Infectious diseases have a major impact on both the development and the severity of asthma. The rise in incidence of asthma in industrialized countries over the last decades has been attributed to increased hygiene standards as well as the concomitant usage of antibiotics, which together lower the incidence of infections. Although this point of view is supported by both clinical studies and experimental approaches in mice, an increasing body of evidence suggests that certain infectious diseases may predispose for the development of asthma, thus challenging the `hygiene hypothesis' in its classical form. Toll-like receptors (TLRs) are centrally involved in orchestrating immune responses towards various micro-organisms. Because of this, it is tempting to speculate that signaling through TLRs may be involved in mechanisms provoking Th1- or Th2-biased immune responses and may, therefore, be an important factor in either preventing or promoting allergic airway disease. This review summarizes clinical and experimental data from mouse models focused on the impact of TLR-signaling on allergic asthma.
Eder W., Ege MJ, von Mutius E.The asthma epidemic. N Engl J Med2006; 355: 2226—2235.
2.
Beasley R., Crane J., Lai CK, Pearce N.Prevalence and etiology of asthma. J Allergy Clin Immunol2000; 105: S466—S472.
3.
Strachan DPHay fever, hygiene, and household size. BMJ1989; 299: 1259—1260.
4.
Strachan DPFamily size, infection and atopy: the first decade of the `hygiene hypothesis' . Thorax2000; 55 (Suppl 1): S2—S10.
5.
von Mutius E. , Pearce N., Beasley R. et al. International patterns of tuberculosis and the prevalence of symptoms of asthma, rhinitis, and eczema. Thorax2000; 55: 449—453.
6.
McIntire JJ, Umetsu SE, Akbari O. et al. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol2001; 2: 1109—1116.
7.
Gereda JE, Leung DY, Thatayatikom A. et al. Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma . Lancet2000; 355: 1680—1683.
8.
Braun-Fahrlander C., Riedler J., Herz U. et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med2002; 347: 869—877.
9.
Johnston SL, Martin RJChlamydophila pneumoniae and Mycoplasma pneumoniae: a role in asthma pathogenesis?Am J Respir Crit Care Med2005; 172: 1078—1089.
10.
Murray CS, Simpson A., Custovic A.Allergens, viruses, and asthma exacerbations. Proc Am Thorac Soc2004; 1: 99—104.
11.
Gern JE, Busse WWRelationship of viral infections to wheezing illnesses and asthma. Nat Rev Immunol2002; 2: 132—138.
12.
Hahn DL, Dodge RW, Golubjatnikov R.Association of Chlamydia pneumoniae (strain TWAR) infection with wheezing, asthmatic bronchitis, and adult-onset asthma. JAMA1991; 266: 225—230.
13.
Sirmatel F. , Ustunsoy H., Sirmatel O., Akdemir I., Dikensoy O.The relationship between Chlamydia pneumoniae seropositivity and peripheral vascular diseases, acute myocardial infarction and late-onset asthma. Infection2003; 31: 367—368.
14.
Normann E., Gnarpe J., Wettergren B., Janson C., Wickman M., Nordvall L.The association between Chlamydia pneumoniae antibodies and wheezing in young children and the influence of sex. Thorax2006; 61: 1054—1058.
Park JH, Gold DR, Spiegelman DL, Burge HA, Milton DKHouse dust endotoxin and wheeze in the first year of life. Am J Respir Crit Care Med2001; 163: 322—328.
Hoebe K., Janssen EM, Kim SO et al. Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trifindependent pathways . Nat Immunol2003; 4: 1223—1229.
Yamamoto M., Sato S., Hemmi H. et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol2003; 4: 1144—1150.
23.
Yamamoto M., Sato S., Hemmi H. et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science2003; 301: 640—643.
24.
Hoebe K., Du X., Georgel P. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature2003; 424: 743—748.
25.
Kawai T., Sato S., Ishii KJ et al. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol2004; 5: 1061—1068.
26.
Schroder NW , Schumann RRSingle nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis2005; 5: 156—164.
27.
Arbour NC, Lorenz E., Schutte BC et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet2000; 25: 187—191.
28.
Raby BA, Klimecki WT, Laprise C. et al. Polymorphisms in Toll-like receptor 4 are not associated with asthma or atopy-related phenotypes. Am J Respir Crit Care Med2002; 166: 1449—1456.
29.
Yang IA, Barton SJ, Rorke S. et al. Toll-like receptor 4 polymorphism and severity of atopy in asthmatics . Genes Immun2004; 5: 41—45.
30.
Adjers K., Karjalainen J., Pessi T., Eklund C., Hurme M.Epistatic effect of TLR4 and IL4 genes on the risk of asthma in females. Int Arch Allergy Immunol2005; 138: 251—256.
31.
Sackesen C. , Karaaslan C., Keskin O. et al. The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma. Allergy2005; 60: 1485—1492.
32.
Eder W., von Mutius E.Genetics in asthma: the solution to a lasting conundrum?Allergy2005; 60: 1482—1484.
33.
Tantisira K. , Klimecki WT, Lazarus R. et al. Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma. Genes Immun2004; 5: 343—346.
34.
Lauener RP, Birchler T., Adamski J. et al. Expression of CD14 and Toll-like receptor 2 in farmers' and non-farmers' children. Lancet2002; 360: 465—466.
35.
Riedler J., Braun-Fahrlander C., Eder W. et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet2001; 358: 1129—1133.
36.
Matsuguchi T., Musikacharoen T., Ogawa T., Yoshikai Y.Gene expressions of Toll-like receptor 2, but not Toll-like receptor 4, is induced by LPS and inflammatory cytokines in mouse macrophages. J Immunol2000; 165: 5767—5772.
37.
Poltorak A. , He X., Smirnova I. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science1998; 282: 2085—2088.
38.
Dabbagh K., Dahl ME, Stepick-Biek P., Lewis DBToll-like receptor 4 is required for optimal development of Th2 immune responses: role of dendritic cells. J Immunol2002; 168: 4524—4530.
39.
Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K. Lipopolysaccharide-enhanced, Toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen . J Exp Med2002; 196: 1645—1651.
40.
Piggott DA, Eisenbarth SC, Xu L. et al. MyD88-dependent induction of allergic Th2 responses to intranasal antigen. J Clin Invest2005; 115: 459—467.
41.
Nigo YI, Yamashita M., Hirahara K. et al. Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function. Proc Natl Acad Sci USA2006; 103: 2286—2291.
42.
Agrawal S., Agrawal A., Doughty B. et al. Different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J Immunol2003; 171: 4984—4989.
43.
Constant SL , Lee KS, Bottomly K.Site of antigen delivery can influence T cell priming: pulmonary environment promotes preferential Th2-type differentiation . Eur J Immunol2000; 30: 840—847.
44.
Redecke V., Hacker H., Datta SK et al. Activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol2004; 172: 2739—2743.
45.
Sel S., Wegmann M., Sel S. et al. Immunomodulatory effects of viral TLR ligands on experimental asthma depend on the additive effects of IL-12 and IL-10. J Immunol2007; 178: 7805—7813.
46.
Michel O., Kips J., Duchateau J. et al. Severity of asthma is related to endotoxin in house dust. Am J Respir Crit Care Med1996; 154: 1641—1646.
47.
Schwartz DA , Thorne PS, Yagla SJ et al. The role of endotoxin in grain dust-induced lung disease. Am J Respir Crit Care Med1995 ; 152: 603—608.
48.
Rodriguez D. , Keller AC, Faquim-Mauro EL et al. Bacterial lipopolysaccharide signaling through Toll-like receptor 4 suppresses asthma-like responses via nitric oxide synthase 2 activity. J Immunol2003; 171: 1001—1008.
49.
Hollingsworth JW, Whitehead GS, Lin KL et al. TLR4 signaling attenuates ongoing allergic inflammation. J Immunol2006; 176: 5856—5862.
50.
Revets H., Pynaert G., Grooten J., De Baetselier P.Lipoprotein I, a TLR2/4 ligand modulates Th2-driven allergic immune responses . J Immunol2005; 174: 1097—1103.
51.
Jung YW, Schoeb TR, Weaver CT, Chaplin DDAntigen and lipopolysaccharide play synergistic roles in the effector phase of airway inflammation in mice. Am J Pathol2006; 168: 1425—1434.
52.
Yamamoto K. , Kawamura I., Ito J., Mitsuyama M.Modification of allergic inflammation in murine model of rhinitis by different bacterial ligands: involvement of mast cells and dendritic cells. Clin Exp Allergy2006 ; 36: 760—769.
53.
Mallia P., Johnston SLHow viral infections cause exacerbation of airway diseases. Chest2006; 130: 1203—1210.
54.
Martin RJInfections and asthma. Clin Chest Med2006 ; 27: 87—98, vi.
55.
Dahl ME, Dabbagh K., Liggitt D., Kim S., Lewis DBViral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells. Nat Immunol2004; 5: 337—343.
56.
Marsland BJ , Kopf M., Le Gros G.Viral infection and allergy. Nat Immunol2004; 5: 865; author reply 865—866.
57.
Marsland BJ , Scanga CB, Kopf M., Le Gros G.Allergic airway inflammation is exacerbated during acute influenza infection and correlates with increased allergen presentation and recruitment of allergen-specific T-helper type 2 cells. Clin Exp Allergy2004; 34: 1299—1306.
58.
Michelsen KS , Aicher A., Mohaupt M. et al. The role of Toll-like receptors (TLRs) in bacteria-induced maturation of murine dendritic cells (DCS). Peptidoglycan and lipoteichoic acid are inducers of DC maturation and require TLR2. J Biol Chem2001; 276: 25680—25686.
59.
Schnare M., Barton GM, Holt AC, Takeda K., Akira S., Medzhitov R.Toll-like receptors control activation of adaptive immune responses. Nat Immunol2001; 2: 947—950.
60.
Pauligk C., Nain M., Reiling N., Gemsa D., Kaufmann A.CD14 is required for influenza A virus-induced cytokine and chemokine production . Immunobiology2004; 209: 3—10.
61.
Marshall-Clarke S., Tasker L., Buchatska O. et al. Influenza H2 haemagglutinin activates B cells via a MyD88-dependent pathway. Eur J Immunol2006; 36: 95—106.
62.
Gerhold K., Blumchen K., Bock A. et al. Endotoxins prevent murine IgE production, T(H)2 immune responses, and development of airway eosinophilia but not airway hyperreactivity. J Allergy Clin Immunol2002; 110: 110—116.
63.
Gerhold K., Bluemchen K., Franke A., Stock P., Hamelmann E.Exposure to endotoxin and allergen in early life and its effect on allergen sensitization in mice. J Allergy Clin Immunol2003; 112: 389—396.
64.
Wang Y., McCusker C.Neonatal exposure with LPS and/or allergen prevents experimental allergic airways disease: development of tolerance using environmental antigens. J Allergy Clin Immunol2006; 118: 143—151.
65.
Gerhold K., Avagyan A., Seib C. et al. Prenatal initiation of endotoxin airway exposure prevents subsequent allergen-induced sensitization and airway inflammation in mice. J Allergy Clin Immunol2006; 118: 666—673.
66.
Lin W., Truong N., Grossman WJ et al. Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol2005; 116: 1106—1115.
67.
Akdis M., Verhagen J., Taylor A. et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med2004; 199: 1567—1575.
68.
Akdis CA, Blesken T., Akdis M., Wuthrich B., Blaser K.Role of interleukin 10 in specific immunotherapy. J Clin Invest1998; 102: 98—106.
69.
Lewkowich IP , Herman NS, Schleifer KW et al. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J Exp Med2005 ; 202: 1549—1561.
70.
Sutmuller RP , den Brok MH, Kramer M. et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest2006; 116: 485—494.
71.
Liu H., Komai-Koma M., Xu D., Liew FYToll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci USA2006; 103: 7048—7053.
72.
Tsitoura DC , Blumenthal RL, Berry G., Dekruyff RH, Umetsu DTMechanisms preventing allergen-induced airways hyperreactivity: role of tolerance and immune deviation. J Allergy Clin Immunol2000; 106: 239—246.
Watanabe J. , Miyazaki Y., Zimmerman GA, Albertine KH, McIntyre TMEndotoxin contamination of ovalbumin suppresses murine immunologic responses and development of airway hyper-reactivity. J Biol Chem2003; 278: 42361—42368.
75.
Stock P., Akbari O., Berry G., Freeman GJ, Dekruyff RH, Umetsu DTInduction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat Immunol2004; 5: 1149—1156.
76.
den Haan JM , Kraal G., Bevan MJLipopolysaccharide induces IL-10-producing regulatory CD4+ T cells that suppress the CD8+ T cell response. J Immunol2007; 178: 5429—5433.
77.
Spiegelberg HL, Broide D., Tighe H., Roman M., Raz E.Inhibition of allergic inflammation in the lung by plasmid DNA allergen immunization. Pediatr Pulmonol Suppl 1999; 18: 118—121.
78.
Sparwasser T., Miethke T., Lipford G. et al. Bacterial DNA causes septic shock. Nature1997; 386: 336—337.
79.
Kline JN, Waldschmidt TJ, Businga TR et al. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J Immunol1998 ; 160: 2555—2559.
80.
Jain VV, Kitagaki K., Businga T. et al. CpG-oligodeoxynucleotides inhibit airway remodeling in a murine model of chronic asthma. J Allergy Clin Immunol2002; 110: 867—872.
81.
Krieg AMTherapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov2006; 5: 471—484.
82.
Liu YJIPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol2005; 23: 275—306.
83.
Hartmann G. , Marschner A., Viveros PR et al. CpG oligonucleotides induce strong humoral but only weak CD4+ T cell responses to protein antigens in rhesus macaques in vivo. Vaccine2005; 23: 3310—3317.
84.
Heikenwalder M., Polymenidou M., Junt T. et al. Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med2004; 10: 187—192.
85.
Creticos PS , Schroeder JT, Hamilton RG et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med2006; 355: 1445—1455.
86.
Simons FE, Shikishima Y., Van Nest G., Eiden JJ, HayGlass KTSelective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J Allergy Clin Immunol2004; 113: 1144—1151.
87.
Jain VV, Businga TR, Kitagaki K., George CL, O'Shaughnessy PT, Kline JN. Mucosal immunotherapy with CpG oligodeoxynucleotides reverses a murine model of chronic asthma induced by repeated antigen exposure . Am J Physiol2003; 285: L1137—L1146.
88.
Fanucchi MV , Schelegle ES, Baker GL et al. Immunostimulatory oligonucleotides attenuate airways remodeling in allergic monkeys. Am J Respir Crit Care Med2004; 170: 1153—1157.
89.
Papadopoulos NG, Psarras S., Manoussakis E., Saxoni-Papageorgiou P.The role of respiratory viruses in the origin and exacerbations of asthma. Curr OpinAllergy Clin Immunol2003; 3: 39—44.
