Pathogenesis of Atopic Dermatitis: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Immunology
Contributor:
Sandrine Dubrac

Atopic dermatitis (AD) is the most common inflammatory skin disorder worldwide, with a prevalence of 1–20% in both children and adults. It is believed to be the first step of the so-called ‘atopic march’ in which AD is followed by allergic rhinoconjunctivitis, allergic bronchial asthma, and food allergies. 

  • atopic dermatitis

1. Atopic Dermatitis

Atopic dermatitis (AD) is the most common inflammatory skin disorder worldwide, with a prevalence of 1–20% in both children and adults (http://isaac.auckland.ac.nz/index.html (accessed on 9 February 2022) [1][2][3][4][5]. It is believed to be the first step of the so-called ‘atopic march’ in which AD is followed by allergic rhinoconjunctivitis, allergic bronchial asthma, and food allergies. However, food allergies might be concomitant to AD in very young children (https://nationaleczema.org/atopic-dermatitis-and-allergies-connection/ (accessed on 9 February 2022)) [6]. AD is a complex disease whose etiology has not yet been fully deciphered due to its heterogeneity resulting from patient age, ethnicity, and lifestyle factors [7][8][9]. Moreover, although a genetic predisposition is undeniable in AD pathogenesis, the relative contribution of (epi)genetic [10][11][12][13] versus environmental factors [14][15][16] remains unknown. Heterogeneity of AD due to genetic polymorphism extends beyond filaggrin (FLG) loss-of-function mutations, since patients with serine peptidase inhibitor Kazal-type 5 (SPINK5) mutations also exhibit a severe AD-like phenotype, as do other patients with inherited disorders [17][18]. In addition, not all AD patients display an allergic systemic profile, especially patients with mild AD [19]. Thus, AD can be considered as a basket of different etiologies producing a similar phenotype. It appears more and more necessary to stratify AD according to its various endotypes to compile pathomechanisms which are specific for each endotype, which should enable a personalized prophylactic approach for many patients, but probably not all. Better knowledge of the pathomechanisms common to all endotypes would also deliver important information for designing effective pan-therapies.

2. Cellular and Molecular Abnormalities in Atopic Dermatitis

AD patients exhibit dry skin owing to impaired epidermal barrier function at all stages of the disease, which precedes or is concomitant to the development of overt skin inflammation and skin lesions. The impaired epidermal barrier is, per se, sufficient to enhance KC proliferation and synthesis of lipid, DNA, and protein in an effort to restore the barrier. This response is part of a hierarchical imperative of sustaining a fully competent barrier in a desiccating terrestrial environment and leads to mild acanthosis in non-lesional AD skin. When the skin becomes itchy, scratching potentially enhances the penetration of antigens or bacteria into the skin [20][21], and also the release of pro-inflammatory lipids, i.e., eicosanoids (see below). This likely induces a response in KCs leading to the production of inflammatory mediators such as TSLP, IL-6, IL-1, and CCL17, and the recruitment of immune cells to the skin, thereby advancing the transition from non-lesional to lesional AD [19][20][22][23]. Antigens, bacteria, and TSLP can directly activate LCs to prime Th2 cells in regional lymph nodes, which are then recruited to the skin [23][24][25][26].
The triggers involved in the development of eczematous lesions remain largely unknown, although stress, pollution, climate, microbiota, and allergens are likely involved. Non-lesional AD skin can either be of normal appearance or exhibit overt xerosis and display several morphological (acanthosis) and immunological (Th2/Th17 subclinical inflammation) abnormalities [27]. After exposure to triggers that often cannot be specified, the skin of AD patients undergoes changes leading to the development of eczematous lesions, exhibiting age-specific distribution patterns [28]. In acute AD, pruritic and eczematous skin lesions are characterized by an exacerbated Th2/Th17 immune response associated with an under-responsive innate immunity [29]. Chronic AD lesions display a complex inflammation signature (Th1/Th2/Th17/Th22/Th9) associated with keratinocyte (KC) hyperproliferation and altered terminal differentiation as well as skin superinfection, especially with Staphylococcus bacteria [9][19][29][30][31][32][33][34][35][36][37]. Th2-skewed adaptive and reduced innate immunity might concertedly promote the colonization of skin with Staphylococcus aureus in chronic lesional AD [9][38]. Interestingly, FLG breakdown products, namely urocanic acid (UCA) and pyrrolidone carboxylic acid (PCA), exert antimicrobial effects, notably against Staphylococcus aureus [39][40]. In line with this, epidermal models knocked down for FLG show increased colonization with Staphylococcus aureus [41]. Thus, reduced amounts of FLG in AD skin, regardless of FLG genotype, might contribute to promoting skin superinfection with Staphylococcus [30][42]. This potentially occurs via reduced amounts of antimicrobial peptides and FLG breakdown products rather than via alkalinization of the skin [43]. Indeed, although surface pH is increased in AD—especially in severe AD lesions—it remains in the acidic range, i.e., ≤6 [44][45][46][47].

3. Pathogenesis of Atopic Dermatitis

While it is clear that AD is a consequence of impaired epidermal barrier function associated with immune hyper-responsiveness, probably resulting from (epi)genetic modifications [10][11][13], it is not clear which abnormality—stratum corneum (SC) versus immune pathology—occurs first. The widely cited work from Kelleher et al. which purportedly showed increased transepidermal water loss (TEWL) in 2-day-old children preceding the development of AD and allergies later on [48] has been recently retracted [49]. This reappraisal of their data does not necessarily undermine the argument in favor of an initial epidermal barrier impairment in AD patients. However, an alternative readout, such as ultrastructural analysis of the epidermis and barrier recovery assay, might be more appropriate than TEWL measurements to verify epidermal barrier dysfunction in very young patients. Mechanistically, it had been hypothesized that epidermal barrier impairment enables the penetration of antigens, pollutants or bacteria into the SC, hence leading to KC and Langerhans cell (LC) activation [20]. However, although this concept is well accepted, it has never been demonstrated and further work is required to better understand disease initiation.
Reduced amounts of FLG in skin, regardless of FLG loss-of-function mutations, might significantly contribute to epidermal barrier impairment. Indeed, FLG deficiency provokes alterations in the lamellar body (LB) cargo system in the stratum granulosum (SG) and LB entombment, disrupted corneodesmosome structures, and corneodesmosome-derived lacunae in the SC [44][50]. In adult patients with AD, amounts of FLG are reduced, regardless of skin lesion presence or absence [51]. However, AD children display normal to increased epidermal FLG, despite a Th2 predominant skin microenvironment, questioning the contribution of FLG deficiency to AD. In light of these data, reduced FLG levels, resulting from loss-of-function mutations or from other skin microenvironment-related factors, can be envisioned as an aggravating factor rather than as a primary factor in AD pathogenesis. Moreover, the upstream signal(s) leading to FLG down-regulation in adult AD skin remain(s) ill-defined. Interestingly, Ovo-Like Transcriptional Repressor 1 (OVOL1) has been identified as a susceptibility gene for AD [10]. OVOL1 is a transcription factor important for the development of epithelial tissues arising from germ cells, and is involved in the expression of skin barrier proteins, including FLG [52][53]. KCs with a weak OVOL1 pathway produce less FLG and fail to efficiently exit proliferation after extrinsic stimulation [54]. Thus, an impaired OVOL1 pathway might account for the decrease of FLG observed in adult FLG wild-type AD skin [55].
AD initiation in very young patients might result from a combination of environmental factors (e.g., climate, airborne and food allergens, pollution) and the relative immaturity of young skin (e.g., simple skin microbiota, low skin innate immunity, immature adaptive immunity) [56][57][58][59][60][61] synergizing to heighten vulnerability. This predisposition might contribute to AD onset in young children with single nucleotide polymorphisms (SNPs) in immunogenic genes [10][13][62]. Then, as the skin matures in these children, it becomes less permeable to environmental triggers, hence explaining the progressive resolution of the disease with age. Non-resolution of the disease or disease relapse in early adulthood might result from constant exposure or re-exposure, respectively, to strong environmental elicitors (e.g., pollution, stress, climate, changes in the skin microbiota) able to chronically trigger Th2 inflammation. The latter has been shown to weaken the epidermal barrier, hence perpetuating a pathogenic vicious cycle [63].
Dry skin is an important component of AD. A recent study showed that, in very young children with AD, dry skin originates from reduced amounts of natural moisturizing factors (NMFs), which leads to corneocyte stiffening [47][64]. Although FLG breakdown products constitute an important source of NMFs, reduced amounts of NMFs in the epidermis of very young patients are not related to FLG status [27][65]. These results support previous work showing that FLG genotype is not involved or has little involvement in disease initiation in very young AD patients [20][27], despite FLG deficiency inducing changes in the lamellar body cargo system and epidermal barrier ultrastructure [44][50].
The role of food allergies as an initiator of AD is still controversial [66]. Food allergies are known to exacerbate AD, but it remains unclear whether food allergies, notably to formula milk, might compromise the epidermal barrier of young AD patients, hence initiating the disease [67]. A recent study in children aged 4–7 showed that epidermal barrier impairment is more pronounced in AD patients with food allergies than in those without known food allergies; however, AD patients without food allergies still display abnormal epidermal barrier function [68].
Exposure to pollutants, allergens, specific microbes and low ambient humidity might lead to impaired epidermal barrier and dry skin via profound and sustained modification of lipid metabolism in the epidermis (https://doi.org/10.3389/fenvs.2014.00011 (accessed on 9 February 2022)) [69][70][71][72], hence contributing to AD pathogenesis [21][73]. For example, low humidity steepens the gradient of water loss across the SC, thereby placing extra stress on an already flawed epidermis. Moreover, alterations of lipid availability in the AD skin microenvironment might play a role in the antimicrobial innate immune response and influence the fate of local skin dendritic cells (DCs) [22].

This entry is adapted from the peer-reviewed paper 10.3390/ijms23042121

References

  1. Williams, H.; Stewart, A.; von Mutius, E.; Cookson, W.; Anderson, H.R. Is eczema really on the increase worldwide? J. Allergy Clin. Immunol. 2008, 121, 947–954.e15.
  2. Asher, M.I.; Montefort, S.; Björkstén, B.; Lai, C.K.; Strachan, D.P.; Weiland, S.K.; Williams, H. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 2006, 368, 733–743.
  3. Kowalska-Olędzka, E.; Czarnecka, M.; Baran, A. Epidemiology of atopic dermatitis in Europe. J. Drug Assess. 2019, 8, 126–128.
  4. Barbarot, S.; Auziere, S.; Gadkari, A.; Girolomoni, G.; Puig, L.; Simpson, E.L.; Margolis, D.J.; de Bruin-Weller, M.; Eckert, L. Epidemiology of atopic dermatitis in adults: Results from an international survey. Allergy 2018, 73, 1284–1293.
  5. Mathiesen, S.M.; Thomsen, S.F. The prevalence of atopic dermatitis in adults: Systematic review on population studies. Dermatol. Online J. 2019, 25.
  6. Werfel, T.; Breuer, K. Role of food allergy in atopic dermatitis. Curr. Opin. Allergy Clin. Immunol. 2004, 4, 379–385.
  7. Croce, E.A.; Levy, M.L.; Adamson, A.S.; Matsui, E.C. Reframing racial and ethnic disparities in atopic dermatitis in Black and Latinx populations. J. Allergy Clin. Immunol. 2021, 148, 1104–1111.
  8. Tokura, Y.; Hayano, S. Subtypes of atopic dermatitis: From phenotype to endotype. Allergol. Int. 2022, 71, 14–24.
  9. Renert-Yuval, Y.; Del Duca, E.; Pavel, A.B.; Fang, M.; Lefferdink, R.; Wu, J.; Diaz, A.; Estrada, Y.D.; Canter, T.; Zhang, N.; et al. The molecular features of normal and atopic dermatitis skin in infants, children, adolescents, and adults. J. Allergy Clin. Immunol. 2021, 148, 148–163.
  10. Marenholz, I.; Esparza-Gordillo, J.; Rüschendorf, F.; Bauerfeind, A.; Strachan, D.P.; Spycher, B.D.; Baurecht, H.; Margaritte-Jeannin, P.; Sääf, A.; Kerkhof, M.; et al. Meta-analysis identifies seven susceptibility loci involved in the atopic march. Nat. Commun. 2015, 6, 8804.
  11. Vaseghi-Shanjani, M.; Smith, K.L.; Sara, R.J.; Modi, B.P.; Branch, A.; Sharma, M.; Lu, H.Y.; James, E.L.; Hildebrand, K.J.; Biggs, C.M.; et al. Inborn errors of immunity manifesting as atopic disorders. J. Allergy Clin. Immunol. 2021, 148, 1130–1139.
  12. Tanaka, N.; Koido, M.; Suzuki, A.; Otomo, N.; Suetsugu, H.; Kochi, Y.; Tomizuka, K.; Momozawa, Y.; Kamatani, Y.; Ikegawa, S.; et al. Eight novel susceptibility loci and putative causal variants in atopic dermatitis. J. Allergy Clin. Immunol. 2021, 148, 1293–1306.
  13. Möbus, L.; Weidinger, S.; Emmert, H. Epigenetic factors involved in the pathophysiology of inflammatory skin diseases. J. Allergy Clin. Immunol. 2020, 145, 1049–1060.
  14. Engebretsen, K.A.; Johansen, J.D.; Kezic, S.; Linneberg, A.; Thyssen, J.P. The effect of environmental humidity and temperature on skin barrier function and dermatitis. J. Eur. Acad. Dermatol. Venereol. 2016, 30, 223–249.
  15. Chang, A.; Robison, R.; Cai, M.; Singh, A.M. Natural History of Food-Triggered Atopic Dermatitis and Development of Immediate Reactions in Children. J. Allergy Clin. Immunol. Pract 2016, 4, 229–236.e1.
  16. Kobayashi, T.; Glatz, M.; Horiuchi, K.; Kawasaki, H.; Akiyama, H.; Kaplan, D.H.; Kong, H.H.; Amagai, M.; Nagao, K. Dysbiosis and Staphylococcus aureus Colonization Drives Inflammation in Atopic Dermatitis. Immunity 2015, 42, 756–766.
  17. Weidinger, S.; Baurecht, H.; Wagenpfeil, S.; Henderson, J.; Novak, N.; Sandilands, A.; Chen, H.; Rodriguez, E.; O’Regan, G.M.; Watson, R.; et al. Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk. J. Allergy Clin. Immunol. 2008, 122, 560–568.e4.
  18. Martin, M.J.; Estravís, M.; García-Sánchez, A.; Dávila, I.; Isidoro-García, M.; Sanz, C. Genetics and Epigenetics of Atopic Dermatitis: An Updated Systematic Review. Genes 2020, 11, 442.
  19. He, H.; Del Duca, E.; Diaz, A.; Kim, H.J.; Gay-Mimbrera, J.; Zhang, N.; Wu, J.; Beaziz, J.; Estrada, Y.; Krueger, J.G.; et al. Mild atopic dermatitis lacks systemic inflammation and shows reduced nonlesional skin abnormalities. J. Allergy Clin. Immunol. 2021, 147, 1369–1380.
  20. Leung, D.Y.M.; Berdyshev, E.; Goleva, E. Cutaneous barrier dysfunction in allergic diseases. J. Allergy Clin. Immunol. 2020, 145, 1485–1497.
  21. Toncic, R.J.; Jakasa, I.; Hadzavdic, S.L.; Goorden, S.M.; Vlugt, K.J.G.; Stet, F.S.; Balic, A.; Petkovic, M.; Pavicic, B.; Zuzul, K.; et al. Altered Levels of Sphingosine, Sphinganine and Their Ceramides in Atopic Dermatitis Are Related to Skin Barrier Function, Disease Severity and Local Cytokine Milieu. Int. J. Mol. Sci. 2020, 21, 1958.
  22. Brombacher, E.C.; Everts, B. Shaping of Dendritic Cell Function by the Metabolic Micro-Environment. Front. Endocrinol. (Lausanne) 2020, 11, 555.
  23. Dubrac, S.; Schmuth, M.; Ebner, S. Atopic dermatitis: The role of Langerhans cells in disease pathogenesis. Immunol. Cell. Biol. 2010, 88, 400–409.
  24. Nakajima, S.; Igyártó, B.Z.; Honda, T.; Egawa, G.; Otsuka, A.; Hara-Chikuma, M.; Watanabe, N.; Ziegler, S.F.; Tomura, M.; Inaba, K.; et al. Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling. J. Allergy Clin. Immunol. 2012, 129, 1048–1055.e6.
  25. Otsuka, M.; Egawa, G.; Kabashima, K. Uncovering the Mysteries of Langerhans Cells, Inflammatory Dendritic Epidermal Cells, and Monocyte-Derived Langerhans Cell-Like Cells in the Epidermis. Front. Immunol. 2018, 9, 1768.
  26. Elentner, A.; Finke, D.; Schmuth, M.; Chappaz, S.; Ebner, S.; Malissen, B.; Kissenpfennig, A.; Romani, N.; Dubrac, S. Langerhans cells are critical in the development of atopic dermatitis-like inflammation and symptoms in mice. J. Cell. Mol. Med. 2009, 13, 2658–2672.
  27. Czarnowicki, T.; He, H.; Krueger, J.G.; Guttman-Yassky, E. Atopic dermatitis endotypes and implications for targeted therapeutics. J. Allergy Clin. Immunol. 2019, 143, 1–11.
  28. Weidinger, S.; Novak, N. Atopic dermatitis. Lancet 2016, 387, 1109–1122.
  29. Moosbrugger-Martinz, V.; Schmuth, M.; Dubrac, S. A Mouse Model for Atopic Dermatitis Using Topical Application of Vitamin D3 or of Its Analog MC903. Methods Mol. Biol. 2017, 1559, 91–106.
  30. Moosbrugger-Martinz, V.; Hackl, H.; Gruber, R.; Pilecky, M.; Knabl, L.; Orth-Höller, D.; Dubrac, S. Initial Evidence of Distinguishable Bacterial and Fungal Dysbiosis in the Skin of Patients with Atopic Dermatitis or Netherton Syndrome. J. Investig. Dermatol. 2021, 141, 114–123.
  31. Hammad, H.; Lambrecht, B.N. Barrier Epithelial Cells and the Control of Type 2 Immunity. Immunity 2015, 43, 29–40.
  32. Czarnowicki, T.; Esaki, H.; Gonzalez, J.; Malajian, D.; Shemer, A.; Noda, S.; Talasila, S.; Berry, A.; Gray, J.; Becker, L.; et al. Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)(+) TH2/TH1 cell imbalance, whereas adults acquire CLA(+) TH22/TC22 cell subsets. J. Allergy Clin. Immunol. 2015, 136, 941–951.e3.
  33. Gittler, J.K.; Krueger, J.G.; Guttman-Yassky, E. Atopic dermatitis results in intrinsic barrier and immune abnormalities: Implications for contact dermatitis. J. Allergy Clin. Immunol. 2013, 131, 300–313.
  34. Brunner, P.M.; Leung, D.Y.M.; Guttman-Yassky, E. Immunologic, microbial, and epithelial interactions in atopic dermatitis. Ann. Allergy Asthma Immunol. 2018, 120, 34–41.
  35. Novak, N.; Bieber, T.; Leung, D.Y. Immune mechanisms leading to atopic dermatitis. J. Allergy Clin. Immunol. 2003, 112 (Suppl. S6), S128–S139.
  36. Guttman-Yassky, E.; Krueger, J.G.; Lebwohl, M.G. Systemic immune mechanisms in atopic dermatitis and psoriasis with implications for treatment. Exp. Dermatol. 2018, 27, 409–417.
  37. Werfel, T.; Allam, J.P.; Biedermann, T.; Eyerich, K.; Gilles, S.; Guttman-Yassky, E.; Hoetzenecker, W.; Knol, E.; Simon, H.U.; Wollenberg, A.; et al. Cellular and molecular immunologic mechanisms in patients with atopic dermatitis. J. Allergy Clin. Immunol. 2016, 138, 336–349.
  38. Honda, T.; Kabashima, K. Reconciling innate and acquired immunity in atopic dermatitis. J. Allergy Clin. Immunol. 2020, 145, 1136–1137.
  39. Brauweiler, A.M.; Bin, L.; Kim, B.E.; Oyoshi, M.K.; Geha, R.S.; Goleva, E.; Leung, D.Y. Filaggrin-dependent secretion of sphingomyelinase protects against staphylococcal α-toxin-induced keratinocyte death. J. Allergy Clin. Immunol. 2013, 131, 421–427.e1-2.
  40. Miajlovic, H.; Fallon, P.G.; Irvine, A.D.; Foster, T.J. Effect of filaggrin breakdown products on growth of and protein expression by Staphylococcus aureus. J. Allergy Clin. Immunol. 2010, 126, 1184–1190.e3.
  41. van Drongelen, V.; Haisma, E.M.; Out-Luiting, J.J.; Nibbering, P.H.; El Ghalbzouri, A. Reduced filaggrin expression is accompanied by increased Staphylococcus aureus colonization of epidermal skin models. Clin. Exp. Allergy 2014, 44, 1515–1524.
  42. Clausen, M.L.; Edslev, S.M.; Andersen, P.S.; Clemmensen, K.; Krogfelt, K.A.; Agner, T. Staphylococcus aureus colonization in atopic eczema and its association with filaggrin gene mutations. Br. J. Dermatol. 2017, 177, 1394–1400.
  43. Leman, G.; Moosbrugger-Martinz, V.; Blunder, S.; Pavel, P.; Dubrac, S. 3D-Organotypic Cultures to Unravel Molecular and Cellular Abnormalities in Atopic Dermatitis and Ichthyosis Vulgaris. Cells 2019, 8, 489.
  44. Gruber, R.; Elias, P.M.; Crumrine, D.; Lin, T.K.; Brandner, J.M.; Hachem, J.P.; Presland, R.B.; Fleckman, P.; Janecke, A.R.; Sandilands, A.; et al. Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function. Am. J. Pathol. 2011, 178, 2252–2263.
  45. Knor, T.; Meholjić-Fetahović, A.; Mehmedagić, A. Stratum corneum hydration and skin surface pH in patients with atopic dermatitis. Acta Dermatovenerol. Croat. 2011, 19, 242–247.
  46. Jungersted, J.M.; Scheer, H.; Mempel, M.; Baurecht, H.; Cifuentes, L.; Høgh, J.K.; Hellgren, L.I.; Jemec, G.B.; Agner, T.; Weidinger, S. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema. Allergy 2010, 65, 911–918.
  47. Kezic, S.; O’Regan, G.M.; Lutter, R.; Jakasa, I.; Koster, E.S.; Saunders, S.; Caspers, P.; Kemperman, P.M.; Puppels, G.J.; Sandilands, A.; et al. Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency. J. Allergy Clin. Immunol. 2012, 129, 1031–1039.e1.
  48. Kelleher, M.; Dunn-Galvin, A.; Hourihane, J.O.; Murray, D.; Campbell, L.E.; McLean, W.H.I.; Irvine, A.D. Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year. J. Allergy Clin. Immunol. 2015, 135, 930–935.e1.
  49. Retraction notice (The Journal of Allergy and Clinical Immunology (2015) 135(4) (930–935.e1), (10.1016/j.jaci.2014.12.013)). J. Allergy Clin. Immunol. 2021, 147, 1526.
  50. Blunder, S.; Rühl, R.; Moosbrugger-Martinz, V.; Krimmel, C.; Geisler, A.; Zhu, H.; Crumrine, D.; Elias, P.M.; Gruber, R.; Schmuth, M.; et al. Alterations in Epidermal Eicosanoid Metabolism Contribute to Inflammation and Impaired Late Differentiation in FLG-Mutated Atopic Dermatitis. J. Investig. Dermatol. 2017, 137, 706–715.
  51. Seguchi, T.; Cui, C.Y.; Kusuda, S.; Takahashi, M.; Aisu, K.; Tezuka, T. Decreased expression of filaggrin in atopic skin. Arch. Dermatol. Res. 1996, 288, 442–446.
  52. Tsuji, G.; Ito, T.; Chiba, T.; Mitoma, C.; Nakahara, T.; Uchi, H.; Furue, M. The role of the OVOL1-OVOL2 axis in normal and diseased human skin. J. Dermatol. Sci. 2018, 90, 227–231.
  53. Tsuji, G.; Hashimoto-Hachiya, A.; Kiyomatsu-Oda, M.; Takemura, M.; Ohno, F.; Ito, T.; Morino-Koga, S.; Mitoma, C.; Nakahara, T.; Uchi, H.; et al. Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis. Cell. Death Dis. 2017, 8, e2931.
  54. Nair, M.; Teng, A.; Bilanchone, V.; Agrawal, A.; Li, B.; Dai, X. Ovol1 regulates the growth arrest of embryonic epidermal progenitor cells and represses c-myc transcription. J. Cell Biol. 2006, 173, 253–264.
  55. Furue, K.; Ito, T.; Tsuji, G.; Ulzii, D.; Vu, Y.H.; Kido-Nakahara, M.; Nakahara, T.; Furue, M. The IL-13-OVOL1-FLG axis in atopic dermatitis. Immunology 2019, 158, 281–286.
  56. Yoshio, H.; Tollin, M.; Gudmundsson, G.H.; Lagercrantz, H.; Jornvall, H.; Marchini, G.; Agerberth, B. Antimicrobial polypeptides of human vernix caseosa and amniotic fluid: Implications for newborn innate defense. Pediatr. Res. 2003, 53, 211–216.
  57. Marchini, G.; Lindow, S.; Brismar, H.; Ståbi, B.; Berggren, V.; Ulfgren, A.K.; Lonne-Rahm, S.; Agerberth, B.; Gudmundsson, G.H. The newborn infant is protected by an innate antimicrobial barrier: Peptide antibiotics are present in the skin and vernix caseosa. Br. J. Dermatol. 2002, 147, 1127–1134.
  58. Reid, G.; Younes, J.A.; Van der Mei, H.C.; Gloor, G.B.; Knight, R.; Busscher, H.J. Microbiota restoration: Natural and supplemented recovery of human microbial communities. Nat. Rev. Microbiol. 2011, 9, 27–38.
  59. Fluhr, J.W.; Bellemère, G.; Ferrari, C.; De Belilovsky, C.; Boyer, G.; Lachmann, N.; McGuckin, C.P.; Forraz, N.; Darlenski, R.; Chadoutaud, B.; et al. Age-Dependent Transformation of Skin Biomechanical Properties and Micromorphology during Infancy and Childhood. J. Investig. Dermatol. 2019, 139, 464–466.
  60. Fluhr, J.W.; Lachmann, N.; Baudouin, C.; Msika, P.; Darlenski, R.; De Belilovsky, C.; Bossert, J.; Colomb, E.; Burdin, B.; Haftek, M. Development and organization of human stratum corneum after birth: Electron microscopy isotropy score and immunocytochemical corneocyte labelling as epidermal maturation’s markers in infancy. Br. J. Dermatol. 2014, 171, 978–986.
  61. Michael-Jubeli, R.; Tfayli, A.; Baudouin, C.; Bleton, J.; Bertrand, D.; Baillet-Guffroy, A. Clustering-based preprocessing method for lipidomic data analysis: Application for the evolution of newborn skin surface lipids from birth until 6 months. Anal. Bioanal. Chem. 2018, 410, 6517–6528.
  62. Möbus, L.; Rodriguez, E.; Harder, I.; Stölzl, D.; Boraczynski, N.; Gerdes, S.; Kleinheinz, A.; Abraham, S.; Heratizadeh, A.; Handrick, C.; et al. Atopic dermatitis displays stable and dynamic skin transcriptome signatures. J. Allergy Clin. Immunol. 2021, 147, 213–223.
  63. Nygaard, U.; van den Bogaard, E.H.; Niehues, H.; Hvid, M.; Deleuran, M.; Johansen, C.; Vestergaard, C. The “Alarmins” HMBG1 and IL-33 Downregulate Structural Skin Barrier Proteins and Impair Epidermal Growth. Acta Derm. Venereol. 2017, 97, 305–312.
  64. Thyssen, J.P.; Jakasa, I.; Riethmüller, C.; Schön, M.P.; Braun, A.; Haftek, M.; Fallon, P.G.; Wróblewski, J.; Jakubowski, H.; Eckhart, L.; et al. Filaggrin Expression and Processing Deficiencies Impair Corneocyte Surface Texture and Stiffness in Mice. J. Investig. Dermatol. 2020, 140, 615–623.e5.
  65. McAleer, M.A.; Jakasa, I.; Stefanovic, N.; McLean, W.H.I.; Kezic, S.; Irvine, A.D. Topical corticosteroids normalize both skin and systemic inflammatory markers in infant atopic dermatitis. Br. J. Dermatol. 2021, 185, 153–163.
  66. Kelleher, M.M.; Cro, S.; Cornelius, V.; Lodrup Carlsen, K.C.; Skjerven, H.O.; Rehbinder, E.M.; Lowe, A.J.; Dissanayake, E.; Shimojo, N.; Yonezawa, K.; et al. Skin care interventions in infants for preventing eczema and food allergy. Cochrane Database Syst. Rev. 2021, 2, Cd013534.
  67. Mastrorilli, C.; Santoro, A.; Caffarelli, C. Primary Prevention of Allergic Diseases: The Role of Early Exposure to Cow’s Milk Formula. Front. Pediatr. 2020, 8, 420.
  68. Leung, D.Y.M.; Calatroni, A.; Zaramela, L.S.; LeBeau, P.K.; Dyjack, N.; Brar, K.; David, G.; Johnson, K.; Leung, S.; Ramirez-Gama, M.; et al. The nonlesional skin surface distinguishes atopic dermatitis with food allergy as a unique endotype. Sci. Transl. Med. 2019, 11, eaav2685.
  69. Dijkhoff, I.M.; Drasler, B.; Karakocak, B.B.; Petri-Fink, A.; Valacchi, G.; Eeman, M.; Rothen-Rutishauser, B. Impact of airborne particulate matter on skin: A systematic review from epidemiology to in vitro studies. Part. Fibre Toxicol. 2020, 17, 35.
  70. Bourgeois, E.A.; Subramaniam, S.; Cheng, T.Y.; De Jong, A.; Layre, E.; Ly, D.; Salimi, M.; Legaspi, A.; Modlin, R.L.; Salio, M.; et al. Bee venom processes human skin lipids for presentation by CD1a. J. Exp. Med. 2015, 212, 149–163.
  71. Mieremet, A.; Boiten, W.; van Dijk, R.; Gooris, G.; Overkleeft, H.S.; Aerts, J.; Bouwstra, J.A.; El Ghalbzouri, A. Unravelling effects of relative humidity on lipid barrier formation in human skin equivalents. Arch. Dermatol. Res. 2019, 311, 679–689.
  72. Goad, N.; Gawkrodger, D.J. Ambient humidity and the skin: The impact of air humidity in healthy and diseased states. J. Eur. Acad. Dermatol. Venereol. 2016, 30, 1285–1294.
  73. Bouwstra, J.A.; Ponec, M. The skin barrier in healthy and diseased state. Biochim. Biophys. Acta 2006, 1758, 2080–2095.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback