9973–9977 (2015). This is a unique study that uses a genetic approach and proposes a distinct role for single TLRs in their capacity to modulate autoimmunity.
Bras, A. & Aguas, A. P. Diabetes-prone NOD mice are resistant to Mycobacterium avium and the infection prevents autoimmune disease. Immunology 89, 20–25 (1996).
Lee, J., Reinke, E. K., Zozulya, A. L., Sandor, M. & Fabry, Z. Mycobacterium bovis bacille Calmette-Guerin infection in the CNS suppresses experimental autoimmune encephalomyelitis and Th17 responses in an IFN-γ-independent manner. J. Immunol. 181, 6201–6212 (2008).
Newland, S. A. et al. PD-L1 blockade overrides Salmonella typhimurium-mediated diabetes prevention in NOD mice: no role for Tregs. Eur. J. Immunol. 41, 2966–2976 (2011).
Drescher, K. M., Kono, K., Bopegamage, S., Carson, S. D. & Tracy, S. Coxsackievirus B3 infection and type 1 diabetes development in NOD mice: insulitis determines susceptibility of pancreatic islets to virus infection. Virology 329, 381–394 (2004).
Tracy, S. et al. Toward testing the hypothesis that group B coxsackieviruses (CVB) trigger insulin-dependent diabetes: inoculating nonobese diabetic mice with CVB markedly lowers diabetes incidence. J. Virol. 76, 12097–12111 (2002).
Davydova, B. et al. Coxsackievirus immunization delays onset of diabetes in non-obese diabetic mice. J. Med. Virol. 69, 510–520 (2003).
Richer, M. J., Straka, N., Fang, D., Shanina, I. & Horwitz, M. S. Regulatory T-cells protect from type 1 diabetes after induction by coxsackievirus infection in the context of transforming growth factor-β. Diabetes 57, 1302–1311 (2008).
Hermitte, L. et al. Paradoxical lessening of autoimmune processes in non-obese diabetic mice after infection with the diabetogenic variant of encephalomyocarditis virus. Eur. J. Immunol. 20, 1297–1303 (1990).
Takei, I. et al. Suppression of development of diabetes in NOD mice by lactate dehydrogenase virus infection. J. Autoimmun. 5, 665–673 (1992).
Wilberz, S., Partke, H. J., Dagnaes-Hansen, F. & Herberg, L. Persistent MHV (mouse hepatitis virus) infection reduces the incidence of diabetes mellitus in non-obese diabetic mice. Diabetologia 34, 2–5 (1991).
Smith, K. A., Efstathiou, S. & Cooke, A. Murine gammaherpesvirus-68 infection alters self-antigen presentation and type 1 diabetes onset in NOD mice. J. Immunol. 179, 7325–7333 (2007).
Mishra, P. K., Patel, N., Wu, W., Bleich, D. & Gause, W. C. Prevention of type 1 diabetes through infection with an intestinal nematode parasite requires IL-10 in the absence of a Th2-type response. Mucosal Immunol. 6, 297–308 (2013).
Saunders, K. A., Raine, T., Cooke, A. & Lawrence, C. E. Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect. Immun. 75, 397–407 (2007).
Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
Inoue, M., Williams, K. L., Gunn, M. D. & Shinohara, M. L. NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 109, 10480–10485 (2012).
Inoue, M. et al. Interferon-β therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome. Sci. Signal. 5, ra38 (2012).
Cuda, C. M., Pope, R. M. & Perlman, H. The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases. Nat. Rev. Rheumatol. 12, 543–558 (2016).
de Souza, H. S. & Fiocchi, C. Immunopathogenesis of IBD: current state of the art. Nat. Rev. Gastroenterol. Hepatol. 13, 13–27 (2016).
von Moltke, J., Ayres, J. S., Kofoed, E. M., Chavarria-Smith, J. & Vance, R. E. Recognition of bacteria by inflammasomes. Annu. Rev. Immunol. 31, 73–106 (2013).
Rzepecka, J. et al. Prophylactic and therapeutic treatment with a synthetic analogue of a parasitic worm product prevents experimental arthritis and inhibits IL-1beta production via NRF2-mediated counter-regulation of the inflammasome. J. Autoimmun. 60, 59–73 (2015).
Patterson, C. et al. Diabetes in the young — a global view and worldwide estimates of numbers of children with type 1 diabetes. Diabetes Res. Clin. Pract. 103, 161–175 (2013).
Giongo, A. et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 5, 82–91 (2011).
Brown, C. T. et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS ONE 6, e25792 (2011).
de Goffau, M. C. et al. Fecal microbiota composition differs between children with beta-cell autoimmunity and those without. Diabetes 62, 1238–1244 (2013).
Murri, M. et al. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med. 11, 46 (2013).
Soyucen, E. et al. Differences in the gut microbiota of healthy children and those with type 1 diabetes. Pediatr. Int. 56, 336–343 (2014).
Davis-Richardson, A. G. et al. Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes. Front. Microbiol. 5, 678 (2014).
Endesfelder, D. et al. Compromised gut microbiota networks in children with anti-islet cell autoimmunity. Diabetes 63, 2006–2014 (2014).
Mejia-Leon, M. E., Petrosino, J. F., Ajami, N. J., Dominguez-Bello, M. G. & de la Barca, A. M. Fecal microbiota imbalance in Mexican children with type 1 diabetes. Sci. Rep. 4, 3814 (2014).
Alkanani, A. K. et al. Alterations in intestinal microbiota correlate with susceptibility to type 1 diabetes. Diabetes 64, 3510–3520 (2015).
Qi, C. J. et al. Imbalance of fecal microbiota at newly diagnosed type 1 diabetes in Chinese children. Chin. Med. J. 129, 1298–1304 (2016).
Maffeis, C. et al. Association between intestinal permeability and faecal microbiota composition in Italian children with beta cell autoimmunity at risk for type 1 diabetes. Diabetes Metab. Res. Rev. 32, 700–709 (2016).
Stewart, C. J. et al. Gut microbiota of Type 1 diabetes patients with good glycaemic control and high physical fitness is similar to people without diabetes: an observational study. Diabet Med. 34, 127–134 (2017).
Miyake, S. et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to Clostridia XIVa and IV clusters. PLoS ONE 10, e0137429 (2015).
Tremlett, H. et al. Gut microbiota in early pediatric multiple sclerosis: a case-control study. Eur. J. Neurol. 23, 1308–1321 (2016).
Chen, J. et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci. Rep. 6, 28484 (2016).
Hevia, A. et al. Intestinal dysbiosis associated with systemic lupus erythematosus. mBio 5, e01548–e01514 (2014).
Wilson, C. S., Elizer, S. K., Marshall, A. F., Stocks, B. T. & Moore, D. J. Regulation of B lymphocyte responses to Toll-like receptor ligand binding during diabetes prevention in non-obese diabetic (NOD) mice. J. Diabetes 8, 120–131 (2016).
Zhang, Y. et al. TLR9 blockade inhibits activation of diabetogenic CD8+ T cells and delays autoimmune diabetes. J. Immunol. 184, 5645–5653 (2010).
Manicassamy, S. et al. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat. Med. 15, 401–409 (2009).
Manoharan, I. et al. TLR2-dependent activation of beta-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. J. Immunol. 193, 4203–4213 (2014).
Li, H. et al. Low dose zymosan ameliorates both chronic and relapsing experimental autoimmune encephalomyelitis. J. Neuroimmunol. 254, 28–38 (2013).
Dillon, S. et al. Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance. J. Clin. Invest. 116, 916–928 (2006).
Barrat, F. J. & Coffman, R. L. Development of TLR inhibitors for the treatment of autoimmune diseases. Immunol. Rev. 223, 271–283 (2008).
Barrat, F. J., Meeker, T., Chan, J. H., Guiducci, C. & Coffman, R. L. Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. Eur. J. Immunol. 37, 3582–3586 (2007).
Wong, F. S. et al. The role of Toll-like receptors 3 and 9 in the development of autoimmune diabetes in NOD mice. Ann. NY Acad. Sci. 1150, 146–148 (2008).
Gulden, E. et al. Toll-like receptor 4 deficiency accelerates the development of insulin-deficient diabetes in non-obese diabetic mice. PLoS ONE 8, e75385 (2013).
Prinz, M. et al. Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. J. Clin. Invest. 116, 456–464 (2006).
Cohen, S. J., Cohen, I. R. & Nussbaum, G. IL-10 mediates resistance to adoptive transfer experimental autoimmune encephalomyelitis in MyD88−/− mice. J. Immunol. 184, 212–221 (2010).
Marta, M., Andersson, A., Isaksson, M., Kampe, O. & Lobell, A. Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis. Eur. J. Immunol. 38, 565–575 (2008).
Miranda-Hernandez, S. et al. Role for MyD88, TLR2 and TLR9 but not TLR1, TLR4 or TLR6 in experimental autoimmune encephalomyelitis. J. Immunol. 187, 791–804 (2011). This is a comprehensive study that examines the impact of TLR invalidation in the development of EAE.
Reynolds, J. M. et al. Toll-like receptor 2 signaling in CD4+ T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity 32, 692–702 (2010).
Christensen, S. R. et al. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25, 417–428 (2006).
Atlas of MS 2013. https://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf
Global tuberculosis report 2016. http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1
Screening for hepatitis during the domestic medical examination for newly arrived refugees. https://www.cdc.gov/immigrantrefugeehealth/pdf/domestic-hepatitis-screening-guidelines.pdf
Caisse des Français de l'Étranger. https://www.cfe.fr/pages/votre-sante/guidespatho.php?id=126 [French]
International Monetary Fund. World Economic Outlook Database. https://www.imf.org/external/pubs/ft/weo/2015/01/weodata/index.aspx
The laboratory of the author was supported by an advanced grant from the European Research Council (ERC, Hygiene N°: 250290).
The author declares no competing financial interests.
A genetic predisposition to the cumulative development of common allergies, for example, atopic dermatitis and allergic asthma. Atopy involves phenomena of cutaneous or general hypersensitivity to allergens.
- Hygiene hypothesis
A hypothesis that postulates that an increased frequency of infections contributes to a decrease in autoimmune and allergic diseases.
- Non-obese diabetic (NOD) mice
An inbred mouse line that spontaneously develops an autoimmune syndrome including insulin-dependent diabetes mellitus (IDDM or type 1 diabetes).
- Traveller's diarrhoea
A digestive tract disorder provoked by eating contaminated food or drinking contaminated water. In the context of our discussion, it is a self-limited pathology that illustrates the presence of a basic health environment.
- Anti-islet β-cell autoantibodies
Autoantibodies to various β-cell-specific autoantigens that are markers of the destruction of insulin-producing β-cells, which is the hallmark of insulin-dependent diabetes mellitus (IDDM or type 1 diabetes).
An imbalance of the microbial flora that most frequently affects the digestive tract. Dysbiosis can also be detected in other 'barrier' organs such as the skin, the lungs or the vagina.
The metabolome consists of all signalling molecules (for example, metabolites and hormones) detected in a biological sample. The metabolome thus defines a given physiological or pathological state and is therefore dynamic.
- Germ-free mice
Mice born by hysterectomy under sterile conditions and raised in isolators to guarantee an environment totally devoid of pathogenic and commensal germs.
- Experimental autoimmune encephalomyelitis
(EAE). A demyelinating allergic encephalomyelitis produced by the injection of brain tissue or purified proteins of the nervous system or their derived peptides in the presence of an adjuvant.
- Gnotobiotic mice
Germ-free mice whose intestinal microflora is reconstituted by a single commensal bacterium (monocolonized mice).
Gut commensal bacteria available as single or combined species delivered orally and putatively endowed with a health benefit.
- Antigenic competition
The competition for recognition of the cognate antigen for soluble factors (cytokines) driving the proliferation and differentiation of antigen-specific lymphocytes.
- Syngeneic islet grafts
Islet transplants between syngeneic (genetically identical) donor and recipient individuals, which therefore does not give rise to allograft rejection. These grafts performed in diabetic non-obese diabetic mice provide a robust model to test for recurrence of the autoimmune disease.
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Bach, J. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat Rev Immunol 18, 105–120 (2018). https://doi.org/10.1038/nri.2017.111
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