title: Epicutaneously applied Der p 2 induces a strong TH 2-biased antibody response in C57BL/6 mice, independent of functional TLR4.
abstract: BACKGROUND
  The major house dust mite allergen Der p 2 is a structural and functional homologue of MD-2 within the TLR4-CD14-MD-2 complex. An asthma mouse model in TLR4-deficient mice recently suggested that the allergic immune response against Der p 2 is solely dependent on TLR4 signaling. We investigated whether similar mechanisms are important for Der p 2 sensitization via the skin.
  
  
  METHODS
  In an epicutaneous sensitization model, the response to recombinant Der p 2 in combination with or without lipopolysaccharide (LPS) was compared between C57BL/6 WT and TLR4-deficient mice. We further analyzed possible adjuvant function of exogenous cysteine proteases.
  
  
  RESULTS
  Sensitization with rDer p 2 induced similar levels of allergen-specific IgG1 and IgE antibodies in both mouse strains. LPS increased the systemic (antibody levels, cytokine release by restimulated splenocytes) and local (infiltration of immune cells into the skin) Th2 immune responses, which against our expectations were stronger in the absence of functional TLR4 expression. Barrier disruption by papain, a protease with structural homology to Der p 1, did not enhance the sensitization capacity of rDer p 2. However, the presence of LPS increased the stability of rDer p 2 against the protease.
  
  
  CONCLUSIONS
  Our data suggest that rDer p 2 alone can cause a strong TH 2-biased response via the skin being enhanced in the presence of LPS. This response is not reliant on functional TLR4, but vice versa TLR4 expression rather protects against epicutaneous sensitization to house dust mite allergen Der p 2.
authors.affiliation: Comparative Immunology and Oncology, Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Stremnitzer
authors.forename: K
authors.initials: K
authors.lastname: Manzano-Szalai
authors.forename: P
authors.initials: P
authors.lastname: Starkl
authors.forename: A
authors.initials: A
authors.lastname: Willensdorfer
authors.forename: S
authors.initials: S
authors.lastname: Schrom
authors.forename: J
authors.initials: J
authors.lastname: Singer
authors.forename: U
authors.initials: U
authors.lastname: Reichart
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.forename: E
authors.initials: E
authors.lastname: Jensen-Jarolim
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology; D039741:Antigens, Dermatophagoides / Q000008:administration & dosage / Q000276:immunology*; D000954:Antigens, Surface / Q000378:metabolism; D060829:Arthropod Proteins / Q000008:administration & dosage / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D037181:Lectins, C-Type / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D039741:Antigens, Dermatophagoides; D000954:Antigens, Surface; D060829:Arthropod Proteins; C498497:Cd207 protein, mouse; D016207:Cytokines; C451163:Dermatophagoides pteronyssinus antigen p 2; D007074:Immunoglobulin G; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D037241:Mannose-Binding Lectins; D051197:Toll-Like Receptor 4; D007073:Immunoglobulin E
keywords: Der p 2; LPS; TLR4; allergic dermatitis; house dust mite
references.citation: Clin Exp Allergy. 2011 Mar;41(3):305-11
references.pmid: 21121984
references.citation: Nature. 2009 Jan 29;457(7229):585-8
references.pmid: 19060881
references.citation: Nat Med. 2009 Apr;15(4):410-6
references.pmid: 19330007
references.citation: Ann Dermatol. 2010 May;22(2):125-37
references.pmid: 20548901
references.citation: Exp Dermatol. 2012 Nov;21(11):842-6
references.pmid: 23163649
references.citation: J Immunol. 2013 Apr 1;190(7):3059-67
references.pmid: 23460742
references.citation: Expert Rev Mol Diagn. 2008 Nov;8(6):697-705
references.pmid: 18999922
references.citation: Int Arch Allergy Immunol. 2002 Sep;129(1):1-18
references.pmid: 12372994
references.citation: J Allergy Clin Immunol. 1994 Sep;94(3 Pt 1):537-46
references.pmid: 7521892
references.citation: Science. 2013 Sep 13;341(6151):1246-9
references.pmid: 23887873
references.citation: Trends Mol Med. 2010 Jul;16(7):321-8
references.pmid: 20605742
references.citation: Clin Exp Allergy. 2007 Jan;37(1):151-61
references.pmid: 17210053
references.citation: Int Arch Allergy Immunol. 2013;161(3):287-8
references.pmid: 23548663
references.citation: J Exp Med. 2002 Dec 16;196(12):1645-51
references.pmid: 12486107
references.citation: Eur Ann Allergy Clin Immunol. 2011 Oct;43(5):141-56
references.pmid: 22145250
references.citation: J Cell Physiol. 2009 Aug;220(2):311-8
references.pmid: 19326394
references.citation: J Exp Med. 2010 Sep 27;207(10):2097-111
references.pmid: 20819925
references.citation: J Immunol. 2004 Dec 15;173(12):7416-25
references.pmid: 15585867
references.citation: Ann Allergy Asthma Immunol. 2003 Jan;90(1):41-4
references.pmid: 12546336
references.citation: Nat Immunol. 2011 Feb;12(2):167-77
references.pmid: 21217759
references.citation: J Mol Biol. 2002 Apr 19;318(1):189-97
references.pmid: 12054778
references.citation: Clin Exp Allergy. 2007 Feb;37(2):231-42
references.pmid: 17250696
references.citation: Nature. 2008 Jul 24;454(7203):445-54
references.pmid: 18650915
references.citation: Int Arch Allergy Immunol. 2012;158(4):347-58
references.pmid: 22472801
references.citation: J Exp Med. 1999 Jun 7;189(11):1777-82
references.pmid: 10359581
references.citation: N Engl J Med. 2011 Oct 6;365(14):1315-27
references.pmid: 21991953
references.citation: Nat Rev Immunol. 2009 Feb;9(2):91-105
references.pmid: 19151746
references.citation: Cell Biochem Funct. 2010 Oct;28(7):597-603
references.pmid: 20941750
references.citation: Nat Rev Immunol. 2004 Jun;4(6):407-19
references.pmid: 15173830
references.citation: Immunology. 2005 May;115(1):1-20
references.pmid: 15819693
references.citation: Nat Immunol. 2011 Feb;12(2):111-2
references.pmid: 21245898
references.citation: Allergol Int. 2013 Sep;62(3):291-6
references.pmid: 23974875
references.citation: Nat Rev Immunol. 2008 Feb;8(2):142-52
references.pmid: 18204469
references.citation: Nat Immunol. 2010 Jul;11(7):608-17
references.pmid: 20495560
references.citation: J Invest Dermatol. 2009 Jan;129(1):31-40
references.pmid: 19078986
references.citation: J Invest Dermatol. 2012 Mar;132(3 Pt 1):739-41
references.pmid: 22113480
references.citation: EMBO Rep. 2007 Dec;8(12):1142-8
references.pmid: 18059313
references.citation: Genes Cells. 2012 Jul;17(7):611-8
references.pmid: 22646506
references.citation: Respir Res. 2011 Sep 24;12:125
references.pmid: 21943186
references.citation: Science. 2013 Sep 13;341(6151):1250-3
references.pmid: 24031018
references.citation: J Immunol. 2009 Jul 15;183(2):1427-34
references.pmid: 19561109
references.citation: Thorax. 2012 Jun;67(6):488-95
references.pmid: 22167364
references.citation: Curr Allergy Asthma Rep. 2005 Sep;5(5):388-93
references.pmid: 16091212
references.citation: Biochem Biophys Res Commun. 1998 Dec 30;253(3):837-40
references.pmid: 9918815
references.citation: Clin Rev Allergy Immunol. 2011 Dec;41(3):254-8
references.pmid: 21181302
references.citation: J Immunol. 1999 Apr 1;162(7):3749-52
references.pmid: 10201887
references.citation: J Clin Invest. 1999 Jul;104(1):123-33
references.pmid: 10393706
references.citation: Annu Rev Immunol. 2010;28:445-89
references.pmid: 20192806
references.citation: Vaccine. 2006 Jun 29;24(26):5461-72
references.pmid: 16678312
references.citation: Nat Immunol. 2008 Mar;9(3):310-8
references.pmid: 18300366
references.citation: J Allergy Clin Immunol. 2011 Dec;128(6):1251-1258.e2
references.pmid: 21762973