Abnormal skin barrier in the etiopathogenesis of atopic dermatitis.
OBJECTIVE
Many recent studies have revealed the key roles played by Th1/Th2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling in the pathogenesis of atopic dermatitis. Accordingly, current therapy has been largely directed towards ameliorating Th2-mediated inflammation and/or pruritus. We will review here emerging evidence that the inflammation in atopic dermatitis results from inherited and acquired insults to the barrier and the therapeutic implications of this new paradigm.


RESULTS
Recent molecular genetic studies have shown a strong association between mutations in FILAGGRIN and atopic dermatitis, particularly in Northern Europeans. But additional acquired stressors to the barrier are required to initiate inflammation. Sustained hapten access through a defective barrier stimulates a Th1 --> Th2 shift in immunophenotype, which in turn further aggravates the barrier. Secondary Staphylococcus aureus colonization not only amplifies inflammation but also further stresses the barrier in atopic dermatitis.


CONCLUSIONS
These results suggest a new 'outside-to-inside, back to outside' paradigm for the pathogenesis of atopic dermatitis. This new concept is providing impetus for the development of new categories of 'barrier repair' therapy.
Elias
Peter M
PM
Veterans Affairs Medical Center, Department of Dermatology, University of California, San Francisco, 94121, USA. eliasp@derm.ucsf.edu
Schmuth
Matthias
M
D002518:Ceramides / Q000627:therapeutic use; D002784:Cholesterol / Q000627:therapeutic use; D003876:Dermatitis, Atopic / Q000150:complications / Q000453:epidemiology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D004338:Drug Combinations; D005227:Fatty Acids / Q000627:therapeutic use; D000091344:Filaggrin Proteins; D020022:Genetic Predisposition to Disease; D006801:Humans; D007111:Immunity, Cellular; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000276:immunology; D011110:Polymorphism, Genetic; D012867:Skin / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D012868:Skin Abnormalities / Q000150:complications / Q000453:epidemiology / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D013207:Staphylococcal Skin Infections / Q000150:complications / Q000453:epidemiology / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D002518:Ceramides; D004338:Drug Combinations; C539259:EpiCeram; C000717249:FLG protein, human; D005227:Fatty Acids; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D002784:Cholesterol