Molecular mechanisms in atopic eczema: insights gained from genetic studies

Journal of Pathology

Volumn 241, Issue 2, 2017, Pages 140-145

  Brown, Sara J ^a  

^a UNIVERSITY OF DUNDEE   (United Kingdom)

Author keywords

atopic eczema; dermatitis; filaggrin; genome wide; phenotype; skin barrier; therapy; transcriptome

Indexed keywords

TRANSCRIPTOME;

ATOPIC DERMATITIS; DISEASE PREDISPOSITION; ECZEMA; ENVIRONMENTAL FACTOR; GENETIC ANALYSIS; GENOME-WIDE ASSOCIATION STUDY; HUMAN; MOLECULAR GENETICS; PATHOGENESIS; PERSONALIZED MEDICINE; PHENOTYPE; PRIORITY JOURNAL; PSORIASIS; REVIEW; ANIMAL; GENETIC PREDISPOSITION; GENETICS; INFLAMMATION; MUTATION; PATHOLOGY; SKIN;

ANIMALS; DERMATITIS, ATOPIC; GENETIC PREDISPOSITION TO DISEASE; HUMANS; INFLAMMATION; MUTATION; PRECISION MEDICINE; SKIN;

EID: 85006295144     PISSN: 00223417     EISSN: 10969896     Source Type: Journal    
DOI: 10.1002/path.4810     Document Type: Review

References (66)

1. Johansson SG, Bieber T, Dahl R, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol 2004; 113: 832–836.
2. Williams HC. Is the prevalence of atopic dermatitis increasing? Clin Exp Dermatol 1992; 17: 385–391.
3. Brown SJ, Relton CL, Liao H, et al. Filaggrin null mutations and childhood atopic eczema: a population-based case-control study. J Allergy Clin Immunol 2008; 121: 940–946.
4. Odhiambo JA, Williams HC, Clayton TO, et al. Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three. J Allergy Clin Immunol 2009; 124: 1251–1258.
5. Bieber T. Atopic dermatitis. N Engl J Med 2008; 358: 1483–1494.
6. Williams HC. Clinical practice. Atopic dermatitis. N Engl J Med 2005; 352: 2314–2324.
7. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 2011; 365: 1315–1327.
8. Deckert S, Kopkow C, Schmitt J. Nonallergic comorbidities of atopic eczema: an overview of systematic reviews. Allergy 2014; 69: 37–45.
9. Schmitt J, Romanos M, Pfennig A, et al. Psychiatric comorbidity in adult eczema. Br J Dermatol 2009; 161: 878–883.
10. Strom MA, Fishbein AB, Paller AS, et al. Association between AD and attention deficit hyperactivity disorder in US children and adults. Br J Dermatol 2016; DOI: 10.1111/bjd.14697.
11. Schmitt J, Schwarz K, Baurecht H, et al. Atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflammatory bowel disease, and a decreased risk for type 1 diabetes. J Allergy Clin Immunol 2016; 137: 130–136.
12. Zhang A, Silverberg JI. Association of atopic dermatitis with being overweight and obese: a systematic review and metaanalysis. J Am Acad Dermatol 2015; 72: 606–616.
13. Silverberg JI, Becker L, Kwasny M, et al. Central obesity and high blood pressure in pediatric patients with atopic dermatitis. JAMA Dermatol 2015; 151: 144–152.
14. Brown SJ. Atopic eczema. Clin Med (Lond) 2016; 16: 66–69.
15. Boguniewicz M, Leung DY. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 2011; 242: 233–246.
16. Brown SJ, McLean WH. Eczema genetics: current state of knowledge and future goals. J Invest Dermatol 2009; 129: 543–552.
17. He JQ, Chan-Yeung M, Becker AB, et al. Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children. Genes Immun 2003; 4: 385–389.
18. Liu X, Nickel R, Beyer K, et al. An IL13 coding region variant is associated with a high total serum IgE level and atopic dermatitis in the German multicenter atopy study (MAS-90). J Allergy Clin Immunol 2000; 106: 167–170.
19. Palmer CN, Irvine AD, Terron-Kwiatkowski A, 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: 441–446.
20. Rodriguez E, Baurecht H, Herberich E, et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol 2009; 123: 1361–1370.
21. Sandilands A, Sutherland C, Irvine A, et al. Filaggrin in the frontline: role in skin barrier function and disease. J Cell Sci 2009; 122: 1285–1294.
22. Brown SJ, McLean WH. One remarkable molecule: filaggrin. J Invest Dermatol 2012; 132: 751–762.
23. Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 2006; 38: 337–342.
24. Brown SJ, Relton CL, Liao H, et al. Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children. Br J Dermatol 2009; 161: 884–889.
25. Brown SJ, Kroboth K, Sandilands A, et al. Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect. J Invest Dermatol 2012; 132: 98–104.
26. Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2007; 120: 150–155.
27. Kim BE, Howell MD, Guttman-Yassky E, et al. TNF-alpha downregulates filaggrin and loricrin through c-Jun N-terminal kinase: role for TNF-alpha antagonists to improve skin barrier. J Invest Dermatol 2011; 131: 1272–1279.
28. Walley AJ, Chavanas S, Moffatt MF, et al. Gene polymorphism in Netherton and common atopic disease. Nat Genet 2001; 29: 175–178.
29. Hubiche T, Ged C, Benard A, et al. Analysis of SPINK 5, KLK 7 and FLG genotypes in a French atopic dermatitis cohort. Acta Derm Venereol 2007; 87: 499–505.
30. Weidinger S, Baurecht H, Wagenpfeil S, 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.
31. Caubet C, Jonca N, Brattsand M, et al. Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J Invest Dermatol 2004; 122: 1235–1244.
32. Takai T, Ikeda S. Barrier dysfunction caused by environmental proteases in the pathogenesis of allergic diseases. Allergol Int 2011; 60: 25–35.
33. Samuelov L, Sarig O, Harmon RM, et al. Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting. Nat Genet 2013; 45: 1244–1248.
34. McAleer MA, Pohler E, Smith FJ, et al. Severe dermatitis, multiple allergies, and metabolic wasting syndrome caused by a novel mutation in the N-terminal plakin domain of desmoplakin. J Allergy Clin Immunol 2015; 136: 1268–1276.
35. Broussard JA, Getsios S, Green KJ. Desmosome regulation and signaling in disease. Cell Tissue Res 2015; 360: 501–512.
36. Paller AS, Renert-Yuval Y, Suprun M, et al. An IL-17-dominant immune profile is shared across the major orphan forms of ichthyosis. J Allergy Clin Immunol 2016; DOI: 10.1016/j.jaci.2016.07.019.
37. Esparza-Gordillo J, Weidinger S, Folster-Holst R, et al. A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat Genet 2009; 41: 596–601.
38. Paternoster L, Standl M, Waage J, et al. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. Nat Genet 2015; 47: 1449–1456.
39. Tang TS, Bieber T, Williams HC. Does ‘autoreactivity’ play a role in atopic dermatitis? J Allergy Clin Immunol 2012; 129: 1209–1215.
40. Taylan F, Nilsson D, Asad S, et al. Whole-exome sequencing of Ethiopian patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol 2015; 136: 507–509.
41. Margolis DJ, Gupta J, Apter AJ, et al. Exome sequencing of filaggrin and related genes in African-American children with atopic dermatitis. J Invest Dermatol 2014; 134: 2272–2274.
42. Margolis DJ, Mitra N, Kim B, et al. Association of HLA-DRB1 genetic variants with the persistence of atopic dermatitis. Hum Immunol 2015; 76: 571–577.
43. Adoue V, Schiavi A, Light N, et al. Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs. Mol Syst Biol 2014; 10: 754.
44. He L, Sedwick C. Lin He. ‘Junk’ DNA isn't. J Cell Biol 2015; 211: 4–5.
45. Ghosh D, Ding L, Sivaprasad U, et al. Multiple transcriptome data analysis reveals biologically relevant atopic dermatitis signature genes and pathways. PLoS One 2015; 10: e0144316.
46. Suarez-Farinas M, Ungar B, Correa da Rosa J, et al. RNA sequencing atopic dermatitis transcriptome profiling provides insights into novel disease mechanisms with potential therapeutic implications. J Allergy Clin Immunol 2015; 135: 1218–1227.
47. Cole C, Kroboth K, Schurch NJ, et al. Filaggrin-stratified transcriptomic analysis of pediatric skin identifies mechanistic pathways in patients with atopic dermatitis. J Allergy Clin Immunol 2014; 134: 82–91.
48. Esaki H, Ewald DA, Ungar B, et al. Identification of novel immune and barrier genes in atopic dermatitis by means of laser capture microdissection. J Allergy Clin Immunol 2015; 135: 153–163.
49. Eyerich S, Onken AT, Weidinger S, et al. Mutual antagonism of T cells causing psoriasis and atopic eczema. N Engl J Med 2011; 365: 231–238.
50. Baurecht H, Hotze M, Brand S, et al. Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms. Am J Hum Genet 2015; 96: 104–120.
51. Brown SJ, Sandilands A, Zhao Y, et al. Prevalent and low-frequency null mutations in the filaggrin gene are associated with early-onset and persistent atopic eczema. J Invest Dermatol 2008; 128: 1591–1594.
52. Weidinger S, Rodriguez E, Stahl C, et al. Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J Invest Dermatol 2007; 127: 724–726.
53. Henderson J, Northstone K, Lee SP, et al. The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study. J Allergy Clin Immunol 2008; 121: 872–877.
54. Gao PS, Rafaels NM, Hand T, et al. Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum. J Allergy Clin Immunol 2009; 124: 507–513.
55. Kelleher MM, Dunn-Galvin A, Gray C, et al. Skin barrier impairment at birth predicts food allergy at 2 years of age. J Allergy Clin Immunol 2016; 137: 1111–1116.
56. Kelleher M, Dunn-Galvin A, Hourihane JO, et al. 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.
57. Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol 2014; 134: 818–823.
58. Horimukai K, Morita K, Narita M, et al. Application of moisturizer to neonates prevents development of atopic dermatitis. J Allergy Clin Immunol 2014; 134: 824–830.
59. Tsianakas A, Stander S. Dupilumab: a milestone in the treatment of atopic dermatitis. Lancet 2016; 387: 4–5.
60. Beck LA, Thaci D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med 2014; 371: 130–139.
61. Thaci D, Simpson EL, Beck LA, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet 2016; 387(10013):40–52.
62. http://ClinicalTrials.gov. A Study to Determine the Safety and Tolerability of Dupilumab (REGN668/SAR231893) in Patients Aged ≥6 to <18 Years With Atopic Dermatitis (Eczema). [Accessed 20 August 2016]. Available from: https://clinicaltrials.gov/show/NCT02407756
63. Noda S, Krueger JG, Guttman-Yassky E. The translational revolution and use of biologics in patients with inflammatory skin diseases. J Allergy Clin Immunol 2015; 135: 324–336.
64. Hotze M, Baurecht H, Rodriguez E, et al. Increased efficacy of omalizumab in atopic dermatitis patients with wild-type filaggrin status and higher serum levels of phosphatidylcholines. Allergy 2014; 69: 132–135.
65. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol 2016; 75: 494–503.
66. Barrett JC, Dunham I, Birney E. Using human genetics to make new medicines. Nat Rev Genet 2015; 16: 561–562.