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Pathophysiologie der atopischen Blepharokeratokonjunktivitis

Pathophysiology of atopic blepharokeratoconjunctivitis

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Zusammenfassung

Die atopische Dermatitis (AD, syn.: atopisches Ekzem, Neurodermitis) ist eine zum Formenkreis der atopischen Erkrankungen gehörende, chronisch persistierende oder chronisch rezidivierende, inflammatorische Systemerkrankung, die insbesondere mit einem unterschiedlich stark ausgeprägten Ekzem und Pruritus einhergeht. Neben dem möglichen Befall des gesamten Integuments findet sich häufig auch eine Beteiligung der periokulären Lidhaut sowie der Augenoberfläche. Ein okulärer Befund kann auch ohne Beteiligung der Gesichts- oder Körperhaut auftreten. Pathophysiologisch stehen neben einer Fehlregulation des Immunsystems genetische Veränderungen in verschiedenen dermalen Strukturproteinen im Vordergrund, die zu einer gestörten Hautbarriere führen. Zusätzlich bestehen regelhaft eine gehäufte Kolonisation mit bakteriellen Erregern und eine erhöhte Anfälligkeit für virale Infektionen der Haut. An den Lidern und auf der Augenoberfläche kommt es zu einem Verlust von Meibomdrüsen und Becherzellen. Konsekutiv bilden sich Augenoberflächendefekte und rezidivierende Binde- und Hornhautinfekte. Eine erhöhte mechanische Manipulation bei Atopie-assoziiertem Pruritus wird als Ursache für die erhöhte Komorbidität mit Keratokonus gesehen. Zudem liegen Einzelfallberichte über verschiedene Malignome der Augenoberfläche bei Atopikern vor. Das Verstehen der pathophysiologischen Zusammenhänge ist essenziell für eine korrekte Diagnostik und Therapie dieses klinisch sehr komplexen Krankheitsbildes.

Abstract

Atopic dermatitis (AD) is a systemic inflammatory disease, which is characterized by pronounced eczema and pruritus. In addition to the involvement of the entire integument, the periocular lid skin and the surface of the eye are frequently involved. Ocular involvement may occur solely without dermatitis of facial or body skin. Pathophysiologically, besides a dysregulated immune response, genetic changes can occur in various dermal structural proteins which will lead to a disturbed skin barrier. Furthermore, there is a regular colonization with bacterial pathogens and an increased susceptibility for viral skin infections. The lid margin reveals a loss of Meibomian glands whereas the conjunctiva shows reduced goblet cells. Consecutively, eye surface defects and recurrent conjunctival and corneal defects can be found. Increased mechanical manipulation in atopia-associated pruritus is seen as a cause of increased comorbidity with keratoconus. In addition, individual cases are reported of various malignomas of the eye surface, which are present in patients with AD. Understanding of the pathophysiological connections is essential for the correct diagnosis and therapy of this clinically very complex disease picture.

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Literatur

  1. Altmeyer P Ekzem atopisches (Übersicht) (2017). In: Enzyklopädie der Dermatologie, Venerologie, Allergologie, Umweltmedizin. http://www.enzyklopaedie-dermatologie.de/artikel?id=1108. Zugegriffen: 15. Nov. 2016

  2. Leung DYM (2013) New insights into atopic dermatitis: role of skin barrier and immune dysregulation. Allergol Int 62:151–161

    Article  CAS  PubMed  Google Scholar 

  3. Cork MJ et al (2009) Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 129:1892–1908

    Article  CAS  PubMed  Google Scholar 

  4. Brown SJ (2016) Molecular mechanisms in atopic eczema: insight gained from genetic studies. J Pathol. doi:10.1002/path.4810

    PubMed Central  Google Scholar 

  5. Werfel T et al (2016) Cellular and molecular immunologic mechanisms in patients with atopic dermatitis. J Allergy Clin Immunol 138:336–349

    Article  CAS  PubMed  Google Scholar 

  6. McAleer MA, Irvine AD (2013) The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol 131:280–291

    Article  CAS  PubMed  Google Scholar 

  7. McLean WHI et al (2008) Filaggrin variants confer susceptibility to asthma. J Allergy Clin Immunol 121(5):1294–1295

    Article  PubMed  Google Scholar 

  8. Boguniewicz M, Leung DYM (2011) Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 242:233–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bieber T (2012) Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy 67:1475–1482

    Article  CAS  PubMed  Google Scholar 

  10. Hon KL, Leung AKC, Barankin B (2013) Barrier repair therapy in atopic dermatitis: an overview. Am J Clin Dermatol 14:389–399

    Article  PubMed  Google Scholar 

  11. Proksch E, Lachapelle J‑M (2005) The management of dry skin with topical emollients – recent perspectives. J Dtsch Dermatol Ges 3:768–774

    Article  PubMed  Google Scholar 

  12. Choi EH, Yoon NY (2014) Pathogenesis of atopic dermatitis. J Korean Med Assoc 57:218–225

    Article  Google Scholar 

  13. Alduraywish SA et al (2016) The march from early life food sensitization to allergic disease: a systematic review and meta-analyses of birth cohort studies. Allergy 71:77–89

    Article  CAS  PubMed  Google Scholar 

  14. Deckert S, Kopkow C, Schmitt J (2014) Nonallergic comorbidities of atopic eczema: an overview of systematic reviews. Allergy 69:37–45

    Article  CAS  PubMed  Google Scholar 

  15. Eyerich K, Novak N (2013) Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy 68:974–982

    Article  CAS  PubMed  Google Scholar 

  16. Thijs J et al (2015) Biomarkers for atopic dermatitis: a systematic review and meta-analysis. Curr Opin Allergy Clin Immunol 15:453–460

    Article  CAS  PubMed  Google Scholar 

  17. Mansouri Y, Guttman-Yassky E (2015) Immune pathways in atopic dermatitis, and definition of biomarkers through broad and targeted therapeutics. J Clin Med 4:858–873

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rebane A et al (2012) Mechanisms of IFN-γ-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis. J Allergy Clin Immunol 129:1297–1306

    Article  CAS  PubMed  Google Scholar 

  19. Trautmann A et al (2000) T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J Clin Invest 106:25–35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Werfel T et al (1996) Allergen specificity of skin-infiltrating T cells is not restricted to a type-2 cytokine pattern in chronic skin lesions of atopic dermatitis. J Invest Dermatol 107:871–876

    Article  CAS  PubMed  Google Scholar 

  21. Thepen T et al (1996) Biphasic response against aeroallergen in atopic dermatitis showing a switch from an initial TH2 response to a TH1 response in situ: an immunocytochemical study. J Allergy Clin Immunol 97:828–837

    Article  CAS  PubMed  Google Scholar 

  22. Ong PY et al (2002) Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 347:1151–1160

    Article  CAS  PubMed  Google Scholar 

  23. Howell MD et al (2006) Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity 24:341–348

    Article  CAS  PubMed  Google Scholar 

  24. Volz T et al (2014) Nonpathogenic bacteria alleviating atopic dermatitis inflammation induce IL-10-producing dendritic cells and regulatory Tr1 cells. J Invest Dermatol 134:96–104

    Article  CAS  PubMed  Google Scholar 

  25. Kaesler S et al (2014) Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4-mediated suppression of IL-10. J Allergy Clin Immunol 134:92–99

    Article  CAS  PubMed  Google Scholar 

  26. Simpson EL et al (2017) Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. doi:10.3410/f.726815273.793527741

    PubMed  Google Scholar 

  27. Thaçi D et al (2016) 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 Lond Engl 387:40–52

    Article  Google Scholar 

  28. Oldhoff JM et al (2005) Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy 60:693–696

    Article  CAS  PubMed  Google Scholar 

  29. Simon D, Hösli S, Kostylina G, Yawalkar N, Simon H‑U (2008) Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol 121:122–128

    Article  CAS  PubMed  Google Scholar 

  30. Navarini AA, French LE, Hofbauer GFL (2011) Interrupting IL-6-receptor signaling improves atopic dermatitis but associates with bacterial superinfection. J Allergy Clin Immunol 128:1128–1130

    Article  CAS  PubMed  Google Scholar 

  31. Buka RL, Resh B, Roberts B, Cunningham BB, Friedlander S (2005) Etanercept is minimally effective in 2 children with atopic dermatitis. J Am Acad Dermatol 53:358–359

    Article  PubMed  Google Scholar 

  32. Hanifin JM et al (1993) Recombinant interferon gamma therapy for atopic dermatitis. J Am Acad Dermatol 28:189–197

    Article  CAS  PubMed  Google Scholar 

  33. Schmitt J et al (2016) Einsatz und Wirksamkeit von Systemtherapien bei Erwachsenen mit schwerer Neurodermitis: Erste Ergebnisse des deutschen Neurodermitis-Registers TREATgermany. J Dtsch Dermatol Ges. doi:10.1111/ddg.12958

    Google Scholar 

  34. Rebane A et al (2014) MicroRNA-146a alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes. J Allergy Clin Immunol 134:836–847.e11

    Article  CAS  PubMed  Google Scholar 

  35. Rebane A, Akdis CA (2013) MicroRNAs: essential players in the regulation of inflammation. J Allergy Clin Immunol 132:15–26

    Article  CAS  PubMed  Google Scholar 

  36. Irvine AD, McLean WHI, Leung DYM (2011) Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 365:1315–1327

    Article  CAS  PubMed  Google Scholar 

  37. Sandilands A, Sutherland C, Irvine AD, McLean WHI (2009) Filaggrin in the frontline: role in skin barrier function and disease. J Cell Sci 122:1285–1294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Proksch E, Brandner JM, Jensen J‑M (2008) The skin: an indispensable barrier. Exp Dermatol 17:1063–1072

    Article  PubMed  Google Scholar 

  39. Bäsler K, Brandner JM (2017) Tight junctions in skin inflammation. Pflügers Arch 469:3–14

    Article  PubMed  Google Scholar 

  40. Tsukita S, Furuse M (2002) Claudin-based barrier in simple and stratified cellular sheets. Curr Opin Cell Biol 14:531–536

    Article  CAS  PubMed  Google Scholar 

  41. Nomura T, Kabashima K (2016) Advances in atopic dermatitis in 2015. J Allergy Clin Immunol 138:1548–1555

    Article  PubMed  Google Scholar 

  42. Dale BA, Resing KA, Lonsdale-Eccles JD (1985) Filaggrin: a keratin filament associated protein. Ann N Y Acad Sci 455:330–342

    Article  CAS  PubMed  Google Scholar 

  43. Gruber R et al (2011) Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function. Am J Pathol 178:2252–2263

    Article  PubMed  PubMed Central  Google Scholar 

  44. Brown SJ, McLean WHI (2012) One remarkable molecule: filaggrin. J Invest Dermatol 132:751–762

    Article  CAS  PubMed  Google Scholar 

  45. Palmer CNA et al (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38:441–446

    Article  CAS  PubMed  Google Scholar 

  46. Weidinger S et al (2008) Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol 121:1203–1209.e1

    Article  CAS  PubMed  Google Scholar 

  47. Brown SJ, McLean WHI (2009) Eczema genetics: current state of knowledge and future goals. J Invest Dermatol 129:543–552

    Article  CAS  PubMed  Google Scholar 

  48. Howell MD et al (2009) Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 124:R7–R12

    Article  CAS  PubMed  Google Scholar 

  49. Weidinger S et al (2013) A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis. Hum Mol Genet 22:4841–4856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bin L, Leung DYM (2016) Genetic and epigenetic studies of atopic dermatitis. Allergy Asthma Clin Immunol. doi:10.1186/s13223-016-0158-5

    PubMed  PubMed Central  Google Scholar 

  51. Sonkoly E et al (2010) MiR-155 is overexpressed in patients with atopic dermatitis and modulates T‑cell proliferative responses by targeting cytotoxic T lymphocyte-associated antigen 4. J Allergy Clin Immunol 126(20):581–589

    Article  CAS  PubMed  Google Scholar 

  52. Lv Y et al (2014) Profiling of serum and urinary microRNAs in children with atopic dermatitis. PLOS ONE 9:e115448

    Article  PubMed  PubMed Central  Google Scholar 

  53. Lack G, Fox D, Northstone K, Golding J, Avon Longitudinal Study of Parents and Children Study Team (2003) Factors associated with the development of peanut allergy in childhood. N Engl J Med 348:977–985

    Article  PubMed  Google Scholar 

  54. Brough HA et al (2015) Atopic dermatitis increases the effect of exposure to peanut antigen in dust on peanut sensitization and likely peanut allergy. J Allergy Clin Immunol 135:164–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Brough HA et al (2014) Peanut allergy: effect of environmental peanut exposure in children with filaggrin loss-of-function mutations. J Allergy Clin Immunol 134:867–875.e1

    Article  PubMed  PubMed Central  Google Scholar 

  56. Silverberg JI, Hanifin J, Simpson EL (2013) Climatic factors are associated with childhood eczema prevalence in US. J Invest Dermatol 133:1752–1759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kim E‑H et al (2015) Indoor air pollution aggravates symptoms of atopic dermatitis in children. PLOS ONE 10:e0119501. doi:10.1371/journal.pone.0119501

    Article  PubMed  PubMed Central  Google Scholar 

  58. Huang CC et al (2015) Prenatal air pollutant exposure and occurrence of atopic dermatitis. Br J Dermatol 173:981–988

    Article  CAS  PubMed  Google Scholar 

  59. Larsen AD et al (2014) Exposure to psychosocial job strain during pregnancy and odds of asthma and atopic dermatitis among 7‑year old children - a prospective cohort study. Scand J Work Environ Health 40:639–648

    Article  PubMed  Google Scholar 

  60. Peters EMJ et al (2014) Mental stress in atopic dermatitis – neuronal plasticity and the cholinergic system are affected in atopic dermatitis and in response to acute experimental mental stress in a randomized controlled pilot study. PLOS ONE 9:e113552

    Article  PubMed  PubMed Central  Google Scholar 

  61. Chen JJ, Applebaum DS, Sun GS, Pflugfelder SC (2014) Atopic keratoconjunctivitis: a review. J Am Acad Dermatol 70:569–575

    Article  PubMed  Google Scholar 

  62. Guglielmetti S, Dart JK, Calder V (2010) Atopic keratoconjunctivitis and atopic dermatitis. Curr Opin Allergy Clin Immunol 10:478–485

    Article  CAS  PubMed  Google Scholar 

  63. Akova YA, Rodriguez A, Foster CS (1994) Atopic keratoconjunctivitis. Ocul Immunol Inflamm 2:125–144

    Article  CAS  PubMed  Google Scholar 

  64. Manzouri B, Flynn T, Ono SJ (2006) Cornea and external eye disease. Springer, Berlin, S 209–224 doi:10.1007/3-540-31226-9_14

    Book  Google Scholar 

  65. Bielory B, Bielory L (2010) Atopic dermatitis and keratoconjunctivitis. Immunol Allergy Clin North Am 30:323–336

    Article  PubMed  Google Scholar 

  66. Takakuwa K et al (2015) Atopic glaucoma: clinical and Pathophysiological analysis. J Glaucoma 24:662–668

    Article  PubMed  Google Scholar 

  67. Hida T, Tano Y, Okinami S, Ogino N, Inoue M (2000) Multicenter retrospective study of retinal detachment associated with atopic dermatitis. Jpn J Ophthalmol 44:407–418

    Article  CAS  PubMed  Google Scholar 

  68. Kallen C et al (2003) Atopic keratoconjunctivitis: probably a risk factor for the development of conjuntival carcinoma. Ophthalmologe 100:808–814

    Article  CAS  PubMed  Google Scholar 

  69. Heinz C, Fanihagh F, Steuhl K‑P (2003) Squamous cell carcinoma of the conjunctiva in patients with atopic eczema. Cornea 22:135–137

    Article  PubMed  Google Scholar 

  70. Rundle P, Mudhar HS, Rennie I (2010) Conjunctival intra-epithelial neoplasia occurring in young patients with asthma. Eye Lond Engl 24:1182–1185

    CAS  Google Scholar 

  71. Bielory L (2000) Allergic and immunologic disorders of the eye. Part II: ocular allergy. J Allergy Clin Immunol 106:1019–1032

    Article  CAS  PubMed  Google Scholar 

  72. Tuft SJ, Ramakrishnan M, Seal DV, Kemeny DM, Buckley RJ (1992) Role of staphylococcus aureus in chronic allergic conjunctivitis. Ophthalmology 99:180–184

    Article  CAS  PubMed  Google Scholar 

  73. Sarkar R et al (2016) Periorbital hyperpigmentation: a comprehensive review. J Clin Aesthetic Dermatol 9:49–55

    Google Scholar 

  74. Suto H et al (1999) NC/Nga mice: a mouse model for atopic dermatitis. Int Arch Allergy Immunol 120(Suppl 1):70–75

    Article  PubMed  Google Scholar 

  75. Inada N, Shoji J, Tabuchi K, Saito K, Sawa M (2004) Histological study on mast cells in conjunctiva of NC/Nga mice. Jpn J Ophthalmol 48:189–194

    Article  PubMed  Google Scholar 

  76. Mayer K, Reinhard T, Reis A, Böhringer D, Sundmacher R (2001) FK 506 ointment 0.1 % – a new therapeutic option for atopic blepharitis. Clinical trial with 14 patients. Klin Monatsbl Augenheilkd 218:733–736

    Article  CAS  PubMed  Google Scholar 

  77. Auw-Haedrich C, Reinhard T (2007) Chronic blepharitis. Pathogenesis, clinical features, and therapy. Ophthalmologe 104(828):817–826

    Article  CAS  PubMed  Google Scholar 

  78. Hu Y et al (2007) The differences of tear function and ocular surface findings in patients with atopic keratoconjunctivitis and vernal keratoconjunctivitis. Allergy 62:917–925

    Article  CAS  PubMed  Google Scholar 

  79. Ibrahim OMA et al (2012) In vivo confocal microscopy evaluation of meibomian gland dysfunction in atopic-keratoconjunctivitis patients. Ophthalmology 119:1961–1968

    Article  PubMed  Google Scholar 

  80. Buckley RJ (1988) Vernal keratoconjunctivitis. Int Ophthalmol Clin 28:303–308

    Article  CAS  PubMed  Google Scholar 

  81. Metz DP, Hingorani M, Calder VL, Buckley RJ, Lightman SL (1997) T‑cell cytokines in chronic allergic eye disease. J Allergy Clin Immunol 100:817–824

    Article  CAS  PubMed  Google Scholar 

  82. Leonardi A, De Dominicis C, Motterle L (2007) Immunopathogenesis of ocular allergy: a schematic approach to different clinical entities. Curr Opin Allergy Clin Immunol 7:429–435

    Article  CAS  PubMed  Google Scholar 

  83. Uchio E, Ono SY, Ikezawa Z, Ohno S (2000) Tear levels of interferon-gamma, interleukin (IL) -2, IL-4 and IL-5 in patients with vernal keratoconjunctivitis, atopic keratoconjunctivitis and allergic conjunctivitis. Clin Exp Allergy 30:103–109

    Article  CAS  PubMed  Google Scholar 

  84. Dogru M et al (2005) Ocular surface and MUC5AC alterations in atopic patients with corneal shield ulcers. Curr Eye Res 30:897–908

    Article  CAS  PubMed  Google Scholar 

  85. Ying S, Meng Q, Corrigan CJ, Lee TH (2006) Lack of filaggrin expression in the human bronchial mucosa. J Allergy Clin Immunol 118:1386–1388

    Article  CAS  PubMed  Google Scholar 

  86. De Benedetto A, Qualia CM, Baroody FM, Beck LA (2008) Filaggrin expression in oral, nasal, and esophageal mucosa. J Invest Dermatol 128:1594–1597

    Article  PubMed  Google Scholar 

  87. Lapp T et al (2013) Analysis of Filaggrin Mutations and Expression in Corneal Specimens from Patients with or without Atopic Dermatitis. Int Arch Allergy Immunol 163:20–24

    Article  PubMed  Google Scholar 

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  1. Klinik für Augenheilkunde, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Killianstr. 5, 79106, Freiburg, Deutschland

    T. Lapp, P. Maier & T. Reinhard

  2. Klinik für Dermatologie und Allergologie, Universitätsklinikum Gießen und Marburg, Standort Gießen, Justus Liebig Universität Gießen, Gießen, Deutschland

    T. Jakob

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Lapp, T., Maier, P., Jakob, T. et al. Pathophysiologie der atopischen Blepharokeratokonjunktivitis. Ophthalmologe 114, 504–513 (2017). https://doi.org/10.1007/s00347-017-0483-1

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