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Adaptation in the innate immune system and heterologous innate immunity


The innate immune system recognizes deviation from homeostasis caused by infectious or non-infectious assaults. The threshold for its activation seems to be established by a calibration process that includes sensing of microbial molecular patterns from commensal bacteria and of endogenous signals. It is becoming increasingly clear that adaptive features, a hallmark of the adaptive immune system, can also be identified in the innate immune system. Such adaptations can result in the manifestation of a primed state of immune and tissue cells with a decreased activation threshold. This keeps the system poised to react quickly. Moreover, the fact that the innate immune system recognizes a wide variety of danger signals via pattern recognition receptors that often activate the same signaling pathways allows for heterologous innate immune stimulation. This implies that, for example, the innate immune response to an infection can be modified by co-infections or other innate stimuli. This “design feature” of the innate immune system has many implications for our understanding of individual susceptibility to diseases or responsiveness to therapies and vaccinations. In this article, adaptive features of the innate immune system as well as heterologous innate immunity and their implications are discussed.

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Fig. 5



Allergic contact dermatitis


B cell receptor


Contact hypersensitivity


C-type lectin receptor


Clustered regularly interspaced short palindromic repeats


Damage-associated molecular pattern


Dendritic cell




Delayed type hypersensitivity




Extracellular matrix


Microbe-associated molecular pattern


Myeloid-derived suppressor cell


Natural killer


NOD-like receptor


Pathogen-associated molecular pattern


Peptide/MHC complex


Pattern recognition receptor


RIG-I like receptor


Systemic acquired resistance


T cell receptor


Toll-like receptor


Regulatory T cell






  1. 1.

    Janeway CA Jr (1989) Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 54(Pt 1):1–13

    PubMed  CAS  Google Scholar 

  2. 2.

    Matzinger P (1994) Tolerance, danger, and the extended family. Annu Rev Immunol 12:991–1045. doi:10.1146/annurev.iy.12.040194.005015

    PubMed  CAS  Google Scholar 

  3. 3.

    Matzinger P (2007) Friendly and dangerous signals: is the tissue in control? Nat Immunol 8(1):11–13. doi:10.1038/ni0107-11

    PubMed  CAS  Google Scholar 

  4. 4.

    Medzhitov R (2009) Approaching the asymptote: 20 years later. Immunity 30(6):766–775. doi:10.1016/j.immuni.2009.06.004

    PubMed  CAS  Google Scholar 

  5. 5.

    Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34(5):637–650. doi:10.1016/j.immuni.2011.05.006

    PubMed  CAS  Google Scholar 

  6. 6.

    Schenten D, Medzhitov R (2011) The control of adaptive immune responses by the innate immune system. Adv Immunol 109:87–124. doi:10.1016/B978-0-12-387664-5.00003-0

    PubMed  CAS  Google Scholar 

  7. 7.

    Victora GD, Nussenzweig MC (2012) Germinal centers. Annu Rev Immunol 30:429–457. doi:10.1146/annurev-immunol-020711-075032

    PubMed  CAS  Google Scholar 

  8. 8.

    Pieper K, Grimbacher B, Eibel H (2013) B-cell biology and development. J Allergy Clin Immunol 131(4):959–971. doi:10.1016/j.jaci.2013.01.046

    PubMed  CAS  Google Scholar 

  9. 9.

    Shlomchik MJ, Weisel F (2012) Germinal center selection and the development of memory B and plasma cells. Immunol Rev 247(1):52–63. doi:10.1111/j.1600-065X.2012.01124.x

    PubMed  Google Scholar 

  10. 10.

    Hale JS, Fink PJ (2010) T-cell receptor revision: friend or foe? Immunology 129(4):467–473. doi:10.1111/j.1365-2567.2010.03250.x

    PubMed  CAS  PubMed Central  Google Scholar 

  11. 11.

    Mueller SN, Gebhardt T, Carbone FR, Heath WR (2013) Memory T cell subsets, migration patterns, and tissue residence. Annu Rev Immunol 31:137–161. doi:10.1146/annurev-immunol-032712-095954

    PubMed  CAS  Google Scholar 

  12. 12.

    Page KR, Scott AL, Manabe YC (2006) The expanding realm of heterologous immunity: friend or foe? Cell Microbiol 8(2):185–196. doi:10.1111/j.1462-5822.2005.00653.x

    PubMed  CAS  Google Scholar 

  13. 13.

    Barrangou R, Marraffini LA (2014) CRISPR-cas systems: prokaryotes upgrade to adaptive immunity. Mol Cell 54(2):234–244. doi:10.1016/j.molcel.2014.03.011

    PubMed  CAS  Google Scholar 

  14. 14.

    Bronkhorst AW, van Rij RP (2014) The long and short of antiviral defense: small RNA-based immunity in insects. Curr Opin Virol 7C:19–28. doi:10.1016/j.coviro.2014.03.010

    PubMed  Google Scholar 

  15. 15.

    Ermolaeva MA, Schumacher B (2014) Insights from the worm: The C. elegans model for innate immunity. Seminar Immunol doi:10.1016/j.smim.2014.04.005

  16. 16.

    Netea MG (2013) Training innate immunity: the changing concept of immunological memory in innate host defence. Eur J Clin Invest 43(8):881–884. doi:10.1111/eci.12132

    PubMed  CAS  Google Scholar 

  17. 17.

    Morris GP, Allen PM (2012) How the TCR balances sensitivity and specificity for the recognition of self and pathogens. Nat Immunol 13(2):121–128. doi:10.1038/ni.2190

    PubMed  CAS  Google Scholar 

  18. 18.

    Garbi N, Hammerling GJ, Probst HC, van den Broek M (2010) Tonic T cell signalling and T cell tolerance as opposite effects of self-recognition on dendritic cells. Curr Opin Immunol 22(5):601–608. doi:10.1016/j.coi.2010.08.007

    PubMed  CAS  Google Scholar 

  19. 19.

    Garbi N, Kreutzberg T (2012) Dendritic cells enhance the antigen sensitivity of T cells. Front Immunol 3:389. doi:10.3389/fimmu.2012.00389

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Kassiotis G, Garcia S, Simpson E, Stockinger B (2002) Impairment of immunological memory in the absence of MHC despite survival of memory T cells. Nat Immunol 3(3):244–250. doi:10.1038/ni766

    PubMed  CAS  Google Scholar 

  21. 21.

    Lam KP, Kuhn R, Rajewsky K (1997) In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90(6):1073–1083

    PubMed  CAS  Google Scholar 

  22. 22.

    Monroe JG (2006) ITAM-mediated tonic signalling through pre-BCR and BCR complexes. Nat Rev Immunol 6(4):283–294. doi:10.1038/nri1808

    PubMed  CAS  Google Scholar 

  23. 23.

    Shin H, Iwasaki A (2013) Tissue-resident memory T cells. Immunol Rev 255(1):165–181. doi:10.1111/imr.12087

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Gebhardt T, Mueller SN, Heath WR, Carbone FR (2013) Peripheral tissue surveillance and residency by memory T cells. Trends Immunol 34(1):27–32. doi:10.1016/

    PubMed  CAS  Google Scholar 

  25. 25.

    Weill JC, Le Gallou S, Hao Y, Reynaud CA (2013) Multiple players in mouse B cell memory. Curr Opin Immunol 25(3):334–338. doi:10.1016/j.coi.2013.05.004

    PubMed  CAS  Google Scholar 

  26. 26.

    Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg GF, Paley MA, Antenus M, Williams KL, Erikson J, Wherry EJ, Artis D (2012) Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37(1):158–170. doi:10.1016/j.immuni.2012.04.011

    PubMed  CAS  PubMed Central  Google Scholar 

  27. 27.

    Abt MC, Artis D (2013) The dynamic influence of commensal bacteria on the immune response to pathogens. Curr Opin Microbiol 16(1):4–9. doi:10.1016/j.mib.2012.12.002

    PubMed  CAS  PubMed Central  Google Scholar 

  28. 28.

    Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11(5):373–384. doi:10.1038/ni.1863

    PubMed  CAS  Google Scholar 

  29. 29.

    Chen GY, Nunez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10(12):826–837. doi:10.1038/nri2873

    PubMed  CAS  PubMed Central  Google Scholar 

  30. 30.

    Sorokin L (2010) The impact of the extracellular matrix on inflammation. Nat Rev Immunol 10(10):712–723. doi:10.1038/nri2852

    PubMed  CAS  Google Scholar 

  31. 31.

    Volkman HE, Stetson DB (2014) The enemy within: endogenous retroelements and autoimmune disease. Nat Immunol 15(5):415–422. doi:10.1038/ni.2872

    PubMed  CAS  Google Scholar 

  32. 32.

    Bhat N, Fitzgerald KA (2014) Recognition of cytosolic DNA by cGAS and other STING-dependent sensors. Eur J Immunol 44(3):634–640. doi:10.1002/eji.201344127

    PubMed  CAS  Google Scholar 

  33. 33.

    Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V (2014) TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J Immunol 192(12):5993–5997. doi:10.4049/jimmunol.1400737

    PubMed  CAS  Google Scholar 

  34. 34.

    Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A (2011) Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci USA 108(13):5354–5359. doi:10.1073/pnas.1019378108

    PubMed  CAS  PubMed Central  Google Scholar 

  35. 35.

    Cerutti A, Cols M, Puga I (2013) Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol 13(2):118–132. doi:10.1038/nri3383

    PubMed  CAS  PubMed Central  Google Scholar 

  36. 36.

    Ganal SC, Sanos SL, Kallfass C, Oberle K, Johner C, Kirschning C, Lienenklaus S, Weiss S, Staeheli P, Aichele P, Diefenbach A (2012) Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity 37(1):171–186. doi:10.1016/j.immuni.2012.05.020

    PubMed  CAS  Google Scholar 

  37. 37.

    Izhak L, Berzofsky JA, Terabe M (2013) Balance is a key for happiness. Oncoimmunology 2(5):e24211. doi:10.4161/onci.24211

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Ohkura N, Kitagawa Y, Sakaguchi S (2013) Development and maintenance of regulatory T cells. Immunity 38(3):414–423. doi:10.1016/j.immuni.2013.03.002

    PubMed  CAS  Google Scholar 

  39. 39.

    Lynch L, Nowak M, Varghese B, Clark J, Hogan AE, Toxavidis V, Balk SP, O’Shea D, O’Farrelly C, Exley MA (2012) Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 37(3):574–587. doi:10.1016/j.immuni.2012.06.016

    PubMed  CAS  Google Scholar 

  40. 40.

    Goubier A, Vocanson M, Macari C, Poyet G, Herbelin A, Nicolas JF, Dubois B, Kaiserlian D (2013) Invariant NKT cells suppress CD8(+) T-cell-mediated allergic contact dermatitis independently of regulatory CD4(+) T cells. J Invest Dermatol 133(4):980–987. doi:10.1038/jid.2012.404

    PubMed  CAS  Google Scholar 

  41. 41.

    El Ali Z, Gerbeix C, Hemon P, Esser PR, Martin SF, Pallardy M, Kerdine-Romer S (2013) Allergic skin inflammation induced by chemical sensitizers is controlled by the transcription factor nrf2. Toxicol Sci 134(1):39–48. doi:10.1093/toxsci/kft084

    PubMed  Google Scholar 

  42. 42.

    Ronald PC, Beutler B (2010) Plant and animal sensors of conserved microbial signatures. Science 330(6007):1061–1064. doi:10.1126/science.1189468

    PubMed  CAS  Google Scholar 

  43. 43.

    Schwessinger B, Ronald PC (2012) Plant innate immunity: perception of conserved microbial signatures. Annu Rev Plant Biol 63:451–482. doi:10.1146/annurev-arplant-042811-105518

    PubMed  CAS  Google Scholar 

  44. 44.

    Fu ZQ, Dong X (2013) Systemic acquired resistance: turning local infection into global defense. Annu Rev Plant Biol 64:839–863. doi:10.1146/annurev-arplant-042811-105606

    PubMed  CAS  Google Scholar 

  45. 45.

    van den Burg HA, Takken FL (2009) Does chromatin remodeling mark systemic acquired resistance? Trends Plant Sci 14(5):286–294. doi:10.1016/j.tplants.2009.02.003

    PubMed  Google Scholar 

  46. 46.

    Conrath U (2011) Molecular aspects of defence priming. Trends Plant Sci 16(10):524–531. doi:10.1016/j.tplants.2011.06.004

    PubMed  CAS  Google Scholar 

  47. 47.

    Holeski LM, Jander G, Agrawal AA (2012) Transgenerational defense induction and epigenetic inheritance in plants. Trends Ecol Evol 27(11):618–626. doi:10.1016/j.tree.2012.07.011

    PubMed  Google Scholar 

  48. 48.

    Monticelli S, Natoli G (2013) Short-term memory of danger signals and environmental stimuli in immune cells. Nat Immunol 14(8):777–784. doi:10.1038/ni.2636

    PubMed  CAS  Google Scholar 

  49. 49.

    Foster SL, Hargreaves DC, Medzhitov R (2007) Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447(7147):972–978. doi:10.1038/nature05836

    PubMed  CAS  Google Scholar 

  50. 50.

    Min-Oo G, Kamimura Y, Hendricks DW, Nabekura T, Lanier LL (2013) Natural killer cells: walking three paths down memory lane. Trends Immunol 34(6):251–258. doi:10.1016/

    PubMed  CAS  PubMed Central  Google Scholar 

  51. 51.

    Cooper MA, Elliott JM, Keyel PA, Yang L, Carrero JA, Yokoyama WM (2009) Cytokine-induced memory-like natural killer cells. Proc Natl Acad Sci USA 106(6):1915–1919. doi:10.1073/pnas.0813192106

    PubMed  CAS  PubMed Central  Google Scholar 

  52. 52.

    Sun JC, Beilke JN, Lanier LL (2009) Adaptive immune features of natural killer cells. Nature 457(7229):557–561. doi:10.1038/nature07665

    PubMed  CAS  PubMed Central  Google Scholar 

  53. 53.

    Sun JC, Lopez-Verges S, Kim CC, DeRisi JL, Lanier LL (2011) NK cells and immune “memory”. J Immunol 186(4):1891–1897. doi:10.4049/jimmunol.1003035

    PubMed  CAS  Google Scholar 

  54. 54.

    O’Leary JG, Goodarzi M, Drayton DL, von Andrian UH (2006) T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat Immunol 7(5):507–516. doi:10.1038/ni1332

    PubMed  Google Scholar 

  55. 55.

    Paust S, Gill HS, Wang BZ, Flynn MP, Moseman EA, Senman B, Szczepanik M, Telenti A, Askenase PW, Compans RW, von Andrian UH (2010) Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat Immunol 11(12):1127–1135. doi:10.1038/ni.1953

    PubMed  CAS  PubMed Central  Google Scholar 

  56. 56.

    Paust S, von Andrian UH (2011) Natural killer cell memory. Nat Immunol 12(6):500–508

    PubMed  CAS  Google Scholar 

  57. 57.

    Peng H, Jiang X, Chen Y, Sojka DK, Wei H, Gao X, Sun R, Yokoyama WM, Tian Z (2013) Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Investig 123(4):1444–1456. doi:10.1172/JCI66381

    PubMed  CAS  PubMed Central  Google Scholar 

  58. 58.

    Locati M, Mantovani A, Sica A (2013) Macrophage activation and polarization as an adaptive component of innate immunity. Adv Immunol 120:163–184. doi:10.1016/B978-0-12-417028-5.00006-5

    PubMed  CAS  Google Scholar 

  59. 59.

    Quintin J, Saeed S, Martens JH, Giamarellos-Bourboulis EJ, Ifrim DC, Logie C, Jacobs L, Jansen T, Kullberg BJ, Wijmenga C, Joosten LA, Xavier RJ, van der Meer JW, Stunnenberg HG, Netea MG (2012) Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microb 12(2):223–232. doi:10.1016/j.chom.2012.06.006

    CAS  Google Scholar 

  60. 60.

    Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, Jacobs C, van Loenhout J, de Jong D, Stunnenberg HG, Xavier RJ, van der Meer JW, van Crevel R, Netea MG (2012) Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci USA 109(43):17537–17542. doi:10.1073/pnas.1202870109

    PubMed  CAS  PubMed Central  Google Scholar 

  61. 61.

    Benn CS, Netea MG, Selin LK, Aaby P (2013) A small jab—a big effect: nonspecific immunomodulation by vaccines. Trends Immunol 34(9):431–439. doi:10.1016/

    PubMed  CAS  Google Scholar 

  62. 62.

    Aaby P, Benn CS (2012) Saving lives by training innate immunity with bacille Calmette-Guerin vaccine. Proc Natl Acad Sci USA 109(43):17317–17318. doi:10.1073/pnas.1215761109

    PubMed  CAS  PubMed Central  Google Scholar 

  63. 63.

    Hooper LV, Littman DR, Macpherson AJ (2012) Interactions between the microbiota and the immune system. Science 336(6086):1268–1273. doi:10.1126/science.1223490

    PubMed  CAS  Google Scholar 

  64. 64.

    Honda K, Littman DR (2012) The microbiome in infectious disease and inflammation. Annu Rev Immunol 30:759–795. doi:10.1146/annurev-immunol-020711-074937

    PubMed  CAS  Google Scholar 

  65. 65.

    Garn H, Neves JF, Blumberg RS, Renz H (2013) Effect of barrier microbes on organ-based inflammation. J Allergy Clin Immunol 131(6):1465–1478. doi:10.1016/j.jaci.2013.04.031

    PubMed  Google Scholar 

  66. 66.

    Manichanh C, Borruel N, Casellas F, Guarner F (2012) The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol 9(10):599–608. doi:10.1038/nrgastro.2012.152

    PubMed  CAS  Google Scholar 

  67. 67.

    Goldszmid RS, Trinchieri G (2012) The price of immunity. Nat Immunol 13(10):932–938. doi:10.1038/ni.2422

    PubMed  CAS  Google Scholar 

  68. 68.

    Stecher B, Maier L, Hardt WD (2013) ‘Blooming’ in the gut: how dysbiosis might contribute to pathogen evolution. Nat Rev Microbiol 11(4):277–284. doi:10.1038/nrmicro2989

    PubMed  CAS  Google Scholar 

  69. 69.

    Borody TJ, Khoruts A (2012) Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol 9(2):88–96. doi:10.1038/nrgastro.2011.244

    CAS  Google Scholar 

  70. 70.

    Stelekati E, Wherry EJ (2012) Chronic bystander infections and immunity to unrelated antigens. Cell Host Microb 12(4):458–469. doi:10.1016/j.chom.2012.10.001

    CAS  Google Scholar 

  71. 71.

    Clark RA (2010) Skin-resident T cells: the ups and downs of on site immunity. J Invest Dermatol 130(2):362–370. doi:10.1038/jid.2009.247

    PubMed  CAS  PubMed Central  Google Scholar 

  72. 72.

    Bevan MJ (2011) Memory T cells as an occupying force. Eur J Immunol 41(5):1192–1195. doi:10.1002/eji.201041377

    PubMed  CAS  PubMed Central  Google Scholar 

  73. 73.

    Carbone FR, Mackay LK, Heath WR, Gebhardt T (2013) Distinct resident and recirculating memory T cell subsets in non-lymphoid tissues. Curr Opin Immunol 25(3):329–333. doi:10.1016/j.coi.2013.05.007

    PubMed  CAS  Google Scholar 

  74. 74.

    Scheper RJ, von Blomberg M, Boerrigter GH, Bruynzeel D, van Dinther A, Vos A (1983) Induction of immunological memory in the skin. Role of local T cell retention. Clin Exp Immunol 51(1):141–148

    PubMed  CAS  PubMed Central  Google Scholar 

  75. 75.

    Rustemeyer T, de Groot J, von Blomberg BM, Bruynzeel DP, Frosch PJ, Scheper RJ (2002) Assessment of contact allergen cross-reactivity by retesting. Exp Dermatol 11(3):257–265

    PubMed  Google Scholar 

  76. 76.

    Moed H, Boorsma DM, Tensen CP, Flier J, Jonker MJ, Stoof TJ, von Blomberg BM, Bruynzeel DP, Scheper RJ, Rustemeyer T, Gibbs S (2004) Increased CCL27-CCR10 expression in allergic contact dermatitis: implications for local skin memory. J Pathol 204(1):39–46. doi:10.1002/path.1619

    PubMed  CAS  Google Scholar 

  77. 77.

    Strachan DP (1989) Hay fever, hygiene, and household size. BMJ 299(6710):1259–1260

    PubMed  CAS  PubMed Central  Google Scholar 

  78. 78.

    Netea MG, Wijmenga C, O’Neill LA (2012) Genetic variation in Toll-like receptors and disease susceptibility. Nat Immunol 13(6):535–542. doi:10.1038/ni.2284

    PubMed  CAS  Google Scholar 

  79. 79.

    Lamkanfi M, Kanneganti TD (2012) The inflammasome: a remote control for metabolic syndrome. Cell Res 22(7):1095–1098. doi:10.1038/cr.2012.55

    PubMed  CAS  PubMed Central  Google Scholar 

  80. 80.

    Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347(12):911–920. doi:10.1056/NEJMra020100

    PubMed  Google Scholar 

  81. 81.

    Matricardi PM (2010) 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: controversial aspects of the ‘hygiene hypothesis’. Clin Exp Immunol 160(1):98–105. doi:10.1111/j.1365-2249.2010.04130.x

    PubMed  CAS  PubMed Central  Google Scholar 

  82. 82.

    Brooks C, Pearce N, Douwes J (2013) The hygiene hypothesis in allergy and asthma: an update. Curr Opin Allergy Clin Immunol 13(1):70–77. doi:10.1097/ACI.0b013e32835ad0d2

    PubMed  Google Scholar 

  83. 83.

    von Mutius E, Vercelli D (2010) Farm living: effects on childhood asthma and allergy. Nat Rev Immunol 10(12):861–868. doi:10.1038/nri2871

    Google Scholar 

  84. 84.

    Ege MJ, Mayer M, Schwaiger K, Mattes J, Pershagen G, van Hage M, Scheynius A, Bauer J, von Mutius E (2012) Environmental bacteria and childhood asthma. Allergy 67(12):1565–1571. doi:10.1111/all.12028

    PubMed  CAS  Google Scholar 

  85. 85.

    Ege MJ, Bieli C, Frei R, van Strien RT, Riedler J, Ublagger E, Schram-Bijkerk D, Brunekreef B, van Hage M, Scheynius A, Pershagen G, Benz MR, Lauener R, von Mutius E, Braun-Fahrlander C, Parsifal Study t (2006) Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J Allergy Clin Immunol 117(4):817–823. doi:10.1016/j.jaci.2005.12.1307

    PubMed  Google Scholar 

  86. 86.

    Ege MJ, Herzum I, Buchele G, Krauss-Etschmann S, Lauener RP, Roponen M, Hyvarinen A, Vuitton DA, Riedler J, Brunekreef B, Dalphin JC, Braun-Fahrlander C, Pekkanen J, Renz H, von Mutius E, Protection Against Allergy Study in Rural Environments Study g (2008) Prenatal exposure to a farm environment modifies atopic sensitization at birth. J Allergy Clin Immunol 122(2):407–412, 412 e401–404. doi:10.1016/j.jaci.2008.06.011

  87. 87.

    Michel S, Busato F, Genuneit J, Pekkanen J, Dalphin JC, Riedler J, Mazaleyrat N, Weber J, Karvonen AM, Hirvonen MR, Braun-Fahrlander C, Lauener R, von Mutius E, Kabesch M, Tost J, Group Ps (2013) Farm exposure and time trends in early childhood may influence DNA methylation in genes related to asthma and allergy. Allergy 68(3):355–364. doi:10.1111/all.12097

    PubMed  CAS  Google Scholar 

  88. 88.

    Debarry J, Hanuszkiewicz A, Stein K, Holst O, Heine H (2010) The allergy-protective properties of Acinetobacter lwoffii F78 are imparted by its lipopolysaccharide. Allergy 65(6):690–697. doi:10.1111/j.1398-9995.2009.02253.x

    PubMed  CAS  Google Scholar 

  89. 89.

    Brand S, Teich R, Dicke T, Harb H, Yildirim AO, Tost J, Schneider-Stock R, Waterland RA, Bauer UM, von Mutius E, Garn H, Pfefferle PI, Renz H (2011) Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. J Allergy Clin Immunol 128(3):618–625, e611–617. doi:10.1016/j.jaci.2011.04.035

  90. 90.

    Brand S, Kesper DA, Teich R, Kilic-Niebergall E, Pinkenburg O, Bothur E, Lohoff M, Garn H, Pfefferle PI, Renz H (2012) DNA methylation of TH1/TH2 cytokine genes affects sensitization and progress of experimental asthma. J Allergy Clin Immunol 129(6):1602–1610, e1606. doi:10.1016/j.jaci.2011.12.963

  91. 91.

    Hagner S, Harb H, Zhao M, Stein K, Holst O, Ege MJ, Mayer M, Matthes J, Bauer J, von Mutius E, Renz H, Heine H, Pfefferle PI, Garn H (2013) Farm-derived Gram-positive bacterium Staphylococcus sciuri W620 prevents asthma phenotype in HDM- and OVA-exposed mice. Allergy 68(3):322–329. doi:10.1111/all.12094

    PubMed  CAS  Google Scholar 

  92. 92.

    Conrad ML, Ferstl R, Teich R, Brand S, Blumer N, Yildirim AO, Patrascan CC, Hanuszkiewicz A, Akira S, Wagner H, Holst O, von Mutius E, Pfefferle PI, Kirschning CJ, Garn H, Renz H (2009) Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. J Exp Med 206(13):2869–2877. doi:10.1084/jem.20090845

    PubMed  CAS  PubMed Central  Google Scholar 

  93. 93.

    Khosravi A, Mazmanian SK (2012) Breathe easy: microbes protect from allergies. Nat Med 18(4):492–494. doi:10.1038/nm.2723

    PubMed  CAS  PubMed Central  Google Scholar 

  94. 94.

    Hill DA, Siracusa MC, Abt MC, Kim BS, Kobuley D, Kubo M, Kambayashi T, Larosa DF, Renner ED, Orange JS, Bushman FD, Artis D (2012) Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med 18(4):538–546. doi:10.1038/nm.2657

    PubMed  CAS  PubMed Central  Google Scholar 

  95. 95.

    Vercelli D (2009) Gene-environment interactions: the road less traveled by in asthma genetics. J Allergy Clin Immunol 123(1):26–27. doi:10.1016/j.jaci.2008.11.031

    PubMed  Google Scholar 

  96. 96.

    Fishbein AB, Fuleihan RL (2012) The hygiene hypothesis revisited: does exposure to infectious agents protect us from allergy? Curr Opin Pediatr 24(1):98–102. doi:10.1097/MOP.0b013e32834ee57c

    PubMed  CAS  Google Scholar 

  97. 97.

    Welsh RM, Selin LK (2002) No one is naive: the significance of heterologous T-cell immunity. Nat Rev Immunol 2(6):417–426. doi:10.1038/nri820

    PubMed  CAS  Google Scholar 

  98. 98.

    Littman DR, Pamer EG (2011) Role of the commensal microbiota in normal and pathogenic host immune responses. Cell Host Microb 10(4):311–323. doi:10.1016/j.chom.2011.10.004

    CAS  Google Scholar 

  99. 99.

    Lamkanfi M, Dixit VM (2012) Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol 28:137–161. doi:10.1146/annurev-cellbio-101011-155745

    PubMed  CAS  Google Scholar 

  100. 100.

    Sancho D, Reis e Sousa C (2012) Signaling by myeloid C-type lectin receptors in immunity and homeostasis. Annu Rev Immunol 30:491–529. doi:10.1146/annurev-immunol-031210-101352

    PubMed  CAS  Google Scholar 

  101. 101.

    Bauernfeind F, Hornung V (2013) Of inflammasomes and pathogens–sensing of microbes by the inflammasome. EMBO Mol Med 5(6):814–826. doi:10.1002/emmm.201201771

    PubMed  CAS  PubMed Central  Google Scholar 

  102. 102.

    Dixit E, Kagan JC (2013) Intracellular pathogen detection by RIG-I-like receptors. Adv Immunol 117:99–125. doi:10.1016/B978-0-12-410524-9.00004-9

    PubMed  CAS  PubMed Central  Google Scholar 

  103. 103.

    Ablasser A, Hertrich C, Wassermann R, Hornung V (2013) Nucleic acid driven sterile inflammation. Clin Immunol 147(3):207–215. doi:10.1016/j.clim.2013.01.003

    PubMed  CAS  Google Scholar 

  104. 104.

    Wu J, Chen ZJ (2014) Innate immune sensing and signaling of cytosolic nucleic acids. Annu Rev Immunol 32:461–488. doi:10.1146/annurev-immunol-032713-120156

    PubMed  CAS  Google Scholar 

  105. 105.

    Reynolds JM, Dong C (2013) Toll-like receptor regulation of effector T lymphocyte function. Trends Immunol 34(10):511–519. doi:10.1016/

    PubMed  CAS  Google Scholar 

  106. 106.

    Rawlings DJ, Schwartz MA, Jackson SW, Meyer-Bahlburg A (2012) Integration of B cell responses through Toll-like receptors and antigen receptors. Nat Rev Immunol 12(4):282–294. doi:10.1038/nri3190

    PubMed  CAS  PubMed Central  Google Scholar 

  107. 107.

    Selin LK, Brehm MA, Naumov YN, Cornberg M, Kim SK, Clute SC, Welsh RM (2006) Memory of mice and men: CD8+ T-cell cross-reactivity and heterologous immunity. Immunol Rev 211:164–181. doi:10.1111/j.0105-2896.2006.00394.x

    PubMed  CAS  Google Scholar 

  108. 108.

    Selin LK, Brehm MA (2007) Frontiers in nephrology: heterologous immunity, T cell cross-reactivity, and alloreactivity. JASN 18(8):2268–2277. doi:10.1681/ASN.2007030295

    PubMed  CAS  Google Scholar 

  109. 109.

    Selin LK, Wlodarczyk MF, Kraft AR, Nie S, Kenney LL, Puzone R, Celada F (2011) Heterologous immunity: immunopathology, autoimmunity and protection during viral infections. Autoimmunity 44(4):328–347. doi:10.3109/08916934.2011.523277

    PubMed  CAS  PubMed Central  Google Scholar 

  110. 110.

    Wlodarczyk MF, Kraft AR, Chen HD, Kenney LL, Selin LK (2013) Anti-IFN-gamma and peptide-tolerization therapies inhibit acute lung injury induced by cross-reactive influenza A-specific memory T cells. J Immunol 190(6):2736–2746. doi:10.4049/jimmunol.1201936

    PubMed  CAS  PubMed Central  Google Scholar 

  111. 111.

    Martin SF (2012) Allergic contact dermatitis: xenoinflammation of the skin. Curr Opin Immunol 24(6):720–729. doi:10.1016/j.coi.2012.08.003

    PubMed  CAS  Google Scholar 

  112. 112.

    Martin SF (2012) Contact dermatitis: from pathomechanisms to immunotoxicology. Exp Dermatol 21(5):382–389. doi:10.1111/j.1600-0625.2012.01471.x

    PubMed  CAS  Google Scholar 

  113. 113.

    Wissinger E, Goulding J, Hussell T (2009) Immune homeostasis in the respiratory tract and its impact on heterologous infection. Semin Immunol 21(3):147–155. doi:10.1016/j.smim.2009.01.005

    PubMed  CAS  Google Scholar 

  114. 114.

    Lijek RS, Weiser JN (2012) Co-infection subverts mucosal immunity in the upper respiratory tract. Curr Opin Immunol 24(4):417–423. doi:10.1016/j.coi.2012.05.005

    PubMed  CAS  PubMed Central  Google Scholar 

  115. 115.

    Metzger DW, Sun K (2013) Immune dysfunction and bacterial coinfections following influenza. J Immunol 191(5):2047–2052. doi:10.4049/jimmunol.1301152

    PubMed  CAS  PubMed Central  Google Scholar 

  116. 116.

    Jamieson AM, Pasman L, Yu S, Gamradt P, Homer RJ, Decker T, Medzhitov R (2013) Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science 340(6137):1230–1234. doi:10.1126/science.1233632

    PubMed  CAS  PubMed Central  Google Scholar 

  117. 117.

    Dietz L, Esser PR, Schmucker SS, Goette I, Richter A, Schnolzer M, Martin SF, Thierse HJ (2010) Tracking human contact allergens: from mass spectrometric identification of peptide-bound reactive small chemicals to chemical-specific naive human T-cell priming. Toxicol Sci 117(2):336–347. doi:10.1093/toxsci/kfq209

    PubMed  CAS  Google Scholar 

  118. 118.

    Padovan E, Mauri-Hellweg D, Pichler WJ, Weltzien HU (1996) T cell recognition of penicillin G: structural features determining antigenic specificity. Eur J Immunol 26(1):42–48. doi:10.1002/eji.1830260107

    PubMed  CAS  Google Scholar 

  119. 119.

    Kang JY, Lee JO (2011) Structural biology of the Toll-like receptor family. Annu Rev Biochem 80:917–941. doi:10.1146/annurev-biochem-052909-141507

    PubMed  CAS  Google Scholar 

  120. 120.

    Ohto U, Fukase K, Miyake K, Shimizu T (2012) Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2. Proc Natl Acad Sci USA 109(19):7421–7426. doi:10.1073/pnas.1201193109

    PubMed  CAS  PubMed Central  Google Scholar 

  121. 121.

    Maeshima N, Fernandez RC (2013) Recognition of lipid A variants by the TLR4-MD-2 receptor complex. Front Cell Infect Microbiol 3:3. doi:10.3389/fcimb.2013.00003

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    van Liempt E, Bank CM, Mehta P, Garcia-Vallejo JJ, Kawar ZS, Geyer R, Alvarez RA, Cummings RD, Kooyk Y, van Die I (2006) Specificity of DC-SIGN for mannose- and fucose-containing glycans. FEBS Lett 580(26):6123–6131. doi:10.1016/j.febslet.2006.10.009

    PubMed  Google Scholar 

  123. 123.

    Song DH, Lee JO (2012) Sensing of microbial molecular patterns by Toll-like receptors. Immunol Rev 250(1):216–229. doi:10.1111/j.1600-065X.2012.01167.x

    PubMed  Google Scholar 

  124. 124.

    Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A (2005) Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol 6(8):769–776. doi:10.1038/ni1223

    PubMed  CAS  PubMed Central  Google Scholar 

  125. 125.

    Kasturi SP, Skountzou I, Albrecht RA, Koutsonanos D, Hua T, Nakaya HI, Ravindran R, Stewart S, Alam M, Kwissa M, Villinger F, Murthy N, Steel J, Jacob J, Hogan RJ, Garcia-Sastre A, Compans R, Pulendran B (2011) Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470(7335):543–547. doi:10.1038/nature09737

    PubMed  CAS  PubMed Central  Google Scholar 

  126. 126.

    Pulendran B, Ahmed R (2011) Immunological mechanisms of vaccination. Nat Immunol 12(6):509–517

    PubMed  CAS  PubMed Central  Google Scholar 

  127. 127.

    Iwasaki A, Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327(5963):291–295. doi:10.1126/science.1183021

    PubMed  CAS  PubMed Central  Google Scholar 

  128. 128.

    Coffman RL, Sher A, Seder RA (2010) Vaccine adjuvants: putting innate immunity to work. Immunity 33(4):492–503. doi:10.1016/j.immuni.2010.10.002

    PubMed  CAS  PubMed Central  Google Scholar 

  129. 129.

    Desmet CJ, Ishii KJ (2012) Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination. Nat Rev Immunol 12(7):479–491. doi:10.1038/nri3247

    PubMed  CAS  Google Scholar 

  130. 130.

    Mbow ML, De Gregorio E, Valiante NM, Rappuoli R (2010) New adjuvants for human vaccines. Curr Opin Immunol 22(3):411–416. doi:10.1016/j.coi.2010.04.004

    PubMed  CAS  Google Scholar 

  131. 131.

    Alving CR, Peachman KK, Rao M, Reed SG (2012) Adjuvants for human vaccines. Curr Opin Immunol 24(3):310–315. doi:10.1016/j.coi.2012.03.008

    PubMed  CAS  PubMed Central  Google Scholar 

  132. 132.

    Sander LE, Davis MJ, Boekschoten MV, Amsen D, Dascher CC, Ryffel B, Swanson JA, Muller M, Blander JM (2011) Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 474(7351):385–389. doi:10.1038/nature10072

    PubMed  CAS  PubMed Central  Google Scholar 

  133. 133.

    Netea MG, Quintin J, van der Meer JW (2011) Trained immunity: a memory for innate host defense. Cell Host Microb 9(5):355–361. doi:10.1016/j.chom.2011.04.006

    CAS  Google Scholar 

  134. 134.

    Haneklaus M, O’Neill LA, Coll RC (2013) Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments. Curr Opin Immunol 25(1):40–45. doi:10.1016/j.coi.2012.12.004

    PubMed  CAS  Google Scholar 

  135. 135.

    Latz E, Xiao TS, Stutz A (2013) Activation and regulation of the inflammasomes. Nat Rev Immunol 13(6):397–411. doi:10.1038/nri3452

    PubMed  CAS  Google Scholar 

  136. 136.

    Ramos HJ, Gale M Jr (2011) RIG-I like receptors and their signaling crosstalk in the regulation of antiviral immunity. Curr Opin Virol 1(3):167–176. doi:10.1016/j.coviro.2011.04.004

    PubMed  CAS  PubMed Central  Google Scholar 

  137. 137.

    Coll RC, O’Neill LA (2010) New insights into the regulation of signalling by Toll-like receptors and nod-like receptors. J Innate Immun 2(5):406–421. doi:10.1159/000315469

    PubMed  CAS  Google Scholar 

  138. 138.

    Roth S, Ruland J (2013) Caspase recruitment domain-containing protein 9 signaling in innate immunity and inflammation. Trends Immunol 34(6):243–250. doi:10.1016/

    PubMed  CAS  Google Scholar 

  139. 139.

    Peiser M, Tralau T, Heidler J, Api AM, Arts JH, Basketter DA, English J, Diepgen TL, Fuhlbrigge RC, Gaspari AA, Johansen JD, Karlberg AT, Kimber I, Lepoittevin JP, Liebsch M, Maibach HI, Martin SF, Merk HF, Platzek T, Rustemeyer T, Schnuch A, Vandebriel RJ, White IR, Luch A (2012) Allergic contact dermatitis: epidemiology, molecular mechanisms, in vitro methods and regulatory aspects. Current knowledge assembled at an international workshop at BfR, Germany. Cell Mol Life Sci 69(5):763–781. doi:10.1007/s00018-011-0846-8

    PubMed  CAS  PubMed Central  Google Scholar 

  140. 140.

    Loveless SE, Api AM, Crevel RW, Debruyne E, Gamer A, Jowsey IR, Kern P, Kimber I, Lea L, Lloyd P, Mehmood Z, Steiling W, Veenstra G, Woolhiser M, Hennes C (2010) Potency values from the local lymph node assay: application to classification, labelling and risk assessment. RTP 56(1):54–66. doi:10.1016/j.yrtph.2009.08.016

    PubMed  CAS  Google Scholar 

  141. 141.

    Esser PR, Kimber I, Martin SF (2014) Correlation of contact sensitizer potency with T cell frequency and TCR repertoire diversity. Exs 104:101–114. doi:10.1007/978-3-0348-0726-5_8

    PubMed  CAS  Google Scholar 

  142. 142.

    Schmidt M, Hupe M, Endres N, Raghavan B, Kavuri S, Geserick P, Goebeler M, Leverkus M (2010) The contact allergen nickel sensitizes primary human endothelial cells and keratinocytes to TRAIL-mediated apoptosis. J Cell Mol Med 14(6B):1760–1776. doi:10.1111/j.1582-4934.2009.00823.x

    PubMed  CAS  Google Scholar 

  143. 143.

    Raghavan B, Martin SF, Esser PR, Goebeler M, Schmidt M (2012) Metal allergens nickel and cobalt facilitate TLR4 homodimerization independently of MD2. EMBO Rep 13(12):1109–1115. doi:10.1038/embor.2012.155

    PubMed  CAS  PubMed Central  Google Scholar 

  144. 144.

    Rachmawati D, Bontkes HJ, Verstege MI, Muris J, von Blomberg BM, Scheper RJ, van Hoogstraten IM (2013) Transition metal sensing by Toll-like receptor-4: next to nickel, cobalt and palladium are potent human dendritic cell stimulators. Contact Dermat 68(6):331–338. doi:10.1111/cod.12042

    CAS  Google Scholar 

  145. 145.

    Martin SF, Dudda JC, Bachtanian E, Lembo A, Liller S, Durr C, Heimesaat MM, Bereswill S, Fejer G, Vassileva R, Jakob T, Freudenberg N, Termeer CC, Johner C, Galanos C, Freudenberg MA (2008) Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity. J Exp Med 205(9):2151–2162. doi:10.1084/jem.20070509

    PubMed  CAS  PubMed Central  Google Scholar 

  146. 146.

    Esser PR, Wolfle U, Durr C, von Loewenich FD, Schempp CM, Freudenberg MA, Jakob T, Martin SF (2012) Contact sensitizers induce skin inflammation via ROS production and hyaluronic acid degradation. PLoS One 7(7):e41340. doi:10.1371/journal.pone.0041340

    PubMed  CAS  PubMed Central  Google Scholar 

  147. 147.

    Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galan JE, Askenase PW, Flavell RA (2006) Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24(3):317–327. doi:10.1016/j.immuni.2006.02.004

    PubMed  CAS  Google Scholar 

  148. 148.

    Watanabe H, Gaide O, Petrilli V, Martinon F, Contassot E, Roques S, Kummer JA, Tschopp J, French LE (2007) Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity. J Invest Dermatol 127(8):1956–1963. doi:10.1038/sj.jid.5700819

    PubMed  CAS  Google Scholar 

  149. 149.

    Weber FC, Esser PR, Muller T, Ganesan J, Pellegatti P, Simon MM, Zeiser R, Idzko M, Jakob T, Martin SF (2010) Lack of the purinergic receptor P2X(7) results in resistance to contact hypersensitivity. J Exp Med 207(12):2609–2619. doi:10.1084/jem.20092489

    PubMed  CAS  PubMed Central  Google Scholar 

  150. 150.

    Hoque R, Farooq A, Mehal WZ (2013) Sterile inflammation in the liver and pancreas. J Gastroenterol Hepatol 28(Suppl 1):61–67. doi:10.1111/jgh.12018

    PubMed  CAS  PubMed Central  Google Scholar 

  151. 151.

    Cumberbatch M, Scott RC, Basketter DA, Scholes EW, Hilton J, Dearman RJ, Kimber I (1993) Influence of sodium lauryl sulphate on 2,4-dinitrochlorobenzene-induced lymph node activation. Toxicology 77(1–2):181–191

    PubMed  CAS  Google Scholar 

  152. 152.

    Grabbe S, Steinert M, Mahnke K, Schwartz A, Luger TA, Schwarz T (1996) Dissection of antigenic and irritative effects of epicutaneously applied haptens in mice. Evidence that not the antigenic component but nonspecific proinflammatory effects of haptens determine the concentration-dependent elicitation of allergic contact dermatitis. J Clin Investig 98(5):1158–1164. doi:10.1172/JCI118899

    PubMed  CAS  PubMed Central  Google Scholar 

  153. 153.

    Agner T, Johansen JD, Overgaard L, Volund A, Basketter D, Menne T (2002) Combined effects of irritants and allergens. Synergistic effects of nickel and sodium lauryl sulfate in nickel- sensitized individuals. Contact Dermat 47(1):21–26

    CAS  Google Scholar 

  154. 154.

    Pedersen LK, Johansen JD, Held E, Agner T (2004) Augmentation of skin response by exposure to a combination of allergens and irritants: a review. Contact Dermat 50(5):265–273. doi:10.1111/j.0105-1873.2004.00342.x

    CAS  Google Scholar 

  155. 155.

    Bonefeld CM, Nielsen MM, Rubin IM, Vennegaard MT, Dabelsteen S, Gimenez-Arnau E, Lepoittevin JP, Geisler C, Johansen JD (2011) Enhanced sensitization and elicitation responses caused by mixtures of common fragrance allergens. Contact Dermat 65(6):336–342. doi:10.1111/j.1600-0536.2011.01945.x

    CAS  Google Scholar 

  156. 156.

    Artik S, von Vultee C, Gleichmann E, Schwarz T, Griem P (1999) Nickel allergy in mice: enhanced sensitization capacity of nickel at higher oxidation states. J Immunol 163(3):1143–1152

    PubMed  CAS  Google Scholar 

  157. 157.

    Takahashi H, Kinbara M, Sato N, Sasaki K, Sugawara S, Endo Y (2011) Nickel allergy-promoting effects of microbial or inflammatory substances at the sensitization step in mice. Int Immunopharmacol 11(10):1534–1540. doi:10.1016/j.intimp.2011.05.010

    PubMed  CAS  Google Scholar 

  158. 158.

    Watanabe H, Gehrke S, Contassot E, Roques S, Tschopp J, Friedmann PS, French LE, Gaide O (2008) Danger signaling through the inflammasome acts as a master switch between tolerance and sensitization. J Immunol 180(9):5826–5832

    PubMed  CAS  Google Scholar 

  159. 159.

    Sanchez-Quintero MJ, Torres MJ, Blazquez AB, Gomez E, Fernandez TD, Dona I, Ariza A, Andreu I, Melendez L, Blanca M, Mayorga C (2013) Synergistic effect between amoxicillin and TLR ligands on dendritic cells from amoxicillin-delayed allergic patients. PLoS One 8(9):e74198. doi:10.1371/journal.pone.0074198

    PubMed  CAS  PubMed Central  Google Scholar 

  160. 160.

    Steinman RM, Hawiger D, Liu K, Bonifaz L, Bonnyay D, Mahnke K, Iyoda T, Ravetch J, Dhodapkar M, Inaba K, Nussenzweig M (2003) Dendritic cell function in vivo during the steady state: a role in peripheral tolerance. Ann N Y Acad Sci 987:15–25

    PubMed  CAS  Google Scholar 

  161. 161.

    Lutz MB (2012) Therapeutic potential of semi-mature dendritic cells for tolerance induction. Front Immunol 3:123. doi:10.3389/fimmu.2012.00123

    PubMed  CAS  PubMed Central  Google Scholar 

  162. 162.

    Hubo M, Trinschek B, Kryczanowsky F, Tuettenberg A, Steinbrink K, Jonuleit H (2013) Costimulatory molecules on immunogenic versus tolerogenic human dendritic cells. Front Immunol 4:82. doi:10.3389/fimmu.2013.00082

    PubMed  PubMed Central  Google Scholar 

  163. 163.

    Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM (2002) Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med 196(12):1627–1638

    PubMed  CAS  PubMed Central  Google Scholar 

  164. 164.

    Idoyaga J, Fiorese C, Zbytnuik L, Lubkin A, Miller J, Malissen B, Mucida D, Merad M, Steinman RM (2013) Specialized role of migratory dendritic cells in peripheral tolerance induction. J Clin Investig 123(2):844–854. doi:10.1172/JCI65260

    PubMed  CAS  PubMed Central  Google Scholar 

  165. 165.

    Grossmann C, Tenbusch M, Nchinda G, Temchura V, Nabi G, Stone GW, Kornbluth RS, Uberla K (2009) Enhancement of the priming efficacy of DNA vaccines encoding dendritic cell-targeted antigens by synergistic Toll-like receptor ligands. BMC Immunol 10:43. doi:10.1186/1471-2172-10-43

    PubMed  PubMed Central  Google Scholar 

  166. 166.

    Luckey U, Schmidt T, Pfender N, Romer M, Lorenz N, Martin SF, Bopp T, Schmitt E, Nikolaev A, Yogev N, Waisman A, Jakob T, Steinbrink K (2012) Crosstalk of regulatory T cells and tolerogenic dendritic cells prevents contact allergy in subjects with low zone tolerance. J Allergy Clin Immunol 130(3):781–797, e711. doi:10.1016/j.jaci.2012.06.022

  167. 167.

    Pulendran B, Artis D (2012) New paradigms in type 2 immunity. Science 337(6093):431–435. doi:10.1126/science.1221064

    PubMed  CAS  PubMed Central  Google Scholar 

  168. 168.

    Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC, Akashi-Takamura S, Miyake K, Zhang J, Lee WP, Muszynski A, Forsberg LS, Carlson RW, Dixit VM (2013) Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341(6151):1246–1249. doi:10.1126/science.1240248

    PubMed  CAS  Google Scholar 

  169. 169.

    Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA (2013) Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341(6151):1250–1253. doi:10.1126/science.1240988

    PubMed  CAS  PubMed Central  Google Scholar 

  170. 170.

    Gilles S, Behrendt H, Ring J, Traidl-Hoffmann C (2012) The pollen enigma: modulation of the allergic immune response by non-allergenic, pollen-derived compounds. Curr Pharm Des 18(16):2314–2319

    PubMed  CAS  Google Scholar 

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I am grateful to Dr. Philipp R. Esser for helpful discussions and careful reading of the manuscript.

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Martin, S.F. Adaptation in the innate immune system and heterologous innate immunity. Cell. Mol. Life Sci. 71, 4115–4130 (2014).

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  • Heterologous immunity
  • Innate immunity
  • Adjuvant
  • T cell
  • Inflammation
  • Contact dermatitis