Abstract
In the rich, developed parts of the world there has been a steady and simultaneous increase in at least three groups of disease: (1) allergies, (2) inflammatory bowel diseases (IBD; e.g. Crohn’s disease and ulcerative colitis) and (3) autoimmunity (e.g. type 1 diabetes and multiple sclerosis). Because the medical world is so compartmentalised it was some time before the connection between these increases was noticed and understood. There is now evidence that the simultaneous increase in these diseases of immunodysregulation is at least partly attributable to malfunction of regulatory T cells (Treg). This paper provides an overview of relevant work in each of these fields of medicine (though with emphasis on the allergic disorders), and concludes that the increasing failure of Treg is a consequence of diminished exposure to certain micro-organisms that are “old friends”, because of their continuous presence throughout mammalian evolution. These organisms, which include saprophytic mycobacteria, helminths and lactobacilli, are recognised by the innate immune system as harmless, and as adjuvants for Treg induction. Polymorphisms of components of the innate immune system such as TLR2 and NOD2 appear to define subsets of the population that will develop immunoregulatory disorders when living in the modern environment. A further role of the “old friends” and of the Treg that they induce might be to maintain the levels of regulatory IL-10 secreting macrophages and antigen-presenting cells, which are depleted in asthma and Crohn’s disease. These concepts are leading to novel therapies based on harmless organisms or their components. Phase I/II clinical trials have yielded some statistically significant results, and phase II trials are in progress.
Similar content being viewed by others
References
Akdis CA, Joss A, Akdis M, et al (2001) Mechanism of IL-10-induced T-cell inactivation in allergic inflammation and normal response to allergens. Int Arch Allergy Immunol 124:180
Alm JS, Sanjeevi CB, Miller EN, et al (2002) Atopy in children in relation to BCG vaccination and genetic polymorphisms at SLC11A1 (formerly NRAMP1) and D2S1471. Genes Immunol 3:71
Ancuta P, Weiss L, Haeffner-Cavaillon N (2000) CD14+CD16++ cells derived in vitro from peripheral blood monocytes exhibit phenotypic and functional dendritic cell-like characteristics. Eur J Immunol 30:1872
Arbour NC, Lorenz E, Schutte BC, et al (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187
Arkwright PD, David TJ (2001) Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J Allergy Clin Immunol 107:531
Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911
Barclay AN, Wright GJ, Brooke G, et al (2002) CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol 23:285
Bashir ME, Andersen P, Fuss IJ, et al (2002) An enteric helminth infection protects against an allergic response to dietary antigen. J Immunol 169:3284
Baxter AG, Horsfall AC, Healey D, et al (1994) Mycobacteria precipitate an SLE-like syndrome in diabetes-prone NOD mice. Immunology 83:227
Belkaid Y, Piccirillo CA, Mendez S, et al (2002) CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420:502
Biggelaar AH van den, van Ree R, Rodrigues LC, et al (2000) Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet 356:1723
Bjorksten B, Naaber P, Sepp E, et al (1999) The intestinal microflora in allergic Estonian and Swedish 2-year-old children. Clin Exp Allergy 29:342
Braun-Fahrlander C, Riedler J, Herz U, et al (2002) Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 347:869
Brown E (2001) Integrin-associated protein (CD47): an unusual activator of G protein signaling. J Clin Invest 107:1499
Brunkow ME, Jeffery EW, Hjerrild KA, et al (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27:68
Bryan SA, O’Connor BJ, Matti S, et al (2000) Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356:2149
Camporota L, Corkhill A, Long H, et al (2003) The effects of Mycobacterium vaccae on allergen-induced airway responses in atopic asthma. Eur Respir J 21:287
Caramalho I, Lopes-Carvalho T, Ostler D, et al (2003) Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 197:403
Clynes RA, Towers TL, Presta LG, et al (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6:443
Coles AJ, Wing M, Smith S, et al (1999) Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 354:1691
Coles AJ, Wing MG, Molyneux P, et al (1999) Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 46:296
Dieli F, Sireci G, Scire E, et al (1999) Impaired contact hypersensitivity to trinitrocholobenzene in interleukin-4-deficient mice. Immunology 98:71
Douek IF, Leech NJ, Gillmor HA, et al (1999) Children with type-1 diabetes and their unaffected siblings have fewer symptoms of asthma. Lancet 353:1850
Du Bois RM (1999) Interferon gamma-1b for the treatment of idiopathic pulmonary fibrosis. N Engl J Med 341:1302
Dutronc Y, Porcelli SA (2002) The CD1 family and T cell recognition of lipid antigens. Tissue Antigens 60:337
Elliott DE, Urban JJ, Argo CK, et al (2000) Does the failure to acquire helminthic parasites predispose to Crohn’s disease? FASEB J 14:1848
Esposito K, Pontillo A, Giugliano F, et al (2003) Association of low interleukin-10 levels with the metabolic syndrome in obese women. J Clin Endocrinol Metab 88:1055
Farooqi IS, Hopkin JM (1998) Early childhood infection and atopic disorder. Thorax 53:927
Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4 (+) CD25 (+) regulatory T cells. Nat Immunol 4:330–336
Ford ES, Giles WH, Dietz WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287:356
Frings W, Dreier J, Sorg C (2002) Only the soluble form of the scavenger receptor CD163 acts inhibitory on phorbol ester-activated T-lymphocytes, whereas membrane-bound protein has no effect. FEBS Lett 526:93
Geijtenbeek TB, Van Vliet SJ, Koppel EA, et al (2003) Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med 197:7
Genain CP, Abel K, Belmar N, et al (1996) Late complications of immune deviation therapy in a nonhuman primate. Science 274:2054
Gerosa F, Nisii C, Righetti S, et al (1999) CD4 (+) T cell clones producing both interferon-gamma and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin Immunol 92:224
Gerosa F, Paganin C, Peritt D, et al (1996) Interleukin-12 primes human CD4 and CD8 T cell clones for high production of both interferon-gamma and interleukin-10. J Exp Med 183:2559
Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23
Grohmann U, Orabona C, Fallarino F, et al (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3:1097
Groux H, O’Garra A, Bigler M, et al (1997) A CD4+ subset inhibits antigen-specific T cell responses and prevents colitis. Nature 389:737
Hanngren A, Odham G, Eklund A, et al (1987) Tuberculostearic acid in lymph nodes from patients with sarcoidosis. Sarcoidosis 4:101
Hansen G, Berry G, DeKruyff RH, et al (1999) Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest 103:175
Heldwein KA, Fenton MJ (2002) The role of Toll-like receptors in immunity against mycobacterial infection. Microbes Infect 4:937
Hernandez-Pando R, Rook GAW (1994) The role of TNFα in T cell-mediated inflammation depends on the Th1/Th2 cytokine balance. Immunology 82:591
Hogg KG, Kumkate S, Anderson S, et al (2003) Interleukin-12 p40 secretion by cutaneous CD11c+ and F4/80+ cells is a major feature of the innate immune response in mice that develp Th1-mediated protective immunity to Schistosoma mansoni. Infect Immun 71:3563
Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057
Hutter C, Poulter LW (1992) The balance of macrophage subsets may be customised at mucosal surfaces. FEMS Microbiol Immunol 5:309
Huynh ML, Fadok VA, Henson PM (2002) Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest 109:41
Kabesch M, Peters W, Carr D, et al (2003) Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations. J Allergy Clin Immunol 111:813
Kalliomaki M, Isolauri E (2003) Role of intestinal flora in the development of allergy. Curr Opin Allergy. Clin Immunol 3:15
Kalliomaki M, Salminen S, Arvilommi H, et al (2001) Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 357:1076
Kam JC, Szefler SJ, Surs W, et al (1993) Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol 151:3460
Kang TJ, Lee SB, Chae GT (2002) A polymorphism in the toll-like receptor 2 is associated with IL-12 production from monocyte in lepromatous leprosy. Cytokine 20:56
Katz JD, Benoist C, Mathis D (1995) T helper cell subsets in insulin-dependent diabetes. Science 268:1185
Kezuka T, Streilein JW (2000) Analysis of in vivo regulatory properties of T cells activated in vitro by TGFbeta2-treated antigen presenting cells. Invest Ophthalmol Vis Sci 41:1410
Khoruts A, Miller SD, Jenkins MK (1995) Neuroantigen-specific Th2 cells are inefficient suppressors of experimental autoimmune encephalomyelitis induced by effector Th1 cells. J Immunol 155:5011
Kleij D van der, Latz E, Brouwers JF, et al (2002) A novel host-parasite lipid cross-talk. schistosomal lyso-phosphatidylserine activates toll-like receptor 2 and affects immune polarization. J Biol Chem 277:48122
Kohashi O, Kohashi Y, Takahashi T, et al (1985) Reverse effect of gram-positive bacteria vs. gram-negative bacteria on adjuvant-induced arthritis in germfree rats. Microbiol Immunol 29:487
Koppelman GH, Reijmerink NE, Colin Stine O, et al (2001) Association of a promoter polymorphism of the CD14 gene and atopy. Am J Respir Crit Care Med 163:965
Krug N, Madden J, Redington AE, et al (1996) T-cell cytokine profile evaluated at the single cell level in BAL and blood in allergic asthma. Am J Respir Cell Mol Biol 14:319
Lammas DA, Casanova JL, Kumararatne DS (2000) Clinical consequences of defects in the IL-12-dependent interferon-gamma (IFN-gamma) pathway. Clin Exp Immunol 121:417
Lauener RP, Birchler T, Adamski J, et al (2002) Expression of CD14 and Toll-like receptor 2 in farmers’ and non-farmers’ children. Lancet 360:465
Lawrence CE, Paterson JC, Higgins LM, et al (1998) IL-4-regulated enteropathy in an intestinal nematode infection. Eur J Immunol 28:2672
Leiter EH, Sundberg JP, Elson CO (2003) Genetic control of colitis susceptibility in IL-10-deficient mice. Inflamm Bowel Dis 9 [Suppl 1]:S6
Lindberg E, Lindquist B, Holmquist L, et al (2000) Inflammatory bowel disease in children and adolescents in Sweden, 1984–1995. J Pediatr Gastroenterol Nutr 30:259
Mallat Z, Besnard S, Duriez M, et al (1999) Protective role of interleukin-10 in atherosclerosis. Circ Res 85:e17
Mallat Z, Heymes C, Ohan J, et al (1999) Expression of interleukin-10 in advanced human atherosclerotic plaques: relation to inducible nitric oxide synthase expression and cell death. Arterioscler Thromb Vasc Biol 19:611
Matricardi PM, Rosmini F, Riondino S, et al (2000) Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study. BMJ 320:412
McIntire JJ, Umetsu SE, Akbari O, et al (2001) Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol 2:1109
Moudgil KD, Kim E, Yun OJ, et al (2001) Environmental modulation of autoimmune arthritis involves the spontaneous microbial induction of T cell responses to regulatory determinants within heat shock protein 65. J Immunol 166:4237
Munn DH, Sharma MD, Lee JR, et al (2002) Potential regulatory function of human dendritic cells expressing indoleamine 2-3-dioxygenase. Science 297:1867
Nouri-Aria KT, Jacobson MR, Durham SR (2002) Grass pollen immunotherapy (IT) increases IL-10 and TGF-beta mRNA expression in the nasal mucosa during the pollen season. J Allergy Clin Immunol 109:S171
O’Brien PE, Dixon JB (2002) The extent of the problem of obesity. Am J Surg 184:4S
Ogura Y, Bonen DK, Inohara N, et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603
Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033
Pinderski LJ, Fischbein MP, Subbanagounder G, et al (2002) Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient mice by altering lymphocyte and macrophage phenotypes. Circ Res 90:1064
Pinderski Oslund LJ, Hedrick CC, Olvera T, et al (1999) Interleukin-10 blocks atherosclerotic events in vitro and in vivo. Arterioscler Thromb Vasc Biol 19:2847
Platts-Mills T, Vaughan J, Squillace S, et al (2001) Sensitisation, asthma and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 357:752
Raby BA, Klimecki WT, Laprise C, et al (2002) Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes. Am J Respir Crit Care Med 166:1449
Rachmilewitz D, Karmeli F, Takabayashi K, et al (2002) Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 122:1428
Read S, Powrie F (2001) CD4+ regulatory T cells. Curr Opin Immunol 13:644
Renz H, mutius E, Illi S, et al (2002) T (H)1/T (H)2 immune response profiles differ between atopic children in eastern and western Germany. J Allergy Clin Immunol 109:338
Riedler J, Braun-Fahrlander C, Eder W, et al (2001) Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 358:1129
Roncarolo M, Levings MK (2000) The role of different subsets of T regulatory cells in controlling autoimmunity. Curr Opin Immunol 12:676
Sawczenko A, Sandhu BK, Logan RF, et al (2001) Prospective survey of childhood inflammatory bowel disease in the British Isles. Lancet 357:1093
Schultz M, Veltkamp C, Dieleman LA, et al (2002) Lactobacillus plantarum 299V in the treatment and prevention of spontaneous colitis in interleukin-10-deficient mice. Inflamm Bowel Dis 8:71
Sepp E, Julge K, Vasar M, et al (1997) Intestinal microflora of Estonian and Swedish infants. Acta Paediatr 86:956
Smit JJ, van Loveren H, Hoekstra MO, et al (2003) Influence of the macrophage bacterial resistance gene, Nramp1 (Slc11a1), on the induction of allergic asthma in the mouse. FASEB J 17:958
Smith DA, Irving SD, Sheldon J, et al (2001) Serum levels of the antiinflammatory cytokine interleukin-10 are decreased in patients with unstable angina. Circulation 104:746
Stene LC, Nafstad P (2001) Relation between occurrence of type 1 diabetes and asthma. Lancet 357:607
Strachan DP, Taylor EM, Carpenter RG (1996) Family structure, neonatal infection, and hay fever in adolescence. Arch Dis Child 74:422
Sudo N, Sawamura S, Tanaka K, et al (1997) The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 159:1739
Sudo N, Yu XN, Aiba Y, et al (2002) An oral introduction of intestinal bacteria prevents the development of a long-term Th2-skewed immunological memory induced by neonatal antibiotic treatment in mice. Clin Exp Allergy 32:1112
Sulahian TH, Hogger P, Wahner AE, et al (2000) Human monocytes express CD163, which is upregulated by IL-10 and identical to p155. Cytokine 12:1312
Terrazas LI, Walsh KL, Piskorska D, et al (2001) The schistosome oligosaccharide lacto-N-neotetraose expands Gr1 (+) cells that secrete anti-inflammatory cytokines and inhibit proliferation of naive CD4 (+) cells: a potential mechanism for immune polarization in helminth infections. J Immunol 167:5294
Tormey VJ, Leonard C, Faul J, et al (1998) Dysregulation of monocyte differentiation in asthmatic subjects is reversed by IL-10. Clin Exp Allergy 28:992
Tremlett HL, Evans J, Wiles CM, et al (2002) Asthma and multiple sclerosis: an inverse association in a case-control general practice population. Q J Med 95:753
Ulyanova T, Shah DD, Thomas ML (2001) Molecular cloning of MIS, a myeloid inhibitory siglec, that binds protein-tyrosine phosphatases SHP-1 and SHP-2. J Biol Chem 276:14451
Uyemura K, Demer LL, Castle SC, et al (1996) Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis. J Clin Invest 97:2130
Verdu EF, Bercik P, Cukrowska B, et al (2000) Oral administration of antigens from intestinal flora anaerobic bacteria reduces the severity of experimental acute colitis in BALB/c mice. Clin Exp Immunol 120:46
Voll RE, Herrmann M, Roth EA, et al (1997) Immunosuppressive effects of apoptotic cells. Nature 390:350
Wakkach A, Fournier N, Brun V, et al (2003) Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. Immunity 18:605
Weiland SK, von Mutius E, Hirsch T, et al (1999) Prevalence of respiratory and atopic disorders among children in the East and West of Germany five years after unification. Eur Respir J 14:862
Wildin RS, Ramsdell F, Peake J, et al (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27:18
Wynn TA, Cheever AW, Jankovic D, et al (1995) An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature 376:594
Yazdanbakhsh M, Kremsner PG, van Ree R (2002) Allergy, parasites, and the hygiene hypothesis. Science 296:490
Zuany-Amorim C, Manlius C, Trifilieff A, et al (2002) Long-term protective and antigen-specific effect of heat-killed Mycobacterium vaccae in a murine model of allergic pulmonary inflammation. J Immunol 169:1492
Zuany-Amorim C, Sawicka E, Manlius C, et al (2002) Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 8:625
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rook, G.A.W., Adams, V., Hunt, J. et al. Mycobacteria and other environmental organisms as immunomodulators for immunoregulatory disorders. Springer Semin Immun 25, 237–255 (2004). https://doi.org/10.1007/s00281-003-0148-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00281-003-0148-9