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Erschienen in: HNO 6/2018

27.03.2018 | Zytokine | Übersichten

Rolle des angeborenen Immunsystems bei Otitis media

verfasst von: M. Wigand, T. K. Hoffmann, A. F. Ryan, B. Wollenberg, PD Dr. A. Leichtle

Erschienen in: HNO | Ausgabe 6/2018

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Zusammenfassung

Die Otitis media (OM) gehört zu den häufigsten Krankheiten im Kindesalter und ist für mehr Arztbesuche, chirurgische Eingriffe und Medikamentenverordnungen verantwortlich als jede andere Infektionskrankheit. Neuesten Forschungsergebnissen zufolge nimmt das angeborene Immunsystem bei der Bekämpfung der Mittelohrentzündung eine entscheidende Rolle ein. Die Mukosa des Mittelohrs identifiziert das eindringende Pathogen, indem sie „pathogenassoziierte molekulare Muster“ (PAMP) über Rezeptoren wie die Toll-like-Rezeptoren (TLR) erkennt. Diese generieren umgehend eine antimikrobielle Immunantwort sowie die Freisetzung von Zytokinen und führen somit zu einer Entzündungsreaktion, wie sie bei der akuten und chronischen OM zu beobachten ist. Durch Interaktion zwischen den verschiedenen TLR kann der Heilungsprozess im Mittelohr sowohl verstärkt als auch gehemmt werden. Um eine Überreaktion auf der einen Seite und eine mangelnde Immunantwort auf der anderen Seite zu verhindern, muss das Signalnetzwerk der Toll-like-Rezeptoren über positive und negative Feedbackschleifen kontrolliert und vernetzt sein. Nur dann kann eine angemessene Immunantwort auf die Infektion im Mittelohr garantiert werden. In der vorliegenden Literaturübersicht liegt das Augenmerk auf der Rolle des angeborenen Immunsystems und der TLR sowie deren Bedeutung bei der Entwicklung von neuen Impfstrategien bzw. Immuntherapien.
Literatur
2.
Zurück zum Zitat Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2:675–680CrossRefPubMed Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2:675–680CrossRefPubMed
3.
Zurück zum Zitat Allen EK, Manichaikul A, Sale MM (2014) Genetic contributors to otitis media: agnostic discovery approaches. Curr Allergy Asthma Rep 14:411CrossRefPubMed Allen EK, Manichaikul A, Sale MM (2014) Genetic contributors to otitis media: agnostic discovery approaches. Curr Allergy Asthma Rep 14:411CrossRefPubMed
4.
Zurück zum Zitat Casey JR, Pichichero ME (2004) Changes in frequency and pathogens causing acute otitis media in 1995–2003. Pediatr Infect Dis J 23:824–828CrossRefPubMed Casey JR, Pichichero ME (2004) Changes in frequency and pathogens causing acute otitis media in 1995–2003. Pediatr Infect Dis J 23:824–828CrossRefPubMed
5.
Zurück zum Zitat Chen R, Lim JH, Jono H et al (2004) Nontypeable Haemophilus influenzae lipoprotein P6 induces MUC5AC mucin transcription via TLR2-TAK1-dependent p38 MAPK-AP1 and IKKbeta-IkappaBalpha-NF-kappaB signaling pathways. Biochem Biophys Res Commun 324:1087–1094CrossRefPubMed Chen R, Lim JH, Jono H et al (2004) Nontypeable Haemophilus influenzae lipoprotein P6 induces MUC5AC mucin transcription via TLR2-TAK1-dependent p38 MAPK-AP1 and IKKbeta-IkappaBalpha-NF-kappaB signaling pathways. Biochem Biophys Res Commun 324:1087–1094CrossRefPubMed
7.
Zurück zum Zitat Demaria TF, Apicella MA, Nichols WA et al (1997) Evaluation of the virulence of nontypeable Haemophilus influenzae lipooligosaccharide htrB and rfaD mutants in the chinchilla model of otitis media. Infect Immun 65:4431–4435PubMedPubMedCentral Demaria TF, Apicella MA, Nichols WA et al (1997) Evaluation of the virulence of nontypeable Haemophilus influenzae lipooligosaccharide htrB and rfaD mutants in the chinchilla model of otitis media. Infect Immun 65:4431–4435PubMedPubMedCentral
9.
Zurück zum Zitat Gorski KS, Waller EL, Bjornton-Severson J et al (2006) Distinct indirect pathways govern human NK-cell activation by TLR-7 and TLR-8 agonists. Int Immunol 18:1115–1126CrossRefPubMed Gorski KS, Waller EL, Bjornton-Severson J et al (2006) Distinct indirect pathways govern human NK-cell activation by TLR-7 and TLR-8 agonists. Int Immunol 18:1115–1126CrossRefPubMed
10.
Zurück zum Zitat Hernandez M, Leichtle A, Pak K et al (2008) Myeloid differentiation primary response gene 88 is required for the resolution of otitis media. J Infect Dis 198:1862–1869CrossRefPubMedPubMedCentral Hernandez M, Leichtle A, Pak K et al (2008) Myeloid differentiation primary response gene 88 is required for the resolution of otitis media. J Infect Dis 198:1862–1869CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Hirano T, Kodama S, Fujita K et al (2007) Role of Toll-like receptor 4 in innate immune responses in a mouse model of acute otitis media. FEMS Immunol Med Microbiol 49:75–83CrossRefPubMed Hirano T, Kodama S, Fujita K et al (2007) Role of Toll-like receptor 4 in innate immune responses in a mouse model of acute otitis media. FEMS Immunol Med Microbiol 49:75–83CrossRefPubMed
13.
Zurück zum Zitat Hoshino K, Takeuchi O, Kawai T et al (1999) Cutting edge: toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162:3749–3752PubMed Hoshino K, Takeuchi O, Kawai T et al (1999) Cutting edge: toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162:3749–3752PubMed
14.
Zurück zum Zitat Ichinohe T, Watanabe I, Ito S et al (2005) Synthetic double-stranded RNA poly(I:C) combined with mucosal vaccine protects against influenza virus infection. J Virol 79:2910–2919CrossRefPubMedPubMedCentral Ichinohe T, Watanabe I, Ito S et al (2005) Synthetic double-stranded RNA poly(I:C) combined with mucosal vaccine protects against influenza virus infection. J Virol 79:2910–2919CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Johnston LC, Feldman HM, Paradise JL et al (2004) Tympanic membrane abnormalities and hearing levels at the ages of 5 and 6 years in relation to persistent otitis media and tympanostomy tube insertion in the first 3 years of life: a prospective study incorporating a randomized clinical trial. Pediatrics 114:e58–e67CrossRefPubMed Johnston LC, Feldman HM, Paradise JL et al (2004) Tympanic membrane abnormalities and hearing levels at the ages of 5 and 6 years in relation to persistent otitis media and tympanostomy tube insertion in the first 3 years of life: a prospective study incorporating a randomized clinical trial. Pediatrics 114:e58–e67CrossRefPubMed
16.
Zurück zum Zitat Kasturi SP, Skountzou I, Albrecht RA et al (2011) Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470:543–547CrossRefPubMedPubMedCentral Kasturi SP, Skountzou I, Albrecht RA et al (2011) Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470:543–547CrossRefPubMedPubMedCentral
17.
Zurück zum Zitat Kaur R, Casey J, Pichichero M (2015) Cytokine, chemokine, and Toll-like receptor expression in middle ear fluids of children with acute otitis media. Laryngoscope 125:E39–E44CrossRefPubMed Kaur R, Casey J, Pichichero M (2015) Cytokine, chemokine, and Toll-like receptor expression in middle ear fluids of children with acute otitis media. Laryngoscope 125:E39–E44CrossRefPubMed
19.
Zurück zum Zitat Ku CL, Von Bernuth H, Picard C 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 204:2407–2422CrossRefPubMedPubMedCentral Ku CL, Von Bernuth H, Picard C 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 204:2407–2422CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Kurabi A, Pak K, Ryan AF et al (2016) Innate immunity: orchestrating inflammation and resolution of Otitis Media. Curr Allergy Asthma Rep 16:6CrossRefPubMed Kurabi A, Pak K, Ryan AF et al (2016) Innate immunity: orchestrating inflammation and resolution of Otitis Media. Curr Allergy Asthma Rep 16:6CrossRefPubMed
21.
Zurück zum Zitat Lee HY, Chung JH, Lee SK et al (2013) Toll-like receptors, cytokines & nitric oxide synthase in patients with otitis media with effusion. Indian J Med Res 138:523–530PubMedPubMedCentral Lee HY, Chung JH, Lee SK et al (2013) Toll-like receptors, cytokines & nitric oxide synthase in patients with otitis media with effusion. Indian J Med Res 138:523–530PubMedPubMedCentral
22.
Zurück zum Zitat Leibovitz E (2006) Acute otitis media in children aged less than 2 years: drug treatment issues. Paediatr Drugs 8:337–346CrossRefPubMed Leibovitz E (2006) Acute otitis media in children aged less than 2 years: drug treatment issues. Paediatr Drugs 8:337–346CrossRefPubMed
23.
Zurück zum Zitat Leibovitz E (2007) The challenge of recalcitrant acute otitis media: pathogens, resistance, and treatment strategy. Pediatr Infect Dis J 26:S8–S11CrossRefPubMed Leibovitz E (2007) The challenge of recalcitrant acute otitis media: pathogens, resistance, and treatment strategy. Pediatr Infect Dis J 26:S8–S11CrossRefPubMed
24.
Zurück zum Zitat Leibovitz E, Jacobs MR, Dagan R (2004) Haemophilus influenzae: a significant pathogen in acute otitis media. Pediatr Infect Dis J 23:1142–1152PubMed Leibovitz E, Jacobs MR, Dagan R (2004) Haemophilus influenzae: a significant pathogen in acute otitis media. Pediatr Infect Dis J 23:1142–1152PubMed
25.
Zurück zum Zitat Leichtle A, Hernandez M, Ebmeyer J et al (2010) CC chemokine ligand 3 overcomes the bacteriocidal and phagocytic defect of macrophages and hastens recovery from experimental otitis media in TNF-/-mice. J Immunol 184:3087–3097CrossRefPubMedPubMedCentral Leichtle A, Hernandez M, Ebmeyer J et al (2010) CC chemokine ligand 3 overcomes the bacteriocidal and phagocytic defect of macrophages and hastens recovery from experimental otitis media in TNF-/-mice. J Immunol 184:3087–3097CrossRefPubMedPubMedCentral
26.
Zurück zum Zitat Leichtle A, Hernandez M, Lee J et al (2012) The role of DNA sensing and innate immune receptor TLR9 in otitis media. Innate Immun 18:3–13CrossRefPubMed Leichtle A, Hernandez M, Lee J et al (2012) The role of DNA sensing and innate immune receptor TLR9 in otitis media. Innate Immun 18:3–13CrossRefPubMed
27.
Zurück zum Zitat Leichtle A, Hernandez M, Pak K et al (2009) The toll-Like receptor adaptor TRIF contributes to otitis media pathogenesis and recovery. BMC Immunol 10:45CrossRefPubMedPubMedCentral Leichtle A, Hernandez M, Pak K et al (2009) The toll-Like receptor adaptor TRIF contributes to otitis media pathogenesis and recovery. BMC Immunol 10:45CrossRefPubMedPubMedCentral
28.
Zurück zum Zitat Leichtle A, Hernandez M, Pak K et al (2009) TLR4-mediated induction of TLR2 signaling is critical in the pathogenesis and resolution of otitis media. Innate Immun 15:205–215CrossRefPubMedPubMedCentral Leichtle A, Hernandez M, Pak K et al (2009) TLR4-mediated induction of TLR2 signaling is critical in the pathogenesis and resolution of otitis media. Innate Immun 15:205–215CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Lemaitre B, Nicolas E, Michaut L et al (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983CrossRefPubMed Lemaitre B, Nicolas E, Michaut L et al (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983CrossRefPubMed
30.
Zurück zum Zitat Lorenz E, Mira JP, Frees KL et al (2002) Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 162:1028–1032CrossRefPubMed Lorenz E, Mira JP, Frees KL et al (2002) Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 162:1028–1032CrossRefPubMed
31.
Zurück zum Zitat Macarthur CJ, Hefeneider SH, Kempton JB et al (2006) C3H/HeJ mouse model for spontaneous chronic otitis media. Laryngoscope 116:1071–1079CrossRefPubMed Macarthur CJ, Hefeneider SH, Kempton JB et al (2006) C3H/HeJ mouse model for spontaneous chronic otitis media. Laryngoscope 116:1071–1079CrossRefPubMed
32.
Zurück zum Zitat Maisonneuve C, Bertholet S, Philpott DJ et al (2014) Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants. Proc Natl Acad Sci U S A 111:12294–12299CrossRefPubMedPubMedCentral Maisonneuve C, Bertholet S, Philpott DJ et al (2014) Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants. Proc Natl Acad Sci U S A 111:12294–12299CrossRefPubMedPubMedCentral
33.
Zurück zum Zitat Mandel EM, Casselbrant ML (2004) Antibiotics for otitis media with effusion. Minerva Pediatr 56:481–495PubMed Mandel EM, Casselbrant ML (2004) Antibiotics for otitis media with effusion. Minerva Pediatr 56:481–495PubMed
34.
Zurück zum Zitat Medzhitov R, Janeway C Jr. (2000) The Toll receptor family and microbial recognition. Trends Microbiol 8:452–456CrossRefPubMed Medzhitov R, Janeway C Jr. (2000) The Toll receptor family and microbial recognition. Trends Microbiol 8:452–456CrossRefPubMed
35.
Zurück zum Zitat Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397CrossRefPubMed Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397CrossRefPubMed
36.
Zurück zum Zitat Medzhitov R, Preston-Hurlburt P, Kopp E et al (1998) MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 2:253–258CrossRefPubMed Medzhitov R, Preston-Hurlburt P, Kopp E et al (1998) MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 2:253–258CrossRefPubMed
37.
Zurück zum Zitat Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22:240–273 (Table of Contents)CrossRefPubMedPubMedCentral Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22:240–273 (Table of Contents)CrossRefPubMedPubMedCentral
38.
Zurück zum Zitat Murphy TF (2005) Vaccine development for non-typeable Haemophilus influenzae and Moraxella catarrhalis: progress and challenges. Expert Rev Vaccines 4:843–853CrossRefPubMed Murphy TF (2005) Vaccine development for non-typeable Haemophilus influenzae and Moraxella catarrhalis: progress and challenges. Expert Rev Vaccines 4:843–853CrossRefPubMed
39.
Zurück zum Zitat Napolitani G, Rinaldi A, Bertoni F et al (2005) Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1‑polarizing program in dendritic cells. Nat Immunol 6:769–776CrossRefPubMedPubMedCentral Napolitani G, Rinaldi A, Bertoni F et al (2005) Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1‑polarizing program in dendritic cells. Nat Immunol 6:769–776CrossRefPubMedPubMedCentral
40.
Zurück zum Zitat O’Brien MA, Prosser LA, Paradise JL et al (2009) New vaccines against otitis media: projected benefits and cost-effectiveness. Pediatrics 123:1452–1463CrossRefPubMed O’Brien MA, Prosser LA, Paradise JL et al (2009) New vaccines against otitis media: projected benefits and cost-effectiveness. Pediatrics 123:1452–1463CrossRefPubMed
41.
Zurück zum Zitat Ogus AC, Yoldas B, Ozdemir T et al (2004) The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 23:219–223CrossRefPubMed Ogus AC, Yoldas B, Ozdemir T et al (2004) The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 23:219–223CrossRefPubMed
42.
Zurück zum Zitat Pelton SI (2002) Acute otitis media in an era of increasing antimicrobial resistance and universal administration of pneumococcal conjugate vaccine. Pediatr Infect Dis J 21:599–604 (discussion 613–594)CrossRefPubMed Pelton SI (2002) Acute otitis media in an era of increasing antimicrobial resistance and universal administration of pneumococcal conjugate vaccine. Pediatr Infect Dis J 21:599–604 (discussion 613–594)CrossRefPubMed
43.
Zurück zum Zitat Poehling KA, Szilagyi PG, Grijalva CG et al (2007) Reduction of frequent otitis media and pressure-equalizing tube insertions in children after introduction of pneumococcal conjugate vaccine. Pediatrics 119:707–715CrossRefPubMed Poehling KA, Szilagyi PG, Grijalva CG et al (2007) Reduction of frequent otitis media and pressure-equalizing tube insertions in children after introduction of pneumococcal conjugate vaccine. Pediatrics 119:707–715CrossRefPubMed
44.
Zurück zum Zitat Poltorak A, He X, Smirnova I et al (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088CrossRefPubMed Poltorak A, He X, Smirnova I et al (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088CrossRefPubMed
45.
Zurück zum Zitat Pulendran B, Ahmed R (2006) Translating innate immunity into immunological memory: implications for vaccine development. Cell 124:849–863CrossRefPubMed Pulendran B, Ahmed R (2006) Translating innate immunity into immunological memory: implications for vaccine development. Cell 124:849–863CrossRefPubMed
46.
Zurück zum Zitat Qiao H, Andrade MV, Lisboa FA et al (2006) FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 107:610–618CrossRefPubMedPubMedCentral Qiao H, Andrade MV, Lisboa FA et al (2006) FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 107:610–618CrossRefPubMedPubMedCentral
47.
Zurück zum Zitat Rye MS, Bhutta MF, Cheeseman MT et al (2011) Unraveling the genetics of otitis media: from mouse to human and back again. Mamm Genome 22:66–82CrossRefPubMed Rye MS, Bhutta MF, Cheeseman MT et al (2011) Unraveling the genetics of otitis media: from mouse to human and back again. Mamm Genome 22:66–82CrossRefPubMed
48.
Zurück zum Zitat Sato S, Nomura F, Kawai T et al (2000) Synergy and cross-tolerance between toll-like receptor (TLR) 2‑ and TLR4-mediated signaling pathways. J Immunol 165:7096–7101CrossRefPubMed Sato S, Nomura F, Kawai T et al (2000) Synergy and cross-tolerance between toll-like receptor (TLR) 2‑ and TLR4-mediated signaling pathways. J Immunol 165:7096–7101CrossRefPubMed
49.
Zurück zum Zitat Shuto T, Xu H, Wang B et al (2001) Activation of NF-kappa B by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2‑TAK1-dependent NIK-IKK alpha /beta-I kappa B alpha and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells. Proc Natl Acad Sci U S A 98:8774–8779CrossRefPubMedPubMedCentral Shuto T, Xu H, Wang B et al (2001) Activation of NF-kappa B by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2‑TAK1-dependent NIK-IKK alpha /beta-I kappa B alpha and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells. Proc Natl Acad Sci U S A 98:8774–8779CrossRefPubMedPubMedCentral
50.
Zurück zum Zitat Si Y, Zhang ZG, Chen SJ et al (2014) Attenuated TLRs in middle ear mucosa contributes to susceptibility of chronic suppurative otitis media. Hum Immunol 75:771–776CrossRefPubMed Si Y, Zhang ZG, Chen SJ et al (2014) Attenuated TLRs in middle ear mucosa contributes to susceptibility of chronic suppurative otitis media. Hum Immunol 75:771–776CrossRefPubMed
51.
Zurück zum Zitat Smirnova I, Mann N, Dols A et al (2003) Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci U S A 100:6075–6080CrossRefPubMedPubMedCentral Smirnova I, Mann N, Dols A et al (2003) Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci U S A 100:6075–6080CrossRefPubMedPubMedCentral
53.
54.
Zurück zum Zitat Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820CrossRefPubMed Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820CrossRefPubMed
55.
Zurück zum Zitat Trinchieri G, Sher A (2007) Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 7:179–190CrossRefPubMed Trinchieri G, Sher A (2007) Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 7:179–190CrossRefPubMed
56.
Zurück zum Zitat Underhill DM, Ozinsky A (2002) Toll-like receptors: key mediators of microbe detection. Curr Opin Immunol 14:103–110CrossRefPubMed Underhill DM, Ozinsky A (2002) Toll-like receptors: key mediators of microbe detection. Curr Opin Immunol 14:103–110CrossRefPubMed
57.
Zurück zum Zitat Zhang SY, Jouanguy E, Ugolini S et al (2007) TLR3 deficiency in patients with herpes simplex encephalitis. Science 317:1522–1527CrossRefPubMed Zhang SY, Jouanguy E, Ugolini S et al (2007) TLR3 deficiency in patients with herpes simplex encephalitis. Science 317:1522–1527CrossRefPubMed
Metadaten
Titel
Rolle des angeborenen Immunsystems bei Otitis media
verfasst von
M. Wigand
T. K. Hoffmann
A. F. Ryan
B. Wollenberg
PD Dr. A. Leichtle
Publikationsdatum
27.03.2018
Verlag
Springer Medizin
Schlagwort
Zytokine
Erschienen in
HNO / Ausgabe 6/2018
Print ISSN: 0017-6192
Elektronische ISSN: 1433-0458
DOI
https://doi.org/10.1007/s00106-018-0501-x

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