What is epidermal barrier dysfunction hypothesis of the pathogenesis of atopic dermatitis (eczema)?

Updated: Mar 13, 2019
  • Author: Brian S Kim, MD, MTR, FAAD; Chief Editor: William D James, MD  more...
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Answer

The epidermal barrier dysfunction hypothesis suggests that AD patients develop AD as a result of skin barrier defects that allow for the entry of antigens, resulting in the production of inflammatory cytokines. Some authors question whether such antigens can also be absorbed from the gut (eg, from food) and/or the lungs (eg, from house dust mites). Xerosis and ichthyosis are known to be associated signs in many AD patients. Clinically, 37-50% of people with ichthyosis vulgaris have atopic disease and up to 37% of people with AD have clinical evidence of ichthyosis vulgaris. Mutations in the gene encoding filaggrin, a key epidermal barrier protein, cause ichthyosis vulgaris and are the strongest known genetic risk factors for the development of AD. [20, 21]  

Further, filaggrin mutations are associated with early-onset AD and with airway disease in the setting of AD. [22] One mechanism by which filaggrin defects may influence inflammation is by the release of epithelial cell‒derived cytokines, including TSLP, IL-25, and IL-33, which are all known to be up-regulated in the context of AD. [23, 24, 25, 26] TSLP has been shown to be a potent promoter of basophil and ILC2 responses in the skin, while IL-25 and IL-33 preferentially elicit ILC2s. [12, 13, 16] Although filaggrin is strongly linked to AD, mutations are only found in 30% of European patients, begging the question of whether other genetic variants may also be responsible for some of the findings in the pathogenesis of AD. Indeed, genetic variants of TSLP have been shown to interact with mutations in filaggrin to influence AD disease persistence in patients. [27]

In AD, transepidermal water loss is increased. Whether the primary immune dysregulation causes secondary epithelial barrier breakdown or primary epithelial barrier breakdown causes secondary immune dysregulation that results in disease remains unknown. However, given the fact that filaggrin is critical for epithelial integrity, it is now thought that loss of filaggrin function leads to increased transepidermal penetration of environmental allergens, increasing inflammation and sensitivity and potentially leading to the atopic march. [28]


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