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• W2051918905 abstract "Atopic dermatitis (AD) is a common, chronic inflammatory skin disease that becomes clinically apparent in the pediatric population. It is well recognized that subjects with AD have an increased susceptibility to cutaneous colonization and infection with bacteria, fungi, and viruses. The notion that subjects with AD have a cutaneous immune defect has received widespread acceptance, and several plausible explanations for this have been proposed. We will review the evidence that this susceptibility to cutaneous infection is at least in part due to a defect in the first line of defense against microbes, namely the innate immune system. Atopic dermatitis (AD) is a common, chronic inflammatory skin disease that becomes clinically apparent in the pediatric population. It is well recognized that subjects with AD have an increased susceptibility to cutaneous colonization and infection with bacteria, fungi, and viruses. The notion that subjects with AD have a cutaneous immune defect has received widespread acceptance, and several plausible explanations for this have been proposed. We will review the evidence that this susceptibility to cutaneous infection is at least in part due to a defect in the first line of defense against microbes, namely the innate immune system. Of all the infectious causes found to affect patients with atopic dermatitis (AD), the best characterized is Staphylococcus aureus. Approximately 90% of patients with AD are colonized with S aureus, whereas in a control or nonatopic population, only 5% to 30% are colonized.1Leung D.Y. Infection in atopic dermatitis.Curr Opin Pediatr. 2003; 15: 399-404Crossref PubMed Scopus (142) Google Scholar In addition to higher colonization rates, up to 50% to 60% of the S aureus found on patients with AD is toxin producing.1Leung D.Y. Infection in atopic dermatitis.Curr Opin Pediatr. 2003; 15: 399-404Crossref PubMed Scopus (142) Google Scholar Also, patients with AD can rapidly advance to superinfection with 107 organisms per square centimeter, as opposed to healthy subjects, who have a much lower bacterial burden.1Leung D.Y. Infection in atopic dermatitis.Curr Opin Pediatr. 2003; 15: 399-404Crossref PubMed Scopus (142) Google Scholar Although rare, patients with AD have also been reported to have S aureus–induced septicemia and osteomyelitis and have increasingly become reservoirs for antibiotic-resistant strains of S aureus. Once present on the skin, S aureus can mediate multiple inflammatory cascades. For example, staphylococcal toxins can activate T cells in a superantigen-driven fashion and induce IgE-specific responses.1Leung D.Y. Infection in atopic dermatitis.Curr Opin Pediatr. 2003; 15: 399-404Crossref PubMed Scopus (142) Google Scholar In fact, these IgE levels have been shown to correspond with disease severity.2Sohn M.H. Kim C.H. Kim W.K. Jang G.C. Kim K.E. Effect of staphylococcal enterotoxin B on specific antibody production in children with atopic dermatitis.Allergy Asthma Proc. 2003; 24: 67-71PubMed Google Scholar, 3Bunikowski R. Mielke M. Skarabis H. Herz U. Bergmann R.L. Wahn U. et al.Prevalence and role of serum IgE antibodies to the Staphylococcus aureus-derived superantigens SEA and SEB in children with atopic dermatitis.J Allergy Clin Immunol. 1999; 103: 119-124Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar Additionally, bacterial superantigens can induce a state of glucocorticoid resistance, which is due in part to production of the glucocorticoid receptor (GR) β, the GR isoform that competes with GRα's ability to bind glucocorticoids.4Hauk P.J. Hamid Q.A. Chrousos G.P. Leung D.Y. Induction of corticosteroid insensitivity in human PBMCs by microbial superantigens.J Allergy Clin Immunol. 2000; 105: 782-787Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar In most studies antistaphylococcal treatments have been shown to improve disease severity.5Breuer K. Haussler S. Kapp A. Werfel T. Staphylococcus aureus: colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis.Br J Dermatol. 2002; 147: 55-61Crossref PubMed Scopus (261) Google Scholar, 6Lever R. Hadley K. Downey D. Mackie R. Staphylococcal colonization in atopic dermatitis and the effect of topical mupirocin therapy.Br J Dermatol. 1988; 119: 189-198Crossref PubMed Scopus (231) Google Scholar In conclusion, it is clear that S aureus is able to induce both nonspecific and specific inflammation in subjects with AD, including that associated with an immediate hypersensitivity reaction. These effects might help initiate and potentiate the disease and might even modify responsiveness to a major therapeutic agent (eg, steroids).The double-stranded DNA viruses, including herpes simplex virus (HSV), molluscum contagiosum virus, and vaccinia virus (VV; smallpox vaccine), are also capable of causing more severe and generalized infections in patients with AD.7Wollenberg A. Wetzel S. Burgdorf W.H. Haas J. Viral infections in atopic dermatitis: pathogenic aspects and clinical management.J Allergy Clin Immunol. 2003; 112: 667-674Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar Eczema herpeticum is a disseminated cutaneous form of HSV and is often considered a medical emergency necessitating prompt systemic antiviral therapy. Epidemiologic studies suggest that patients with AD with more clinically severe disease and higher serum total IgE levels are at greater risk for eczema herpeticum.7Wollenberg A. Wetzel S. Burgdorf W.H. Haas J. Viral infections in atopic dermatitis: pathogenic aspects and clinical management.J Allergy Clin Immunol. 2003; 112: 667-674Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar These data suggest that patients with AD with greater TH2 polarization might be at greater risk for cutaneous infections that require a robust TH1 response. Even less is known about the clinical characteristics of subjects with AD who had eczema vaccinatum, the severe disseminated vaccinia infection that develops in subjects with AD exposed to individuals who were recently vaccinated with smallpox or who received the vaccination themselves. We will review the recent data that suggest that TH2 cytokines inhibit the release of antimicrobial peptides (AMPs) important for the immune response to cutaneous infections with HSV or VV.Lastly, yeast belonging to the genera Malassezia and Candida, are also thought to be relevant pathogens in AD. In 1983, Clemmensen and Hjorth8Clemmensen O.J. Hjorth N. Treatment of atopic dermatitis of the head and neck with ketoconazole in patients with type I sensitivity to Pityrosporum orbiculare.Semin Dermatol. 1983; 2: 26-29Google Scholar found that adult patients with head and neck AD who had positive skin test responses to Malassezia species had an improvement in their AD when treated with the antifungal agent ketoconazole. More recently, a Swedish multicenter study of 132 subjects with AD revealed that 60% had a positive skin test response to Malassezia species in comparison with no positive test responses in the nonatopic subjects and subjects with seborrheic dermatitis.9Johansson C. Sandstrom M.H. Bartosik J. Sarnhult T. Christiansen J. Zargari A. et al.Atopy patch test reactions to Malassezia allergens differentiate subgroups of atopic dermatitis patients.Br J Dermatol. 2003; 148: 479-488Crossref PubMed Scopus (102) Google Scholar Additionally, Candida species have been isolated more commonly from the skin of those with AD compared with those with psoriasis and healthy controls subjects.10Arzumanyan V.G. Magarshak O.O. Semenov B.F. Yeast fungi in patients with allergic diseases: species variety and sensitivity to antifungal drugs.Bull Exp Biol Med. 2000; 129: 601-604Crossref PubMed Scopus (18) Google ScholarIn summary, there is considerable evidence that subjects with AD have an unusual propensity for colonization by certain microbes (S aureus and Candida species) and aggravated infections with others (HSV and VV). Additionally, these microbes are thought to exacerbate the disease itself. Some of the biologic explanations for these observations have been identified and are highlighted below.Innate immunityIt is now widely accepted that the immune system is comprised of 2 separate branches: innate and adaptive. Adaptive immunity relies on antigen-presenting cells to encounter pathogen and deliver antigen to T and B cells, which take days to mature. In contrast, innate immunity is built on the premise of genetically encoded receptors and antimicrobial proteins that would provide an immediate response to pathogens and thereby provide critical protection while the adaptive response matures. This notion was first introduced in 1989 by Janeway,11Janeway Jr., C.A. Approaching the asymptote? Evolution and revolution in immunology.Cold Spring Harb Symp Quant Biol. 1989; 54: 1-13Crossref PubMed Google Scholar who defined the components of the innate immune system, including pattern-recognition receptors (PRRs), pathogen-associated molecular patterns (PAMPs), and AMPs. PRRs, including Toll-like receptors (TLRs) and the collectin proteins, are engineered to respond to highly conserved structures within common pathogens, otherwise known as PAMPs, which include bacterial cell-wall products, such as LPS, peptidoglycan (PGN), and lipoteichoic acid (LTA); the fungal cell-wall product zymosan; and viral double-stranded RNA. When PRRs bind PAMPs, they initiate a signal transduction cascade that stimulates an immediate cellular response to the challenge.12Medzhitov R. Janeway Jr., C. Innate immunity.N Engl J Med. 2000; 343: 338-344Crossref PubMed Scopus (1715) Google Scholar This cellular response includes the release of AMPs, cytokines, and chemokines, which are important for the recruitment of effector leukocytes or have direct antimicrobial effects that are collectively important for the immediate containment of the infection.13Esche C. Stellato C. Beck L.A. Chemokines: key players in innate and adaptive immunity.J Invest Dermatol. 2005; 125: 615-628Crossref PubMed Scopus (281) Google ScholarDuring the previous decade, there have been multiple studies evaluating different aspects of the innate immune system in AD and atopy in general. The findings have ranged from genetic polymorphisms in proteins relevant for innate immunity to defects in AMP production and neutrophil migration. Below we review the components of the cutaneous innate immune system and highlight those that might be relevant for patients with AD (Fig 1).Stratum corneum/barrier functionThe epidermis functions at least in part as a protective barrier, and the majority of the protection occurs at the level of the stratum corneum (SC). The SC is formed by lipid-depleted corneocytes and a lipid-rich extracellular matrix. This creates a barrier that is able to keep water within the body and prevent the entrance of pathogens and allergens.14Elias P.M. Stratum corneum defensive functions: an integrated view.J Invest Dermatol. 2005; 125: 183-200Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar The terminal differentiation of keratinocytes from granular cells to corneocytes is a critical step for maintenance of this barrier. During this differentiation, profilaggrin is cleaved into multiple filaggrin polypeptides, which are cross-linked by transglutaminases and result in the cornified cell envelope. The importance of the SC was highlighted in a recent publication that identified 2 common loss-of-function mutations in the gene encoding filaggrin and found they were associated with an increased risk of AD and asthma associated with AD.15Palmer C.N. Irvine A.D. Terron-Kwiatkowski A. Zhao Y. Liao H. Lee S.P. et al.Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.Nat Genet. 2006; 38: 441-446Crossref PubMed Scopus (2235) Google Scholar This latter association suggests that asthma develops as a consequence of sensitization events that begin in the skin. This work also suggests that the skin barrier defect precedes the development of AD, which was first proposed when it was recognized that subjects with AD had reduced levels of the SC lipids ceramide and sphingosine. The sphingosine reduction correlates with the degree of bacterial colonization, and this is in keeping with the evidence that it has antimicrobial properties.16Arikawa J. Ishibashi M. Kawashima M. Takagi Y. Ichikawa Y. Imokawa G. Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus.J Invest Dermatol. 2002; 119: 433-439Crossref PubMed Scopus (216) Google Scholar A number of studies have demonstrated reduced ceramide levels, which is thought to be due to the increased expression of sphingomyelin deacylase, an enzyme that competes for glucosylceramide, the precursor to ceramide.17Hara J. Higuchi K. Okamoto R. Kawashima M. Imokawa G. High-expression of sphingomyelin deacylase is an important determinant of ceramide deficiency leading to barrier disruption in atopic dermatitis.J Invest Dermatol. 2000; 115: 406-413Crossref PubMed Scopus (212) Google Scholar, 18Imokawa G. Abe A. Jin K. Higaki Y. Kawashima M. Hidano A. Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin?.J Invest Dermatol. 1991; 96: 523-526Abstract Full Text PDF PubMed Scopus (0) Google Scholar Physiologic stress can also disrupt the epidermal barrier through the production of endogenous glucocorticoids, which suppress epidermal lipid production.14Elias P.M. Stratum corneum defensive functions: an integrated view.J Invest Dermatol. 2005; 125: 183-200Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar The SC is also a significant source of antimicrobial cationic peptides in addition to the lipid-rich antimicrobial proteins (sphingosines and ceramides), and this will be discussed later in this review. Lastly, a hallmark of AD is intense pruritus, which inevitably leads to extensive scratching and ultimately further breakdown of the skin barrier. It is clear that an intact and functional SC is required for an effective cutaneous innate immune response.C-type lectinsNumerous PRRs have been identified and characterized, including the collectin and ficolin families, which are both C-type lectins. The collectin family is composed of mannan-binding lectin (MBL) and surfactant proteins. These PRRs recognize unique sugars present on both gram-positive and gram-negative bacteria, fungi, and viruses. They can act directly as opsonins by coating the pathogen and making them accessible for phagocytosis or they can directly activate the complement pathway.19Lu J. Teh C. Kishore U. Reid K.B. Collectins and ficolins: sugar pattern recognition molecules of the mammalian innate immune system.Biochim Biophys Acta. 2002; 1572: 387-400Crossref PubMed Scopus (189) Google Scholar Of the C-type lectins, MBL is the best characterized. MBL is synthesized by the liver and secreted into the serum and is structurally and functionally similar to C1q, the first component of the complement activation pathway. MBL deficiency has been shown to predispose individuals to bacterial and viral infections, including HSV and S aureus.20Gadjeva M. Paludan S.R. Thiel S. Slavov V. Ruseva M. Eriksson K. et al.Mannan-binding lectin modulates the response to HSV-2 infection.Clin Exp Immunol. 2004; 138: 304-311Crossref PubMed Scopus (70) Google Scholar, 21Shi L. Takahashi K. Dundee J. Shahroor-Karni S. Thiel S. Jensenius J.C. et al.Mannose-binding lectin-deficient mice are susceptible to infection with Staphylococcus aureus.J Exp Med. 2004; 199: 1379-1390Crossref PubMed Scopus (238) Google ScholarThe role of MBL in asthma and atopy has been debated in the literature, with a few studies finding an association between reduced MBL levels and development of airway hyperresponsiveness or more frequent asthma exacerbations, as well as an association between the MBL2 allele and childhood asthma.22Hogaboam C.M. Takahashi K. Ezekowitz R.A. Kunkel S.L. Schuh J.M. Mannose-binding lectin deficiency alters the development of fungal asthma: effects on airway response, inflammation, and cytokine profile.J Leukoc Biol. 2004; 75: 805-814Crossref PubMed Scopus (49) Google Scholar, 23Aittoniemi J. Soranummi H. Rovio A.T. Hurme M. Pessi T. Nieminen M. et al.Mannose-binding lectin 2 (MBL2) gene polymorphism in asthma and atopy among adults.Clin Exp Immunol. 2005; 142: 120-124Crossref PubMed Scopus (36) Google Scholar, 24Gardner E.T. Stierman L.M. Jovanovic B. Shannon J.J. Saltoun C.A. Grammer L.C. et al.Reduced serum levels of innate immune molecules in subjects with frequent asthma exacerbations.J Allergy Clin Immunol. 2006; 117 ([abstract]): S14Abstract Full Text Full Text PDF Google Scholar Importantly, undetectable MBL levels were noted in 3 members of a Turkish family who presented with recurrent cutaneous abscesses, pruritus, and AD, suggesting that MBL or other C-type lectins might play a role in the development of AD or in the susceptibility to infection seen in subjects with AD.25Brandrup F. Homburg K.M. Wang P. Garred P. Madsen H.O. Mannan-binding lectin deficiency associated with recurrent cutaneous abscesses, prurigo and possibly atopic dermatitis. A family study.Br J Dermatol. 1999; 140: 180-181Crossref PubMed Scopus (14) Google ScholarToll-like receptorsThe Toll-like receptors (TLRs) were originally identified and characterized in the fruit fly Drosophila melanogaster.26McInturff J.E. Modlin R.L. Kim J. The role of toll-like receptors in the pathogenesis and treatment of dermatological disease.J Invest Dermatol. 2005; 125: 1-8Crossref PubMed Scopus (153) Google Scholar In response to the appropriate PAMP, TLRs transduce a signal through the intracellular adapter molecule MyD88, which leads to the nuclear translocation of nuclear factor κB and transcription of inflammatory mediators (cytokines, chemokines, and AMPs). Human TLRs 1 through 10 have been identified, and each receptor has been characterized on the basis of its specificity for a microbial ligand or ligands.26McInturff J.E. Modlin R.L. Kim J. The role of toll-like receptors in the pathogenesis and treatment of dermatological disease.J Invest Dermatol. 2005; 125: 1-8Crossref PubMed Scopus (153) Google Scholar Originally recognized for their expression on antigen-presenting cells, TLRs have also been identified on epithelial cells, including keratinocytes. Keratinocytes constitutively express mRNA for TLRs 1, 2, 3, and 5 and potentially 4, 6, 9, and 10 as well.26McInturff J.E. Modlin R.L. Kim J. The role of toll-like receptors in the pathogenesis and treatment of dermatological disease.J Invest Dermatol. 2005; 125: 1-8Crossref PubMed Scopus (153) Google Scholar, 27Kollisch G. Kalali B.N. Voelcker V. Wallich R. Behrendt H. Ring J. et al.Various members of the Toll-like receptor family contribute to the innate immune response of human epidermal keratinocytes.Immunology. 2005; 114: 531-541Crossref PubMed Scopus (281) Google Scholar The functions of TLRs 1 through 5 have been implied by the expression of immune response genes after TLR-specific ligand stimulation.26McInturff J.E. Modlin R.L. Kim J. The role of toll-like receptors in the pathogenesis and treatment of dermatological disease.J Invest Dermatol. 2005; 125: 1-8Crossref PubMed Scopus (153) Google Scholar, 28Howell M.D. Gallo R.L. Boguniewicz M. Jones J.F. Wong C. Streib J.E. et al.Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus.Immunity. 2006; 24: 341-348Abstract Full Text Full Text PDF PubMed Scopus (271) Google ScholarMice deficient in TLR2 and its downstream effector, MyD88, were found to be highly susceptible to an intravenous inoculation with S aureus.29Takeuchi O. Hoshino K. Akira S. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection.J Immunol. 2000; 165: 5392-5396PubMed Google Scholar This is in keeping with the evidence that the purified staphylococcal cell-wall components LTA and PGN are known to signal through TLR2. Recently, it was reported that a missense mutation in the TLR2 gene R753Q was found with increased frequency in patients with AD and that it correlated with a more severe phenotype, higher serum total IgE levels, and greater susceptibility to S aureus colonization.30Werfel T. Heeg K. Neumaier M. Renz H. 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype.J Allergy Clin Immunol. 2004; 113: 565-567Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar Little is known about the role that keratinocyte-derived TLR3 plays in host defense to viral pathogens, such as HSV and VV, although a recent publication revealed that stimulation of keratinocytes with VV led to induction of cathelicidin (LL-37) through TLR3.28Howell M.D. Gallo R.L. Boguniewicz M. Jones J.F. Wong C. Streib J.E. et al.Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus.Immunity. 2006; 24: 341-348Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar Nomura et al31Nomura I. Goleva E. Howell M.D. Hamid Q.A. Ong P.Y. Hall C.F. et al.Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.J Immunol. 2003; 171: 3262-3269PubMed Google Scholar looked at mRNA expression for TLRs 1, 2, 3, 5, and 6 and found no significant difference between skin biopsy specimens taken from patients with AD and those from patients with psoriasis. This is in agreement with our studies,32McGirt LY BM, Bankova LG, Beck LA. Keratinocyte expression of receptors relevant for the innate immune response to Staphylococcus aureus in subjects with atopic dermatitis [abstract]. J Invest Dermatol 2006;126:116.Google Scholar which demonstrate no difference in TLR2 expression by means of flow cytometry on nonlesional keratinocytes isolated from subjects with AD and subjects with psoriasis.IL-1 familyThe IL-1 receptor (IL-1R) pathway has also been implicated in the host response to S aureus. IL-1α and IL-1β are known ligands of IL-1R, and IL-1α levels have been shown to be increased in the skin of mice during S aureus infection. Similar to TLRs, IL-1R has been shown to use the adaptor protein MyD88. In a recent publication both IL-1R and MyD88 knockout mice were shown to have impaired neutrophil chemotaxis in response to a cutaneous S aureus challenge, whereas a TLR2 knockout mouse did not demonstrate a similar impairment.33Miller L.S. O'Connell R.M. Gutierrez M.A. Pietras E.M. Shahangian A. Gross C.E. et al.MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus.Immunity. 2006; 24: 79-91Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar These findings suggest a greater role for the IL-1R pathway than TLR2 in response and containment of S aureus at the skin surface.33Miller L.S. O'Connell R.M. Gutierrez M.A. Pietras E.M. Shahangian A. Gross C.E. et al.MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus.Immunity. 2006; 24: 79-91Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar Inflammatory skin diseases, including AD, have also been shown to have an increased ratio of IL-1R antagonist to IL-1α in the SC, which would have an inhibitory effect on IL-1–mediated actions.34Terui T. Hirao T. Sato Y. Uesugi T. Honda M. Iguchi M. et al.An increased ratio of interleukin-1 receptor antagonist to interleukin-1alpha in inflammatory skin diseases.Exp Dermatol. 1998; 7: 327-334Crossref PubMed Scopus (70) Google Scholar Another member of the IL-1 family, IL-18, known to be a mediator of inflammation and innate immunity, has recently been shown to be expressed by keratinocytes and, like IL-1β, is downregulated by corticotropin-releasing hormone.35Park H.J. Kim H.J. Lee J.H. Lee J.Y. Cho B.K. Kang J.S. et al.Corticotropin-releasing hormone (CRH) downregulates interleukin-18 expression in human HaCaT keratinocytes by activation of p38 mitogen-activated protein kinase (MAPK) pathway.J Invest Dermatol. 2005; 124: 751-755Crossref PubMed Scopus (51) Google Scholar Because inflammatory skin diseases are known to be exacerbated by stress, it can be hypothesized that the stress-induced release of corticotropin-releasing hormone and the ensuing reduction of IL-18 and IL-1β levels might also play a role in the susceptibility to cutaneous infections in patients with AD.35Park H.J. Kim H.J. Lee J.H. Lee J.Y. Cho B.K. Kang J.S. et al.Corticotropin-releasing hormone (CRH) downregulates interleukin-18 expression in human HaCaT keratinocytes by activation of p38 mitogen-activated protein kinase (MAPK) pathway.J Invest Dermatol. 2005; 124: 751-755Crossref PubMed Scopus (51) Google ScholarNucleotide-binding oligomerization domainNucleotide-binding oligomerization domain (NOD) 1 and NOD2 are cytosolic proteins that respond to the degradation products of PGN.36Girardin S.E. Philpott D.J. Mini-review: the role of peptidoglycan recognition in innate immunity.Eur J Immunol. 2004; 34: 1777-1782Crossref PubMed Scopus (104) Google Scholar Specifically, NOD1 senses diaminopimelic acid–type PGN, which is produced by gram-negative bacteria, and NOD2 senses muramyl dipeptide, a motif found in PGNs from all bacteria, including S aureus.36Girardin S.E. Philpott D.J. Mini-review: the role of peptidoglycan recognition in innate immunity.Eur J Immunol. 2004; 34: 1777-1782Crossref PubMed Scopus (104) Google Scholar Recently, keratinocytes were shown to express NOD1 and NOD2, which were presumed to be functional because stimulation with PGN resulted in IL-6 production.37Song P.I. Prado R. Kang Y. Kolot A. Armstrong C.A. Ansel J.C. Keratinocytes express nucleotide-binding oligomerization domain (NOD) 1 and 2: implications for cutaneous innate immunity.J Invest Dermatol. 2004; 122 ([abstract]): A754Google Scholar Furthermore, keratinocytes stimulated with the NOD2-specific ligand muramyl dipeptide produced the AMP human β-defensin 2.38Voss E. Wehkamp K. Schroder J.M. Harder J. Induction of the skin-derived antimicrobial peptide human beta-definsin-2 via NOD2/CARD15.J Invest Dermatol. 2004; 123 ([abstract]): A204Google Scholar An association between NOD1 polymorphisms and AD has been suggested,39Weidinger S. Klopp N. Rummler L. Wagenpfeil S. Novak N. Baurecht H.J. et al.Association of NOD1 polymorphisms with atopic eczema and related phenotypes.J Allergy Clin Immunol. 2005; 116: 177-184Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar but there are no reports looking at NOD2 expression or function in AD, which would be the PRR more relevant for the response to S aureus.CD14CD14 is a multifunctional receptor for LPS and other bacterial wall components.40Koppelman G.H. Postma D.S. The genetics of CD14 in allergic disease.Curr Opin Allergy Clin Immunol. 2003; 3: 347-352Crossref PubMed Scopus (19) Google Scholar Because CD14 has also been found to induce cellular activation in response to LTA through a TLR2-dependent pathway41Schroder N.W. Morath S. Alexander C. Hamann L. Hartung T. Zahringer U. et al.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. 2003; 278: 15587-15594Crossref PubMed Scopus (496) Google Scholar and has binding affinity for PGN,42Dziarski R. Recognition of bacterial peptidoglycan by the innate immune system.Cell Mol Life Sci. 2003; 60: 1793-1804Crossref PubMed Scopus (141) Google Scholar it is thought to play a role in host response to S aureus as well. Similar to TLR2 signaling, CD14 uses MyD88 to activate nuclear factor κB. It is also known to produce IL-1β through a caspase 1–dependent pathway.43Tschopp J. Martinon F. Burns K. NALPs: a novel protein family involved in inflammation.Nat Rev Mol Cell Biol. 2003; 4: 95-104Crossref PubMed Scopus (590) Google Scholar Although it is expressed as a soluble or membrane-bound receptor predominantly on monocytes, it has also been found on a variety of cells, including keratinocytes.44Song P.I. Park Y.M. Abraham T. Harten B. Zivony A. Neparidze N. et al.Human keratinocytes express functional CD14 and toll-like receptor 4.J Invest Dermatol. 2002; 119: 424-432Crossref PubMed Scopus (164) Google ScholarFueled by the hygiene hypothesis and the epidemiologic data showing that the presence of LPS in house dust is inversely correlated with atopy, numerous genetic studies of atopic populations have been performed looking at specific CD14 variants.40Koppelman G.H. Postma D.S. The genetics of CD14 in allergic disease.Curr Opin Allergy Clin Immunol. 2003; 3: 347-352Crossref PubMed Scopus (19) Google Scholar These studies have shown an association of variants in the CD14 gene with both the prevention and severity of atopy. However, phenotype definitions and the allele that showed association have differed between studies.40Koppelman G.H. Postma D.S. The genetics of CD14 in allergic disease.Curr Opin Allergy Clin Immunol. 2003; 3: 347-352Crossref PubMed Scopus (19) Google Scholar Additionally, children with AD have been shown to have reduced levels of soluble CD14 (sCD14) compared with nonatopic children,45Zdolsek H.A. Jenmalm M.C. Reduced levels of soluble CD14 in atopic children.Clin Exp Allergy. 2004; 34: 532-539Crossref PubMed Scopus (41) Google Scholar and a small study also found that reduced levels of sCD14 in breast milk were associated with the development of eczema at 6 months of age.46Jones C.A. Holloway J.A. Popplewell E.J. Diaper N.D. 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• W2051918905 created "2016-06-24" @default.
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• W2051918905 title "Innate immune defects in atopic dermatitis" @default.
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