Reviews and feature article
The multifunctional role of filaggrin in allergic skin disease

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Filaggrin is a major structural protein in the stratum corneum of the epidermis. Mutations in the filaggrin gene are the most significant known genetic risk factor for the development of atopic dermatitis. Mutations in the human filaggrin gene (FLG) also confer risk for the associated allergic diseases of food allergy, asthma, and allergic rhinitis. These discoveries have highlighted the importance of skin barrier function in the pathogenesis of atopic diseases and have motivated a surge in research characterizing the filaggrin-deficient skin barrier and its consequences. In this review we discuss the mechanisms through which mutations in this protein contribute to the pathogenesis of atopic dermatitis and associated atopic conditions. We focus on recent human and murine discoveries characterizing the filaggrin-deficient epidermis with respect to biophysical, immunologic, and microbiome abnormalities.

Section snippets

Epidermal structure and function: Role of filaggrin

The epidermis, particularly the outermost stratum corneum (SC) layer, is the first line of defense between the host organism and its environment. Other important innate defense mechanisms of the epidermis are reviewed in detail by Dr Lisa Beck and colleagues in another review in this series. The SC also minimizes water loss from the body and protects against both everyday and extreme environmental insults.7 The SC is the end product of a highly organized differentiation process in which

Filaggrin: Disease associations

In 2006, FLG mutations were shown to be strongly associated with AD in an Irish population and with AD plus asthma in a Scottish population.18 This highly significant association has been replicated in more than 30 independent studies.11 Meta-analyses of these data have estimated the odds ratio (OR) of having AD in association with an FLG-null genotype to be 4.7819 and 3.12.20

FLG-null mutations are seen in less than a third of the total population with AD.18, 21 Among patients with

Filaggrin: Environmental interactions

The prevalence of AD has more than doubled in industrialized countries, with no clear cause.1, 39 Environmental factors are thought to contribute to this increasing prevalence. It has been postulated that the impaired skin barrier seen with FLG might potentiate the effects of environmental allergens.40 Some studies have investigated putative environmental risk factors for atopic disease genotype with regard to FLG status.

Two cohort studies, one from Denmark and the United Kingdom and the other

Characterization of the filaggrin-deficient skin barrier

The barrier integrity phenotype associated with FLG mutations is becoming better understood, with human and murine studies supporting the theory that FLG mutations lead to a functional epidermal barrier defect and subsequent allergic sensitization.

FLG genotype has been shown to be the major determinant of SC NMF in human studies. The SC levels of the filaggrin breakdown products PCA, UCA, and histadine, which are major components of NMF, in epidermal tape strips, strongly correlate with FLG

Mechanistic insights from murine models

Mouse models of filaggrin deficiency have demonstrated barrier impairment with enhanced percutaneous allergen sensitization.51, 52, 53, 54 The spontaneous flaky tail (ft) mouse arose on the background of an existing recessive hair phenotype, matted (ma). Flaky tail mice carry a 1-bp deletional mutation in the murine filaggrin gene (Flg). The relative contribution of Flg and ma to the compound phenotype has yet to be fully defined. Flaky tail mice have spontaneous dermatitis with increased IgE

Filaggrin status and immune dysregulation: A complex interaction

Both innate and adaptive immunity contribute to the immunopathology of AD. Innate responses occur rapidly, are efficient at killing pathogens, and are involved in regulating the magnitude and specific outcomes of the adaptive immune response.56 The cutaneous innate immune system consists of 3 major components: the physical barrier, which includes the SC and intracellular junctions; the cellular component (antigen-presenting cells, keratinocytes, mast cells, and neutrophils); and secretory

Filaggrin deficiency and the microbiome

The skin microbiome, which consists of both commensal and pathogenic bacteria, affects the skin barrier and epithelial innate immune responses. Skin microbes are thought to have a critical role in the development of AD. Patients with AD experience frequent bacterial and viral cutaneous infections. More than 90% of patients with atopic eczema are colonized with S aureus in comparison with 5% of healthy subjects.105 The severity of dermatitis correlates with both colony counts of S aureus

Conclusion

With the discovery of the role of FLG mutations and CNV, inherited SC epithelial barrier integrity is now recognized as a critical factor in the development of AD and subsequent allergic sensitization. This has directed the development of skin barrier–focused therapies. However, the pathomechanisms of AD are complex and include interplay between these and other epidermal structural abnormalities, immunologic dysregulation, and the microbiome. The relative roles of these major players in disease

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  • Cited by (0)

    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, and William T. Shearer, MD, PhD

    Supported by the National Children's Research Centre, Dublin.

    Disclosure of potential conflict of interest: A. D. Irvine has consultant arrangements with Janssen and Galderma, has received grants from the Wellcome Trust and the National Children's Research Centre, has received payment for lectures from Janssen, and has received royalties from Wiley. M. A. McAleer declares no relevant conflicts of interest.

    Terms in boldface and italics are defined in the glossary on page 281.

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