Reviews and feature articleThe multifunctional role of filaggrin in allergic skin disease
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.