Reviews and feature article
Filaggrin in atopic dermatitis

https://doi.org/10.1016/j.jaci.2008.08.002Get rights and content

The recent identification of loss-of-function mutations in the structural protein filaggrin as a widely replicated major risk factor for eczema sheds new light on disease mechanisms in eczema, a disease that had heretofore largely been considered to have a primarily immunologic etiopathogenesis. The filaggrin gene (FLG) mutation findings are consistent with a recently proposed unifying hypothesis that offers a mechanistic understanding of eczema pathogenesis synthesizing a heritable epithelial barrier defect and resultant diminished epidermal defense mechanisms to allergens and microbes, followed by polarized TH2 lymphocyte responses with resultant chronic inflammation, including autoimmune mechanisms. Although compelling evidence from genetic studies on FLG implicates perturbed barrier function as a key player in the pathogenesis of eczema in many patients, much is still unknown about the sequence of biologic, physicochemical, and aberrant regulatory events that constitute the transition from an inherited barrier defect to clinical manifestations of inflammatory eczematous lesions and susceptibility to related atopic disorders. The exact contribution of FLG to the wider atopic story, factors modifying FLG expression, and the role of other barrier proteins remain to be delineated. In this review we highlight recent advances in our understanding of the FLG genetics in the cause of eczema and related complex diseases.

Section snippets

FLG expression and function

The giant inactive precursor profilaggrin is a large, complex, highly phosphorylated polypeptide that is the main constituent of the keratohyalin F granules that are visible in the granular cell layer of the epidermis (Fig 1, A). During formation of the cornified cell envelope, profilaggrin is dephosphorylated and proteolytically cleaved by serine proteases, including channel-activating serine protease/Prss and matriptase/matriptase, to release multiple copies of the functional FLG repeat

FLG mutations confer strong genetic susceptibility to eczema

The discovery of the association of FLG mutations with atopic diseases followed insights into a common disorder of keratinization, ichthyosis vulgaris (IV). IV is the most common of the ichthyotic disorders, estimated to affect 1 in 250 individuals, and is characterized by generalized fine white scale, palmoplantar hyperlinearity, and keratosis pilaris. For more than 20 years, much indirect evidence pointed toward mutations in FLG as causative; however, many confounders delayed confirmation of

FLG: Epistatic effects?

Other genetic associations within pathways that modulate filaggrin have been reported, including common maternally derived polymorphisms in the serine protease inhibitor SPINK5 (particularly Glu420Lys) that have been shown to modify the risk of eczema, asthma, and IgE, suggesting that this pathway might lie in altered expression of environmental proteases. Pathologic loss-of-function mutations in SPINK5, as found in patients with Netherton syndrome, are associated with a profound barrier defect

FLG and eczema pathogenesis: Mechanisms and speculations

Although the very strong genetic association of FLG mutations with eczema is now clear, the mechanistic pathways from inherited FLG haploinsufficiency to the typical inflammatory lesions of eczema requires further elucidation. FLG deficiency leads to reduced NMF,23 which is likely a contributor to the xerotic phenotype seen in many patients with eczema. The initiation of the typical inflammatory response is of great interest, and with this in mind, one should remember that around 40% of all

Conclusion

FLG mutations are the strongest and most widely replicated genetic risks for eczema identified to date. They have a clear permissive effect in the early inflammatory effects that characterize eczema and affect both priming of disease and chronicity. The identification of these mutations has enlivened the field of eczema genetics. Their identification raises the potential for targeted intervention and therapy and might lead to a consideration of a new molecular classification of eczema. The

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    Disclosure of potential conflict of interest: W. H. I. McLean has received research support from DEBRA UK and the Medical Research Council. The rest of the authors have declared that they have no conflict of interest.

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