The role of filaggrin in atopic dermatitis and allergic disease

Drislane, Catherine; Irvine, Alan D.

doi:10.1016/j.anai.2019.10.008

Cited by 211 publications

(202 citation statements)

References 141 publications

(159 reference statements)

Supporting

Mentioning

194

Contrasting

Unclassified

Order By: Relevance

“…Since the identification of FLG LOF mutations as a strong risk factor for AD in Irish population, 6 many replication studies followed revealing large variability in the prevalence and type of FLG mutation across different populations. 6,12,13,24,25 This study reports for the first time low prevalence of FLG mutations in Croatian AD patients, supporting the view of a north-south gradient in the FLG mutation frequency in Europe. In line with these findings, we found no difference in the SC levels of FLG degradation products (NMF) between healthy subjects and nonlesional skin of AD patients.…”

Section: Discussionsupporting

confidence: 78%

“…23 In Northern Europe, R501X and 2282del4 are the most common and make up to 80% of the mutation load. 6,12,13,24,25 About 8-10% of normal Northern Europeans are heterozygous carriers of common FLG mutations. 26 Most genetic association studies in AD were carried out in the Northern Europe population of Caucasian ancestry, reporting frequencies of mutation carriers in AD patients between 17% and 50%, with a population attributable risk of 13.5%.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Filaggrin loss‐of‐function mutations and levels of filaggrin degradation products in adult patients with atopic dermatitis in Croatia

Tončić

Kežić

Jakaša

et al. 2020

Acad Dermatol Venereol

View full text Add to dashboard Cite

Background FLG loss-of-function mutations (FLG LOF) represent the strongest genetic risk factor for atopic dermatitis (AD) and are associated with early-onset and more severe disease. The prevalence of FLG mutations varies greatly across Europe. At present, there are no data on FLG mutation prevalence in Croatian AD patients. Objectives To investigate the prevalence of FLG LOF mutations in adult patients with AD and healthy controls. Next to measure the stratum corneum (SC) levels of filaggrin degradation products (NMF), transepidermal water loss (TEWL) and pH in lesional and non-lesional skin. Methods We recruited 100 AD patients with moderate to severe disease and 50 healthy controls. They were screened for three FLG mutations (R501X, 2282del4 and R2447X). Samples of the SC for NMF analysis were collected by adhesive tapes. TEWL and skin surface pH levels were determined on the lesional and non-lesional skin. Results The combined mutation frequency was 4% in the AD group, and all patients with FLG mutations were homozygous carriers. In the control group, no mutations were found. The most common FLG mutation in AD patients was 2282del4 (3%), followed by R501X (1%). As compared to healthy controls, NMF values were strongly reduced in lesional skin; however, no significant difference was found for non-lesional skin. AD patients had elevated TEWL in both lesional and non-lesional skin. The same pattern was observed for pH. Conclusions Our study expands understanding of the landscape of FLG mutations in the European population. The low frequency of FLG mutations and similar levels of filaggrin degradation products in healthy controls and in non-lesional skin of AD patients suggest that filaggrin deficiency does not confer a major risk for AD in the Croatian population.

show abstract

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Filaggrin loss‐of‐function mutations and levels of filaggrin degradation products in adult patients with atopic dermatitis in Croatia

Tončić

Kežić

Jakaša

et al. 2020

Acad Dermatol Venereol

View full text Add to dashboard Cite

show abstract

“…In Asian populations, FLG P478S and C3321delA variants, not commonly found in European populations, are associated with increased risk of AD. 18 In black children, loss-of-function mutations in FLG2 are associated with increased AD risk. Several novel FLG gene mutations, not commonly seen in European Americans, were recently described in blacks with AD.…”

Section: Flg Deficiency As the Paradigm For Skin Barrier Dysfunctionmentioning

confidence: 99%

Cutaneous barrier dysfunction in allergic diseases

Leung

Berdyshev

Goleva

2020

Journal of Allergy and Clinical Immunology

117

112

View full text Add to dashboard Cite

The fundamental defect(s) that drives atopic dermatitis (AD) remains controversial. ''Outside in'' proponents point to the important association of filaggrin gene mutations and other skin barrier defects with AD. The ''inside out'' proponents derive support from evidence that AD occurs in genetic animal models with overexpression of type 2 immune pathways in their skin, and humans with gain-of-function mutations in their type 2 response develop severe AD. The observation that therapeutic biologics, targeting type 2 immune responses, can reverse AD provides compelling support for the importance of ''inside out'' mechanisms of AD. In this review, we propose a central role for epithelial cell dysfunction that accounts for the dual role of skin barrier defects and immune pathway activation in AD. The complexity of AD has its roots in the dysfunction of the epithelial barrier that allows the penetration of allergens, irritants, and microbes into a cutaneous milieu that facilitates the induction of type 2 immune responses. The AD phenotypes and endotypes that result in chronic skin inflammation and barrier dysfunction are modified by genes, innate/adaptive immune responses, and different environmental factors that cause skin barrier dysfunction. There is also compelling evidence that skin barrier dysfunction can alter the course of childhood asthma, food allergy, and allergic rhinosinusitis. Effective management of AD requires a multipronged approach, not only restoring cutaneous barrier function, microbial flora, and immune homeostasis but also enhancing INFORMATION FOR CATEGORY 1 CME CREDIT Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.

show abstract

“…Filaggrin loss-of-function (LoF) mutations, which impair epidermal tight junctions (TJs), are the most replicated genetic risk factors in developing AD and are associated with the most severe forms of AD. 25 Despite not being detected in the airway epithelium nor the digestive tract, filaggrin is also associated with other allergic diseases including asthma and FA. [25][26][27] Encoded by the FLG gene, the 400-kDa precursor proprotein profilaggrin is proteolytically cleaved to form filaggrin in the stratum corneum, in which it regulates epidermal homeostasis and water retention; 28,29 FLG LoF mutations were found to lower epidermal barrier integrity.…”

Section: Epithelial Barrier Dysfunctionmentioning

confidence: 99%

The origins of allergy from a systems approach

Krempski

Dant

Nadeau

2020

Annals of Allergy, Asthma & Immunology

View full text Add to dashboard Cite

Allergy in its various manifestations is a systems disease consisting of networks among multiple organs. The epithelium plays a central role in allergic disorders, and allergic sensitization occurs through the skin unless tolerance is induced through the gastrointestinal tract. Filaggrin loss-of-function mutations result in impaired epithelial barrier integrity and are substantial genetic risk factors for atopic dermatitis, asthma, allergic rhinitis, and food allergy in children. Dysregulated growth and repair pathways and interplay between airway epithelium asthma gene loci and viral, allergen, or microbial exposure are substantial factors for early-onset asthma development and exacerbation. As a critical sensor of environmental stimuli, the epithelia of the lungs, gut, and skin are affected by an altered microbiome, air pollution, food allergens in a changed diet, and chemicals in modern detergents, all of which account for an increase in the prevalence of allergic diseases. A beneficial diverse microbiome is critical in protecting against allergic diseases, and early oral exposure to food allergens are effective at preventing specific food allergies.

show abstract

The role of filaggrin in atopic dermatitis and allergic disease

Cited by 211 publications

References 141 publications

Filaggrin loss‐of‐function mutations and levels of filaggrin degradation products in adult patients with atopic dermatitis in Croatia

Filaggrin loss‐of‐function mutations and levels of filaggrin degradation products in adult patients with atopic dermatitis in Croatia

Cutaneous barrier dysfunction in allergic diseases

The origins of allergy from a systems approach

Contact Info

Product

Resources

About