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"i How Does Cutaneous Innate Immunity Work?
The skin protects lIS from pathogens by providingphysicallanatomical barriers and by activating its innate immune system, namely cellular sentineis with cognate receptors and chemicallsecretory defence molecules.
The PhysicallAl1alomical BmTier The physicallanatomical barriers of the skin include the stratum corneum of the epidermis with several layers of cornified keratinocrtes embedded in a lipid matrix of water-retaining ceramides, cholesterol and sphingosines with direct antibacterial activities, thus preventing pathogen entry [IJ. Historically, keratinocyte functions were believed to be Iimited to maintaining the structure of the epidermis and to providing a physical barrier to various exogenous micro-organisms. Today, it is weil
The best-known I'RRs are the TolI-like receptors (TLRs), a fall1ily of currently 11 ll1ell1bers in hllmans [6J. TLRs are located on the cell sl\l'face 01' in intracellular com partments r6). Struclurally. they are transmembrane proteins with an extracellular leucine-rich repeat dOlllain needed for pathogen recognition and 0 cytoplasmic sig naling part, wh ich resembles the interleukin (JL) 1 receptor, called TIR [7J. Ligand binding induces a common signal transduction pathway mainly based on the interac tion between the adaptor molecule MyD88 and TIR which in turn results in the acti vation ofIRAK and subsequent oligomeri,ation ofTRAF6 [81, Followed by activation of downstream kinases. this MyD88-IRAK-TRAF pathway leads 1'0 the activation of MAI' kinases and the transcription factor NF-Kß, finally culminating in the expres sion of pro-innammatory media tors [9. 10). I'athogen-associated moleculaI' patterns originating from different pothogens can be distinguished by various TLR combina lions. each ofthem providing 0 specific immune response (11). Soon after the discovery of the TLRs it became dear that these PRRs could not account for full host protection due 1'0 their inability to sense intracellular pathogens. Indeed subsequent studies identified furlher crtosolic PRRs belonging to the Nod-Iike receptor (NLR) f"mily. and bio-informatic analyses revealed the existence of more than 20 NLR genes in the human genome [12J. Based on the struclure of the N-terminal domains. NLRs can be c1assified illto 3 subgroups also referred to as CARD-containing NODs. PYD-containing NALPs, or BIR-containing NAIPs. While the leucille-rich repeat domoin at the C terminus is responsible for pathogen recognition, exposition of
Innale lmmunily in Mopic Dermatitis
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the protein-protein interaction site at the N terminus mediates the recruitmentand acti vation ofCARD- l1nd PYD-containing effector molecules [13J. This ends in the activa tion ofthe NF-KB and MAI' kinase patllways which together upregulate the expression of pro-inflammatory molecules. Further innate imnlllne receptors are the mannose receptors (CD206) [14) and the retinoid acid-inducible gene I-Iike receptors [15J
Secretory E{fector Molewles of the Cutaileous Irll1nte 1111111 11 ne System: Cytokines Qnd Antil7'licrobial Peptides TLR activation ends in the release of effector molecules, mai nil' pro-inflammatory cytokines and antimicrobial peptides. Two cytokines that are of special interest in this context are tumour necrosis factor (TNF) and IL-l, which Irigger adhesion molecule expression on endothelial cells, thereby conlributing to the recruHmfllt of phagocytic cells to the sites ofinfection [16, 17]. In addition, the so-called novel cytokines IL-18 l1nd IL-17 have recenlly been shown to be parlicularly relevant for pl1thogen c1ear ance. Here, lL-18 is functionally simiJar to IL-12 in that it activates natural killer cells and induces IL-I and TNF secretion [18]. In contrasl, IL-17 potentiates neutrophilic cytotoxic;ty and phagocytosis [19). Mice infected by extracellular bacterial patho gens, for example Klebsie/la pne
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29 Henderson J. Northstone K, Lee SP, Ul'O H. Zh
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46 DidJerJ;1urent A, ßrissoni ß, Velin 0, Aebi N, T:lrdlvd A. KasJin E, Sirard JC, Angelov G, Tsehopp J. ßurns K: Tollip rcgulates proinllmnmalory
responses to interleukin-l amI lipopolys;1ccharide.
Mol Gell DioI2006,26,735-742.
47 Schimmlng TT. P:Ir\\'CZ Q, Pelrasch~P;1rwez E. Nothnagel M, Epplen JT. Horijan 5: Associ:ltion or Toll.interacling proceln gene polymorphisms wi!h alopie d~rmalilis. ßMC Derm;1tol 2007;7:3. 48 Malstli E. Kancko H. Teramolo T. Fukao T, InOlle R. Kasahara K. et al: R~dueed IFN-y prodllction in response to I L-l? stimul:uion and/or IL-12 produc lion in atopic r'3Iicnt5. Clin Exp Allergy 2000;30: 1250-1256. 49 One PY, Ohlakc T, Brandl C. Strickland I, Bogu niewicz M, Ganz T, et Oll: Endocenolls OIll1lmicrobial peptides :md skin il1(ce!ions in alopic dermatitis. N Engl J Me
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Marcus Maurel, MD Professor of Dermatology and Aliergy, Department of DermatoJogy and Alle/gy Allergie·Centrum·Charite, Charite·Universitatsmedizin Berlin Chariteplatz 1, DE-10117 Berlin fGermany) Tel. +49 30 450 518 043. Fax +49 30 450518972, E·Mail
[email protected]
Innate Immuniry in Atopic Dermatitis
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