Skin barrier compromise is a defining characteristic of atopic dermatitis (AD). Research has uncovered several possible explanations for this barrier disruption including lipid and structural defects in the stratum corneum (SC), mutations of the filaggrin gene, and various genetic or acquired abnormalities of proteases and their inhibitors. Scratching irritated skin doesn’t help, either. Part and parcel with this is a persistent, inflammatory Th2-dominant microenvironment. In this month’s issue, De Benedetto et al. (J Allergy Clin Immunol 2011; 127:773-786.e7), for the NIH/NIAID/Atopic Dermatis and Vaccinia Network, report novel evidence that the barrier dysfunction doesn’t stop at the SC.
De Benedetto et al. provide the first evidence that strongly implicates abnormalities of tight junctions (TJs) found in the stratum granulosum in AD patients. They find that claudin-1, a critical component of TJ is significantly reduced in nonlesional epidermis from AD patients. This finding was specific to AD as skin biopsies from psoriasis patients had levels of claudin-1 equal to that of nonatopic, healthy controls. Additionally, nonlesional AD epidermis has increased permeability and decreased trans-epithelial electrical resistance (TEER). Clinically, decreased claudin-1 production was strongly associated with increased total serum IgE and total Eosinophil count in AD patients, as well.
In vitro claudin-1 knockdown caused increased TJ permeability and decreased TEER without affecting other structural components of TJ or the SC, suggesting that claudin-1 is required for a competent epidermal TJ barrier. Further, claudin-1 knockdown caused increased keratinocyte proliferation. De Benedetto et al. speculate that the hyper-proliferation effect of claudin-1 depletion may account for increased epithelial thickness observed even in nonlesional AD skin. Findings that claudin-1 knockdown increased small- and large-pore permeability leads the authors to suggest that AD skin may be more easily breached by allergens, irritants, nanoparticles and microbial products or enable the dendritic processes of antigen presenting cells to sample these products on the skin surface.
In a twist, they find that Th2 cytokines enhance TJ function and increase claudin-1 expression in differentiated keratinocyte monolayers, leading the authors to conclude that impaired claudin-1 expression and TJ dysfunction are not likely the result of Th2 cytokine dominance in AD. In fact they suggest that the TJ defects may be promoting a Th2 immune response that is a response designed to minimize reactions to environmental allergens.
De Benedetto et al. also report on gene association studies in two populations, African Americans (EA) and European Americans (EA). Significant associations were found between CLDN1 gene SNPs and AD or disease severity in both AA and EA.
The authors conclude that barrier compromise in AD involves the secondary skin barrier as well as the stratum corneum and that correlation of serum IgE and total Eosinophil count and claudin-1 expression demonstrates that this deficiency promotes Th2 responses as well.
We asked lead author Anna De Benedetto for more about the implications of this study:
JACI: How do you reconcile the relative importance of claudin defects in comparison with the other defects in barrier function that have now been reported?
Dr. De Benedetto: Our work demonstrating that subjects with atopic dermatitis have a tight junction (TJ) defect complements studies that have reported a number of stratum corneum (SC) defects including altered lipid composition, dysregulated EDC genes, altered protease/antiprotease activity and simply trauma from scratching. We think it is no coincidence that the skin epidermis, which must endure significant environmental exposures, has two formidable barrier structures, namely the SC and TJ. Once the SC is compromised the TJ located just below provide a second line of defense. We believe that immunological responsiveness to environmental insults requires a breach in both structures and that this occurs in subjects with AD. We hope our work will spawn further studies to address the interaction between these two barrier structures and address treatment strategies that would improve either TJ or SC function. If our hypothesis that immunologic responses require a hit to both SC and TJ it may be possible that enhancing the function of one of these barrier structures would be an effective strategy.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
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