Archivum Immunologiae et Therapiae Experimentalis

, Volume 61, Issue 6, pp 427–443 | Cite as

Toll-Like Receptors’ Pathway Disturbances are Associated with Increased Susceptibility to Infections in Humans

  • Josias Brito Frazão
  • Paolo Ruggero Errante
  • Antonio Condino-Neto


Toll-like receptors (TLRs) sense microbial products and play an important role in innate immunity. Currently, 11 members of TLRs have been identified in humans, with important function in host defense in early steps of the inflammatory response. TLRs are present in the plasma membrane (TLR1, TLR2, TLR4, TLR5, TLR6) and endosome (TLR3, TLR7, TLR8, TLR9) of leukocytes. TLRs and IL-1R are a family of receptors related to the innate immune response that contain an intracellular domain known as the Toll-IL-1R (TIR) domain that recruits the TIR-containing cytosolic adapters MyD88, TRIF, TIRAP and TRAM. The classical pathway results in the activation of both nuclear factor κB and MAPKs via the IRAK complex, with two active kinases (IRAK-1 and IRAK-4) and two non-catalytic subunits (IRAK-2 and IRAK-3/M). The classical pro-inflammatory TLR signaling pathway leads to the synthesis of inflammatory cytokines and chemokines, such as IL-1β, IL-6, IL-8, IL-12 and TNF-α. In humans, genetic defects have been identified that impair signaling of the TLR pathway and this may result in recurrent pyogenic infections, as well as virus and fungi infections. In this review, we discuss the main mechanisms of microbial recognition and the defects involving TLRs.


Toll-like receptors Immunodeficiencies Recurrent infections NF-kappaB IRAK-4 



Autosomal dominant


Antigen-presenting cells


Bacillus Calmette-Guérin


Brutons’s tyrosine kinase


CD62 ligand


Central nervous system


Common variable immunodeficiency


Dendritic cells


Double-stranded RNA


Ectodermal dysplasia with immunodeficiency


Hypochlorous acid


Heme oxygenase 1


Herpes simplex virus-encephalitis


Herpes simplex virus type 1




Inhibitor of NF-κB kinase complex




IL-1 receptor-associated kinase 4




Lipoteichoic acid


Macrophage-activating lipopeptide-2


Mitogen-activated protein kinases


Mannose-binding lectin


Myeloid differentiation factor 88


Nicotinamide adenine dinucleotide oxidase


NF-κB essential modulator


Nuclear factor kappaB


NOD leucine-rich repeat and pyrin domain containing proteins


Leucine-rich repeat-containing receptors


Pathogen-associated molecular patterns


Peripheral blood mononuclear cells


Plasmacytoid DCs


Poly-riboinosinicribocytidylic acid


Primary immunodeficiency diseases


Polymorphonuclear cells


Pattern-recognition receptors


Retinoic acid-inducible gene I protein


Single-stranded RNA


Toll-IL-1R domain


TIR domain-containing adapter protein


Toll-like receptors


TRIF-related adapter molecule


TIR domain-containing adapter-inducing IFN-β


X-linked immune deficiency


X-linked agammaglobulinemia


Conflict of interest

All authors declare no conflict of interest.


  1. Abad C, Gonzalez-Escribano MF et al (2011) Association of Toll-like receptor 10 and susceptibility to Crohn’s disease independent of NOD2. Genes Immun 12:635–642PubMedGoogle Scholar
  2. Adachi O, Kawai T et al (1998) Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9:143–150PubMedGoogle Scholar
  3. Akira S, Hemmi H (2003) Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett 85:85–95PubMedGoogle Scholar
  4. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511PubMedGoogle Scholar
  5. Akira S, Uematsu S et al (2006) Pathogen recognition and innate immunity. Cell 124:783–801PubMedGoogle Scholar
  6. Baeuerle PA, Henkel T (1994) Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 12:141–179PubMedGoogle Scholar
  7. Barchet W, Cella M et al (2005) Plasmacytoid dendritic cells–virus experts of innate immunity. Semin Immunol 17:253–261PubMedGoogle Scholar
  8. Beutler B (2004) Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430:257–263PubMedGoogle Scholar
  9. Bochud PY, Magaret AS et al (2007) Polymorphisms in TLR2 are associated with increased viral shedding and lesional rate in patients with genital herpes simplex virus Type 2 infection. J Infect Dis 196:505–509PubMedGoogle Scholar
  10. Botto M, Kirschfink M et al (2009) Complement in human diseases: lessons from complement deficiencies. Mol Immunol 46:2774–2783PubMedGoogle Scholar
  11. Bousfiha A, Picard C et al (2010) Primary immunodeficiencies of protective immunity to primary infections. Clin Immunol 135:204–209PubMedGoogle Scholar
  12. Bradley LA, Sweatman AK et al (1994) Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis. Hum Mol Genet 3:79–83PubMedGoogle Scholar
  13. Bsibsi M, Ravid R et al (2002) Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61:1013–1021PubMedGoogle Scholar
  14. Bsibsi M, Persoon-Deen C et al (2006) Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia 53:688–695PubMedGoogle Scholar
  15. Bunk S, Sigel S et al (2010) Internalization and coreceptor expression are critical for TLR2-mediated recognition of lipoteichoic acid in human peripheral blood. J Immunol 185:3708–3717PubMedGoogle Scholar
  16. Buwitt-Beckmann U, Heine H et al (2005) Lipopeptide structure determines TLR2 dependent cell activation level. FEBS J 272:6354–6364PubMedGoogle Scholar
  17. Cai Z, Pang Y et al (2003) Differential roles of tumor necrosis factor-alpha and interleukin-1 beta in lipopolysaccharide-induced brain injury in the neonatal rat. Brain Res 975:37–47PubMedGoogle Scholar
  18. Cardenes M, von Bernuth H et al (2006) Autosomal recessive interleukin-1 receptor-associated kinase 4 deficiency in fourth-degree relatives. J Pediatr 148:549–551PubMedGoogle Scholar
  19. Carpentier PA, Begolka WS et al (2005) Differential activation of astrocytes by innate and adaptive immune stimuli. Glia 49:360–374PubMedGoogle Scholar
  20. Carpentier PA, Duncan DS et al (2008) Glial Toll-like receptor signaling in central nervous system infection and autoimmunity. Brain Behav Immun 22:140–147PubMedGoogle Scholar
  21. Casrouge A, Zhang SY et al (2006) Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314:308–312PubMedGoogle Scholar
  22. Chao CC, Hu S et al (1992) Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J Immunol 149:2736–2741PubMedGoogle Scholar
  23. Chapel H, Geha R et al (2003) Primary immunodeficiency diseases: an update. Clin Exp Immunol 132:9–15PubMedGoogle Scholar
  24. Chapel H, Puel A et al (2005) Shigella sonnei meningitis due to interleukin-1 receptor-associated kinase-4 deficiency: first association with a primary immune deficiency. Clin Infect Dis 40:1227–1231PubMedGoogle Scholar
  25. Chapgier A, Kong XF et al (2009) A partial form of recessive STAT1 deficiency in humans. J Clin Invest 119:1502–1514PubMedGoogle Scholar
  26. Chin AC, Fournier B et al (2009) CD47 and TLR-2 cross-talk regulates neutrophil transmigration. J Immunol 183:5957–5963PubMedGoogle Scholar
  27. Chuang TH, Ulevitch RJ (2000) Cloning and characterization of a sub-family of human Toll-like receptors: hTLR7, hTLR8 and hTLR9. Eur Cytokine Netw 11:372–378PubMedGoogle Scholar
  28. Chuang T, Ulevitch RJ (2001) Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochim Biophys Acta 1518:157–161PubMedGoogle Scholar
  29. Chung J, Gao AG et al (1997) Thrombospondin acts via integrin-associated protein to activate the platelet integrin alphaIIbbeta3. J Biol Chem 272:14740–14746PubMedGoogle Scholar
  30. Clemente A, Pons J et al (2011) B cells from common variable immunodeficiency patients fail to differentiate to antibody secreting cells in response to TLR9 ligand (CpG-ODN) or anti-CD40+IL21. Cell Immunol 268:9–15PubMedGoogle Scholar
  31. Comeau JL, Lin TJ et al (2008) Staphylococcal pericarditis, and liver and paratracheal abscesses as presentations in two new cases of interleukin-1 receptor associated kinase 4 deficiency. Pediatr Infect Dis J 27:170–174PubMedGoogle Scholar
  32. Costa-Carvalho BT, Nudelman V et al (1998) Immune system and infections. J Pediatr 74(Suppl 1):S3–S11Google Scholar
  33. Cunningham-Rundles C, Bodian C (1999) Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol 92:34–48PubMedGoogle Scholar
  34. Cunningham-Rundles C, Radigan L et al (2006) TLR9 activation is defective in common variable immune deficiency. J Immunol 176:1978–1987PubMedGoogle Scholar
  35. Dasari P, Nicholson IC et al (2005) Expression of Toll-like receptors on B lymphocytes. Cell Immunol 236:140–145PubMedGoogle Scholar
  36. Davidson DJ, Currie AJ et al (2006) IRAK-4 mutation (Q293X): rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells. J Immunol 177:8202–8211PubMedGoogle Scholar
  37. De Tiege X, Rozenberg F et al (2008) The spectrum of herpes simplex encephalitis in children. Eur J Paediatr Neurol 12:72–81PubMedGoogle Scholar
  38. Deering RP, Orange JS (2006) Development of a clinical assay to evaluate Toll-like receptor function. Clin Vaccine Immunol 13:68–76PubMedGoogle Scholar
  39. Deininger S, Stadelmaier A et al (2003) Definition of structural prerequisites for lipoteichoic acid-inducible cytokine induction by synthetic derivatives. J Immunol 170:4134–4138PubMedGoogle Scholar
  40. Demeure CE, Tanaka H et al (2000) CD47 engagement inhibits cytokine production and maturation of human dendritic cells. J Immunol 164:2193–2199PubMedGoogle Scholar
  41. Dorahy DJ, Thorne RF et al (1997) Stimulation of platelet activation and aggregation by a carboxyl-terminal peptide from thrombospondin binding to the integrin-associated protein receptor. J Biol Chem 272:1323–1330PubMedGoogle Scholar
  42. Doyle SL, O’Neill LA (2006) Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol 72:1102–1113PubMedGoogle Scholar
  43. Doyle SL, Jefferies CA et al (2005) Bruton’s tyrosine kinase is involved in p65-mediated transactivation and phosphorylation of p65 on serine 536 during NFkappaB activation by lipopolysaccharide. J Biol Chem 280:23496–23501PubMedGoogle Scholar
  44. Doyle SL, Jefferies CA et al (2007) Signaling by Toll-like receptors 8 and 9 requires Bruton’s tyrosine kinase. J Biol Chem 282:36953–36960PubMedGoogle Scholar
  45. Dupuis S, Jouanguy E et al (2003) Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet 33:388–391PubMedGoogle Scholar
  46. Dziarski R, Gupta D (2005) Staphylococcus aureus peptidoglycan is a Toll-like receptor 2 activator: a reevaluation. Infect Immun 73:5212–5216PubMedGoogle Scholar
  47. Dziarski R, Gupta D (2006) The peptidoglycan recognition proteins (PGRPs). Genome Biol 7:232PubMedGoogle Scholar
  48. Ear T, McDonald PP (2008) Cytokine generation, promoter activation, and oxidant-independent NF-kappaB activation in a transfectable human neutrophilic cellular model. BMC Immunol 9:14PubMedGoogle Scholar
  49. Enoch T, Zinn K et al (1986) Activation of the human beta-interferon gene requires an interferon-inducible factor. Mol Cell Biol 6:801–810PubMedGoogle Scholar
  50. Escobar D, Pons J et al (2010) Defective B cell response to TLR9 ligand (CpG-ODN), Streptococcus pneumoniae and Haemophilus influenzae extracts in common variable immunodeficiency patients. Cell Immunol 262:105–111PubMedGoogle Scholar
  51. Ezekowitz RA, Sastry K et al (1990) Molecular characterization of the human macrophage mannose receptor: demonstration of multiple carbohydrate recognition-like domains and phagocytosis of yeasts in Cos-1 cells. J Exp Med 172:1785–1794PubMedGoogle Scholar
  52. Farina C, Krumbholz M et al (2005) Preferential expression and function of Toll-like receptor 3 in human astrocytes. J Neuroimmunol 159:12–19PubMedGoogle Scholar
  53. Fitzgerald KA, McWhirter SM et al (2003) IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4:491–496PubMedGoogle Scholar
  54. Galli SJ, Borregaard N et al (2011) Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol 12:1035–1044PubMedGoogle Scholar
  55. Gewirtz AT, Vijay-Kumar M et al (2006) Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn’s disease. Am J Physiol Gastrointest Liver Physiol 290:G1157–G1163PubMedGoogle Scholar
  56. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35PubMedGoogle Scholar
  57. Guirado M, Gil H et al (2012) Association between C13ORF31, NOD2, RIPK2 and TLR10 polymorphisms and urothelial bladder cancer. Hum Immunol 73:668–672PubMedGoogle Scholar
  58. Guo Y, Audry M et al (2011) Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med 208:2083–2098PubMedGoogle Scholar
  59. Hammarstrom L, Vorechovsky I et al (2000) Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 120:225–231PubMedGoogle Scholar
  60. Han X, Sterling H et al (2000) CD47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation. J Biol Chem 275:37984–37992PubMedGoogle Scholar
  61. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394PubMedGoogle Scholar
  62. Hansson GK, Edfeldt K (2005) Toll to be paid at the gateway to the vessel wall. Arterioscler Thromb Vasc Biol 25:1085–1087PubMedGoogle Scholar
  63. Harte M, Haga IR et al (2003) The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense. J Exp Med 197:343–351PubMedGoogle Scholar
  64. Hasan U, Chaffois C et al (2005) Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol 174:2942–2950PubMedGoogle Scholar
  65. Hashimoto S, Tsukada S et al (1996) Identification of Bruton’s tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan. Blood 88:561–573PubMedGoogle Scholar
  66. Hashimoto M, Tawaratsumida K et al (2006a) Lipoprotein is a predominant Toll-like receptor 2 ligand in Staphylococcus aureus cell wall components. Int Immunol 18:355–362PubMedGoogle Scholar
  67. Hashimoto M, Tawaratsumida K et al (2006b) Not lipoteichoic acid but lipoproteins appear to be the dominant immunobiologically active compounds in Staphylococcus aureus. J Immunol 177:3162–3169PubMedGoogle Scholar
  68. Hashimoto M, Furuyashiki M et al (2007) Evidence of immunostimulating lipoprotein existing in the natural lipoteichoic acid fraction. Infect Immun 75:1926–1932PubMedGoogle Scholar
  69. Hawn TR, Wu H et al (2005) A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. Proc Natl Acad Sci USA 102:10593–10597PubMedGoogle Scholar
  70. Hayashi F, Smith KD et al (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099–1103PubMedGoogle Scholar
  71. Herman M, Ciancanelli M et al (2012) Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. J Exp Med 209:1567–1582PubMedGoogle Scholar
  72. Hermaszewski RA, Webster AD (1993) Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med 86:31–42PubMedGoogle Scholar
  73. Hickey MJ, Kubes P (2009) Intravascular immunity: the host-pathogen encounter in blood vessels. Nat Rev Immunol 9:364–375PubMedGoogle Scholar
  74. Hochrein H, Schlatter B et al (2004) Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and -independent pathways. Proc Natl Acad Sci USA 101:11416–11421PubMedGoogle Scholar
  75. Hoebe K, Georgel P et al (2005) CD36 is a sensor of diacylglycerides. Nature 433:523–527PubMedGoogle Scholar
  76. Hornung V, Rothenfusser S et al (2002) Quantitative expression of Toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 168:4531–4537PubMedGoogle Scholar
  77. Ip WK, Takahashi K et al (2008) Mannose-binding lectin enhances Toll-like receptors 2 and 6 signaling from the phagosome. J Exp Med 205:169–181PubMedGoogle Scholar
  78. Iwasaki A, Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327:291–295PubMedGoogle Scholar
  79. Jack CS, Arbour N et al (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 175:4320–4330PubMedGoogle Scholar
  80. Janeway CA Jr (1992) The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol Today 13:11–16PubMedGoogle Scholar
  81. Jefferies CA, Doyle S et al (2003) Bruton’s tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. J Biol Chem 278:26258–26264PubMedGoogle Scholar
  82. Jimenez-Dalmaroni MJ, Xiao N et al (2009) Soluble CD36 ectodomain binds negatively charged diacylglycerol ligands and acts as a co-receptor for TLR2. PLoS ONE 4:e7411PubMedGoogle Scholar
  83. Jin MS, Kim SE et al (2007) Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130:1071–1082PubMedGoogle Scholar
  84. Jouault T, Ibata-Ombetta S et al (2003) Candida albicans phospholipomannan is sensed through Toll-like receptors. J Infect Dis 188:165–172PubMedGoogle Scholar
  85. Kang JY, Nan X et al (2009) Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer. Immunity 31:873–884PubMedGoogle Scholar
  86. Kawai T, Akira S (2007) Antiviral signaling through pattern recognition receptors. J Biochem 141:137–145PubMedGoogle Scholar
  87. Khazen W, M’Bika JP et al (2005) Expression of macrophage-selective markers in human and rodent adipocytes. FEBS Lett 579:5631–5634PubMedGoogle Scholar
  88. Kopp E, Medzhitov R (2003) Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol 15:396–401PubMedGoogle Scholar
  89. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318PubMedGoogle Scholar
  90. Krombach F, Munzing S et al (1997) Cell size of alveolar macrophages: an interspecies comparison. Environ Health Perspect 105(Suppl 5):1261–1263PubMedGoogle Scholar
  91. Krutzik SR, Ochoa MT et al (2003) Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat Med 9:525–532PubMedGoogle Scholar
  92. Ku CL, von Bernuth H et al (2007) Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med 204:2407–2422PubMedGoogle Scholar
  93. Ku JK, Kwon HJ et al (2008) Expression of Toll-like receptors in verruca and molluscum contagiosum. J Korean Med Sci 23:307–314PubMedGoogle Scholar
  94. Kuhns DB, Long Priel DA et al (1997) Endotoxin and IL-1 hyporesponsiveness in a patient with recurrent bacterial infections. J Immunol 158:3959–3964PubMedGoogle Scholar
  95. Lafaille FG, Pessach IM et al (2012) Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature 491:769–773PubMedGoogle Scholar
  96. Laflamme N, Rivest S (2001) Toll-like receptor 4: the missing link of the cerebral innate immune response triggered by circulating Gram-negative bacterial cell wall components. FASEB J 15:155–163PubMedGoogle Scholar
  97. Lai Y, Gallo RL (2008) Toll-like receptors in skin infections and inflammatory diseases. Infect Disord Drug Targets 8:144–155PubMedGoogle Scholar
  98. Lehnardt S, Lachance C et al (2002) The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 22:2478–2486PubMedGoogle Scholar
  99. Lemaitre B, Nicolas E et al (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983PubMedGoogle Scholar
  100. Lenardo MJ, Fan CM et al (1989) The involvement of NF-kappa B in beta-interferon gene regulation reveals its role as widely inducible mediator of signal transduction. Cell 57:287–294PubMedGoogle Scholar
  101. Li Q, Cherayil BJ (2004) Toll-like receptor 4 mutation impairs the macrophage TNFalpha response to peptidoglycan. Biochem Biophys Res Commun 325:91–96PubMedGoogle Scholar
  102. Lindberg FP, Bullard DC et al (1996) Decreased resistance to bacterial infection and granulocyte defects in IAP-deficient mice. Science 274:795–798PubMedGoogle Scholar
  103. Liu Y, Merlin D et al (2001) The role of CD47 in neutrophil transmigration. Increased rate of migration correlates with increased cell surface expression of CD47. J Biol Chem 276:40156–40166PubMedGoogle Scholar
  104. Lokensgard JR, Gekker G et al (1997) Proinflammatory cytokines inhibit HIV-1(SF162) expression in acutely infected human brain cell cultures. J Immunol 158:2449–2455PubMedGoogle Scholar
  105. Maguire O, Collins C et al (2011) Quantifying nuclear p65 as a parameter for NF-kappaB activation: correlation between ImageStream cytometry, microscopy, and Western blot. Cytometry A 79:461–469PubMedGoogle Scholar
  106. McKimmie CS, Fazakerley JK (2005) In response to pathogens, glial cells dynamically and differentially regulate Toll-like receptor gene expression. J Neuroimmunol 169:116–125PubMedGoogle Scholar
  107. Medvedev AE, Lentschat A et al (2003) Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 198:521–531PubMedGoogle Scholar
  108. Mempel M, Kalali BN et al (2007) Toll-like receptors in dermatology. Dermatol Clin 25:531–540, viiiGoogle Scholar
  109. Mizel SB, Honko AN et al (2003) Induction of macrophage nitric oxide production by Gram-negative flagellin involves signaling via heteromeric Toll-like receptor 5/Toll-like receptor 4 complexes. J Immunol 170:6217–6223PubMedGoogle Scholar
  110. Moore ML, McKissic EL et al (2004) Fatal disseminated mouse adenovirus type 1 infection in mice lacking B cells or Bruton’s tyrosine kinase. J Virol 78:5584–5590PubMedGoogle Scholar
  111. Morath S, Geyer A et al (2001) Structure-function relationship of cytokine induction by lipoteichoic acid from Staphylococcus aureus. J Exp Med 193:393–397PubMedGoogle Scholar
  112. Morath S, Stadelmaier A et al (2002) Synthetic lipoteichoic acid from Staphylococcus aureus is a potent stimulus of cytokine release. J Exp Med 195:1635–1640PubMedGoogle Scholar
  113. Moreira J, Aragao-Filho WC et al (2012) Human leucocytes response to viable, extended freeze-drying or heat-killed Mycobacterium bovis bacillus Calmette-Guerin. Scand J Immunol 75:96–101PubMedGoogle Scholar
  114. Morgan AR, Lam WJ et al (2012) Genetic variation within TLR10 is associated with Crohn’s disease in a New Zealand population. Hum Immunol 73:416–420PubMedGoogle Scholar
  115. Mulla MJ, Myrtolli K et al (2013) Cutting-edge report: TLR10 plays a role in mediating bacterial peptidoglycan-induced trophoblast apoptosis. Am J Reprod Immunol 69:449–453PubMedGoogle Scholar
  116. Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737PubMedGoogle Scholar
  117. Netea MG, van der Graaf C et al (2004) Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system. J Leukoc Biol 75:749–755PubMedGoogle Scholar
  118. Netea MG, Gow NA et al (2006) Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J Clin Invest 116:1642–1650PubMedGoogle Scholar
  119. Oliveira RB, Ochoa MT et al (2003) Expression of Toll-like receptor 2 on human Schwann cells: a mechanism of nerve damage in leprosy. Infect Immun 71:1427–1433PubMedGoogle Scholar
  120. O’Neill LA (2008) When signaling pathways collide: positive and negative regulation of Toll-like receptor signal transduction. Immunity 29:12–20PubMedGoogle Scholar
  121. O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7:353–364PubMedGoogle Scholar
  122. O’Neill LA, Dinarello CA (2000) The IL-1 receptor/Toll-like receptor superfamily: crucial receptors for inflammation and host defense. Immunol Today 21:206–209PubMedGoogle Scholar
  123. Oosting M, Ter Hofstede H et al (2011) TLR1/TLR2 heterodimers play an important role in the recognition of Borrelia spirochetes. PLoS ONE 6:e25998PubMedGoogle Scholar
  124. Orange JS, Levy O et al (2004) Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. J Allergy Clin Immunol 114:650–656PubMedGoogle Scholar
  125. Orange JS, Levy O et al (2005) Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation. Immunol Rev 203:21–37PubMedGoogle Scholar
  126. Park H, Wahl MI et al (1996) Regulation of Btk function by a major autophosphorylation site within the SH3 domain. Immunity 4:515–525PubMedGoogle Scholar
  127. Park HJ, Hahn WH et al (2011) Association between Toll-like receptor 10 (TLR10) gene polymorphisms and childhood IgA nephropathy. Eur J Pediatr 170:503–509PubMedGoogle Scholar
  128. Parkos CA, Colgan SP et al (1996) CD47 mediates post-adhesive events required for neutrophil migration across polarized intestinal epithelia. J Cell Biol 132:437–450PubMedGoogle Scholar
  129. Perez de Diego R, Sancho-Shimizu V et al (2010) Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity 33:400–411PubMedGoogle Scholar
  130. Perry VH, Gordon S (1988) Macrophages and microglia in the nervous system. Trends Neurosci 11:273–277PubMedGoogle Scholar
  131. Pettersen RD, Hestdal K et al (1999) CD47 signals T cell death. J Immunol 162:7031–7040PubMedGoogle Scholar
  132. Picard C, Puel A et al (2003) Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299:2076–2079PubMedGoogle Scholar
  133. Picard C, von Bernuth H et al (2010) Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 89:403–425PubMedGoogle Scholar
  134. Picard C, Casanova JL et al (2011) Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IkappaBalpha deficiency. Clin Microbiol Rev 24:490–497PubMedGoogle Scholar
  135. Poltorak A, He X et al (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088PubMedGoogle Scholar
  136. Requena T, Gazquez I et al (2013) Allelic variants in TLR10 gene may influence bilateral affectation and clinical course of Meniere’s disease. Immunogenetics 65:345–355PubMedGoogle Scholar
  137. Rivieccio MA, John GR et al (2005) The cytokine IL-1beta activates IFN response factor 3 in human fetal astrocytes in culture. J Immunol 174:3719–3726PubMedGoogle Scholar
  138. Rivieccio MA, Suh HS et al (2006) TLR3 ligation activates an antiviral response in human fetal astrocytes: a role for viperin/cig5. J Immunol 177:4735–4741PubMedGoogle Scholar
  139. Rock FL, Hardiman G et al (1998) A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 95:588–593PubMedGoogle Scholar
  140. Ruckdeschel K, Mannel O et al (2001) Yersinia outer protein P of Yersinia enterocolitica simultaneously blocks the nuclear factor-kappa B pathway and exploits lipopolysaccharide signaling to trigger apoptosis in macrophages. J Immunol 166:1823–1831PubMedGoogle Scholar
  141. Ryser O, Morell A et al (1988) Primary immunodeficiencies in Switzerland: first report of the national registry in adults and children. J Clin Immunol 8:479–485PubMedGoogle Scholar
  142. Salio M, Cerundolo V (2005) Viral immunity: cross-priming with the help of TLR3. Curr Biol 15:R336–R339PubMedGoogle Scholar
  143. Sancho-Shimizu V, Perez de Diego R et al (2011) Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. J Clin Invest 121:4889–4902PubMedGoogle Scholar
  144. Sato A, Linehan MM et al (2006) Dual recognition of herpes simplex viruses by TLR2 and TLR9 in dendritic cells. Proc Natl Acad Sci USA 103:17343–17348PubMedGoogle Scholar
  145. Schlaepfer E, Audige A et al (2006) TLR7/8 triggering exerts opposing effects in acute versus latent HIV infection. J Immunol 176:2888–2895PubMedGoogle Scholar
  146. Schmitz ML, Bacher S et al (2001) I kappa B-independent control of NF-kappa B activity by modulatory phosphorylations. Trends Biochem Sci 26:186–190PubMedGoogle Scholar
  147. Schroder NW, Morath S et al (2003) Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. J Biol Chem 278:15587–15594PubMedGoogle Scholar
  148. Schwartz M, Butovsky O et al (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29:68–74PubMedGoogle Scholar
  149. Segal AW (2005) How neutrophils kill microbes. Annu Rev Immunol 23:197–223PubMedGoogle Scholar
  150. Seo HS, Michalek SM et al (2008) Lipoteichoic acid is important in innate immune responses to Gram-positive bacteria. Infect Immun 76:206–213PubMedGoogle Scholar
  151. Seya T, Akazawa T et al (2003) Role of Toll-like receptors and their adaptors in adjuvant immunotherapy for cancer. Anticancer Res 23:4369–4376PubMedGoogle Scholar
  152. Seya T, Akazawa T et al (2006) Role of Toll-like receptors in adjuvant-augmented immune therapies. Evid Based Complement Alternat Med 3:31–38 discussion 133–137PubMedGoogle Scholar
  153. Sharma S, ten Oever BR et al (2003) Triggering the interferon antiviral response through an IKK-related pathway. Science 300:1148–1151PubMedGoogle Scholar
  154. Shearer WT, Paul ME et al (1994) Laboratory assessment of immunodeficiency disorders. Immunol Allergy Clin 14:265–297Google Scholar
  155. Si Q, Zhao ML et al (2004) 15-deoxy-Delta12,14-prostaglandin J2 inhibits IFN-inducible protein 10/CXC chemokine ligand 10 expression in human microglia: mechanisms and implications. J Immunol 173:3504–3513PubMedGoogle Scholar
  156. Sing A, Rost D et al (2002) Yersinia V-antigen exploits Toll-like receptor 2 and CD14 for interleukin 10-mediated immunosuppression. J Exp Med 196:1017–1024PubMedGoogle Scholar
  157. Sivula J, Cordova ZM et al (2012) Toll-like receptor gene polymorphisms confer susceptibility to graft-versus-host disease in allogenic hematopoietic stem cell transplantation. Scand J Immunol 76:336–341PubMedGoogle Scholar
  158. Stevens VL, Hsing AW et al (2008) Genetic variation in the Toll-like receptor gene cluster (TLR10-TLR1-TLR6) and prostate cancer risk. Int J Cancer 123:2644–2650PubMedGoogle Scholar
  159. Streit WJ, Conde JR et al (2005) Role of microglia in the central nervous system’s immune response. Neurol Res 27:685–691PubMedGoogle Scholar
  160. Stuart LM, Deng J et al (2005) Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain. J Cell Biol 170:477–485PubMedGoogle Scholar
  161. Suh HS, Zhao ML et al (2007) Astrocyte indoleamine 2,3-dioxygenase is induced by the TLR3 ligand poly(I:C): mechanism of induction and role in antiviral response. J Virol 81:9838–9850PubMedGoogle Scholar
  162. Suzuki N, Suzuki S et al (2002) Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416:750–756PubMedGoogle Scholar
  163. Szabo J, Dobay O et al (2007) Recurrent infection with genetically identical pneumococcal isolates in a patient with interleukin-1 receptor-associated kinase-4 deficiency. J Med Microbiol 56(Pt 6):863–865PubMedGoogle Scholar
  164. Tada H, Nemoto E et al (2002) Saccharomyces cerevisiae- and Candida albicans-derived mannan induced production of tumor necrosis factor alpha by human monocytes in a CD14- and Toll-like receptor 4-dependent manner. Microbiol Immunol 46:503–512PubMedGoogle Scholar
  165. Takeuchi O, Hoshino K et al (2000) Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol 165:5392–5396PubMedGoogle Scholar
  166. Town T, Jeng D et al (2006) Microglia recognize double-stranded RNA via TLR3. J Immunol 176:3804–3812PubMedGoogle Scholar
  167. Travassos LH, Girardin SE et al (2004) Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep 5:1000–1006PubMedGoogle Scholar
  168. Veltkamp M, van Moorsel CH et al (2012) Genetic variation in the Toll-like receptor gene cluster (TLR10-TLR1-TLR6) influences disease course in sarcoidosis. Tissue Antigens 79:25–32PubMedGoogle Scholar
  169. Vijayan V, Baumgart-Vogt E et al (2011) Bruton’s tyrosine kinase is required for TLR-dependent heme oxygenase-1 gene activation via Nrf2 in macrophages. J Immunol 187:817–827PubMedGoogle Scholar
  170. von Aulock S, Hartung T et al (2007) Comment on “Not lipoteichoic acid but lipoproteins appear to be the dominant immunobiologically active compounds in Staphylococcus aureus”. J Immunol 178:2610Google Scholar
  171. von Bernuth H, Ku CL et al (2006) A fast procedure for the detection of defects in Toll-like receptor signaling. Pediatrics 118:2498–2503Google Scholar
  172. von Bernuth H, Picard C et al (2008) Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321:691–696Google Scholar
  173. Wang J, Fei B et al (2010) Quantitative analysis of protein translocations by microfluidic total internal reflection fluorescence flow cytometry. Lab Chip 10:2673–2679PubMedGoogle Scholar
  174. Weih F, Warr G et al (1997) Multifocal defects in immune responses in RelB-deficient mice. J Immunol 158:5211–5218PubMedGoogle Scholar
  175. WHO (1997) Primary immunodeficiency diseases. Report of a WHO scientific group. Clin Exp Immunol 109(Suppl 1):1–28Google Scholar
  176. Winkelstein JA, Marino MC et al (2006) X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine 85:193–202PubMedGoogle Scholar
  177. Wlasiuk G, Khan S et al (2009) A history of recurrent positive selection at the Toll-like receptor 5 in primates. Mol Biol Evol 26:937–949PubMedGoogle Scholar
  178. Xu N, Yao HP et al (2012) Downregulation of TLR7/9 leads to deficient production of IFN-alpha from plasmacytoid dendritic cells in chronic hepatitis B. Inflamm Res 61:997–1004PubMedGoogle Scholar
  179. Yang M, Gan H et al (2012) Effect of LPS on the level of TLR4 and on the expression of NF-kappaB and Notch1 in monocytes from patients with type 2 diabetic nephropathy. Zhong Nan Da Xue Xue Bao Yi Xue Ban 37:578–585PubMedGoogle Scholar
  180. Zemskov AM, Zemskov VM et al (2005) Problem of specific and nonspecific factors in the induction and regulation of immunological reactions. Zh Mikrobiol Epidemiol Immunobiol 4:105–109PubMedGoogle Scholar
  181. Zhang SY, Jouanguy E et al (2007) TLR3 deficiency in patients with herpes simplex encephalitis. Science 317:1522–1527PubMedGoogle Scholar
  182. Zheng W, Zheng X et al (2012) TNFalpha and IL-1beta are mediated by both TLR4 and Nod1 pathways in the cultured HAPI cells stimulated by LPS. Biochem Biophys Res Commun 420:762–767PubMedGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013

Authors and Affiliations

  • Josias Brito Frazão
    • 1
  • Paolo Ruggero Errante
    • 1
  • Antonio Condino-Neto
    • 1
  1. 1.Department of Immunology, Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil

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