Increased loss-of-function filaggrin gene mutation prevalence in atopic dermatitis patients across northern latitudes indicates genetic fitness: A systematic review and meta-analysis.

Loss-of-function (LoF) mutations in the filaggrin gene (FLG) constitute the strongest genetic risk for atopic dermatitis (AD). A latitude-dependent difference in the prevalence of LoF FLG mutations was systematically evaluated. A systematic review and meta-analysis were performed to estimate the prevalence of LoF FLG mutations in AD patients and the general population by geography and ethnicity. Risk of bias was assessed by Newcastle-Ottawa Scale and Jadad score. StatsDirect, version 3 software was used to calculate all outcomes. PubMed and EMBASE were searched until 9th December 2021. Studies were included if they contained data on the prevalence of LoF FLG mutations in AD patients or from the general population or associations between AD and LoF FLG mutations and were authored in English. Overall, 248 studies and 229 310 AD patients and individuals of the general population were included in the quantitative analysis. The prevalence of LoF FLG mutations was 19.1% (95% CI, 17.3-21.0) in AD patients and 5.8% (95% CI, 5.3-6.2) in the general population. There was a significant positive association between AD and LoF FLG mutations in all latitudes in the Northern hemisphere, but not in all ethnicities. The prevalence of LoF FLG mutations became gradually more prevalent in populations residing farther north of the Equator but was negligible in Middle Easterners and absent in most African populations. FLG LoF mutations are common and tend to increase with northern latitude, suggesting potential clinical implications for future AD management. The existence of possible genetic fitness from FLG LoF mutations remains unknown.

Sphingolipid-Enriched Porcine Placental Extract Promotes the Expression of Structural Genes and Desquamation Enzyme Genes in Cultured Human Keratinocytes.

Porcine placental extract (PPE) is commonly used in various health foods and cosmetics. PPE use in cosmetics predominantly consist of the water-soluble fraction derived from the entire placenta. In this report, we examined the effect of the hydrophobic constituents of the PPE, specifically the sphingolipid-enriched fraction designated as the sphingolipid-enriched porcine placental extract (SLPPE), on the expression of genes associated with skin function in cultured normal human epidermal keratinocytes. Using quantitative RT-PCR (qRT-PCR) analysis, we found that SLPPE concentrations ranging from 25 to 100 µg/mL upregulated the gene expression of key components associated with the cornified envelope structure (filaggrin (FLG), involucrin (IVL) and loricrin (LOR)), cornification enzymes (transglutaminase 1 (TGM1) and TGM5) and the desquamation enzymes (kallikrein 5 (KLK5) and KLK7). Additionally, KLK5p and FLG protein (FLGp) were detected in the culture supernatants of keratinocytes treated with SLPPE at these concentrations. These findings suggest that SLPPE is possible to promote the cornification and desquamation in epidermal keratinocytes, and it may offer potential benefits in cosmetics.

Rare Filaggrin Variants Are Associated with Pustular Skin Diseases in Asians.

Reactive pustular eruptions (RPEs) can manifest in a variety of conditions, including pustular psoriasis (PP) and adult-onset immunodeficiency syndrome due to anti-interferon-γ autoantibody (AOID). These RPEs can be attributed to different causes, one of which is genetic factors. However, the genetic basis for pustular skin diseases remains poorly understood. In our study, we conducted whole-exome sequencing on a cohort of 17 AOID patients with pustular reactions (AOID-PR) and 24 PP patients. We found that 76% and 58% of the AOID-PR and PP patients, respectively, carried rare genetic variations within the filaggrin (FLG) gene family. A total of 12 out of 21 SNPs on FLG had previously received clinical classifications, with only p.Ser2706Ter classified as pathogenic. In contrast, none of the FLG3 SNPs identified in this study had prior clinical classifications. Overall, these variations had not been previously documented in cases of pustular disorders, and two of them were entirely novel discoveries. Immunohistochemical analysis of skin biopsies revealed that FLG variants like p.Ser860Trp, p.Gly3903Ter, p.Gly2440Glu, and p.Glu2133Asp caused reductions in FLG levels similar to the pathogenic FLG p.Ser2706Ter. These results highlight rare FLG variants as potential novel genetic risk factors contributing to pustule formation in both AOID and PP.

Are the Head and Tail Domains of Intermediate Filaments Really Unstructured Regions?

Intermediate filaments (IFs) are integral components of the cytoskeleton which provide cells with tissue-specific mechanical properties and are involved in a plethora of cellular processes. Unfortunately, due to their intricate architecture, the 3D structure of the complete molecule of IFs has remained unresolved. Even though most of the rod domain structure has been revealed by means of crystallographic analyses, the flanked head and tail domains are still mostly unknown. Only recently have studies shed light on head or tail domains of IFs, revealing certainsecondary structures and conformational changes during IF assembly. Thus, a deeper understanding of their structure could provide insights into their function.

Atopic Dermatitis: Disease Background and Risk Factors.

Multiple risk factors have been associated with the development of atopic dermatitis (AD). Recent advances in understanding the role of genetics in this disease have been made, with discovery of the filaggrin (FLG) gene as the most notable so far. In addition to FLG gene mutations as a risk factor for AD, a positive family history of atopic or allergic disease in either parent has been shown to confer a greater risk of developing AD. Atopic dermatitis usually presents early in life and is thought to represent the initial step in the "atopic march," which is characterized by the development of other atopic diseases later in life such as asthma, allergic rhinitis, and/or rhinoconjunctivitis, food allergies, and hay fever. Other comorbid diseases that have been associated with AD include increase risk of viral and bacterial skin infections, neuropsychiatric diseases such as attention-deficit hyperactivity disorders (ADHD), and autistic spectrum disorder (ASD). Patients with AD have also been found to have worse sleep quality overall compared to patients without AD. In this chapter, we will discuss the risk factors associated with development of atopic dermatitis as well as the most commonly reported comorbidities in patients with this disease.

(S)-(-)-blebbistatin O-benzoate has the potential to improve atopic dermatitis symptoms in NC/Nga mice by upregulating epidermal barrier function and inhibiting type 2 alarmin cytokine induction.

Atopic dermatitis is a multi-pathogenic disease characterized by chronic skin inflammation and barrier dysfunction. Therefore, improving the skin's ability to form an epidermal barrier and suppressing the production of cytokines that induce type 2 inflammatory responses are important for controlling atopic dermatitis symptoms. (-)-Blebbistatin, a non-muscle myosin II inhibitor, has been suggested to improve pulmonary endothelial barrier function and control inflammation by suppressing immune cell migration; however, its efficacy in atopic dermatitis is unknown. In this study, we investigated whether (S)-(-)-blebbistatin O-benzoate, a derivative of (-)-blebbistatin, improves dermatitis symptoms in a mite antigen-induced atopic dermatitis model using NC/Nga mice. The efficacy of the compound was confirmed using dermatitis scores, ear thickness measurements, serum IgE levels, histological analysis of lesions, and filaggrin expression analysis, which is important for barrier function. (S)-(-)-Blebbistatin O-benzoate treatment significantly reduced the dermatitis score and serum IgE levels compared to those in the vehicle group (p < 0.05). Furthermore, the histological analysis revealed enhanced filaggrin production and a decreased number of mast cells (p < 0.05), indicating that (S)-(-)-blebbistatin O-benzoate improved atopic dermatitis symptoms in a pathological model. In vitro analysis using cultured keratinocytes revealed increased expression of filaggrin, loricrin, involucrin, and ceramide production pathway-related genes, suggesting that (S)-(-)-blebbistatin O-benzoate promotes epidermal barrier formation. Furthermore, the effect of (S)-(-)-blebbistatin O-benzoate on type 2 alarmin cytokines, which are secreted from epidermal cells upon scratching or allergen stimulation and are involved in the pathogenesis of atopic dermatitis, was evaluated using antigens derived from mite feces. The results showed that (S)-(-)-blebbistatin O-benzoate inhibited the upregulation of these cytokines. Based on the above, (S)-(-)-blebbistatin O-benzoate has the potential to be developed as an atopic dermatitis treatment option that controls dermatitis symptoms by suppressing inflammation and improving barrier function by acting on multiple aspects of the pathogenesis of atopic dermatitis.

Keratinocyte-derived small extracellular vesicles supply antigens for CD1a-resticted T cells and promote their type 2 bias in the context of filaggrin insufficiency.

Introduction: Exosome-enriched small extracellular vesicles (sEVs) are nanosized organelles known to participate in long distance communication between cells, including in the skin. Atopic dermatitis (AD) is a chronic inflammatory skin disease for which filaggrin (FLG) gene mutations are the strongest genetic risk factor. Filaggrin insufficiency affects multiple cellular function, but it is unclear if sEV-mediated cellular communication originating from the affected keratinocytes is also altered, and if this influences peptide and lipid antigen presentation to T cells in the skin. Methods: Available mRNA and protein expression datasets from filaggrin-insufficient keratinocytes (shFLG), organotypic models and AD skin were used for gene ontology analysis with FunRich tool. sEVs secreted by shFLG and control shC cells were isolated from conditioned media by differential centrifugation. Mass spectrometry was carried out for lipidomic and proteomic profiling of the cells and sEVs. T cell responses to protein, peptide, CD1a lipid antigens, as well as phospholipase A2-digested or intact sEVs were measured by ELISpot and ELISA. Results: Data analysis revealed extensive remodeling of the sEV compartment in filaggrin insufficient keratinocytes, 3D models and the AD skin. Lipidomic profiles of shFLGsEV showed a reduction in the long chain (LCFAs) and polyunsaturated fatty acids (PUFAs; permissive CD1a ligands) and increased content of the bulky headgroup sphingolipids (non-permissive ligands). This resulted in a reduction of CD1a-mediated interferon-γ T cell responses to the lipids liberated from shFLG-generated sEVs in comparison to those induced by sEVs from control cells, and an increase in interleukin 13 secretion. The altered sEV lipidome reflected a generalized alteration in the cellular lipidome in filaggrin-insufficient cells and the skin of AD patients, resulting from a downregulation of key enzymes implicated in fatty acid elongation and desaturation, i.e., enzymes of the ACSL, ELOVL and FADS family. Discussion: We determined that sEVs constitute a source of antigens suitable for CD1a-mediated presentation to T cells. Lipids enclosed within the sEVs secreted on the background of filaggrin insufficiency contribute to allergic inflammation by reducing type 1 responses and inducing a type 2 bias from CD1a-restricted T cells, thus likely perpetuating allergic inflammation in the skin.

Filaggrin Mutation Status and Prevention of Atopic Dermatitis with Maternal Probiotic Supplementation.

The World Allergy Organization recommends probiotics in the prevention of atopic dermatitis in high-risk populations. Mutations in the filaggrin gene (FLG) result in an increased risk of atopic dermatitis through disruption of the skin keratin layer. This exploratory study investigated whether the preventive effect of maternal probiotics was evident in children with and without FLG mutations. DNA was collected from children (n = 228) from the Probiotic in the Prevention of Allergy among Children in Trondheim (ProPACT) study. Samples were analysed for 3 common FLG mutations (R501X, R2447X, and 2282del4). Overall, 7% of children had heterozygous FLG mutations; each child had only one of the 3 mutations. Mutation status had no association with atopic dermatitis (RR = 1.1; 95% CI 0.5 to 2.3). The risk ratio (RR) for having atopic dermatitis following maternal probiotics was 0.6 (95% CI 0.4 to 0.9) and RR was similar if the child expressed an FLG mutation (RR = 0.6; 95% CI 0.1 to 4.1) or wildtype FLG (RR = 0.6; 95% CI 0.4 to 0.9). The preventive  effect of probiotics for atopic dermatitis was also evident in children without FLG mutation. Larger confirmatory studies are needed.

Filaggrin loss-of-function variants are associated with atopic dermatitis phenotypes in a diverse, early-life prospective cohort.

Loss-of-function (LoF) variants in the filaggrin (FLG) gene are the strongest known genetic risk factor for atopic dermatitis (AD), but the impact of these variants on AD outcomes is poorly understood. We comprehensively identified genetic variants through targeted region sequencing of FLG in children participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort. Twenty FLG LoF variants were identified, including 1 novel variant and 9 variants not previously associated with AD. FLG LoF variants were found in the cohort. Among these children, the presence of 1 or more FLG LoF variants was associated with moderate/severe AD compared with those with mild AD. Children with FLG LoF variants had a higher SCORing for Atopic Dermatitis (SCORAD) and higher likelihood of food allergy within the first 2.5 years of life. LoF variants were associated with higher transepidermal water loss (TEWL) in both lesional and nonlesional skin. Collectively, our study identifies established and potentially novel AD-associated FLG LoF variants and associates FLG LoF variants with higher TEWL in lesional and nonlesional skin.

Early skin inflammatory biomarker is predictive of development and persistence of atopic dermatitis in infants.

BACKGROUND: The Short-Term Topical Application for Prevention of Atopic Dermatitis (STOP AD) study, a randomized, open-label trial evaluating the effect of short-term (from the first 4 postnatal days to age 8 weeks) skin barrier protection using Aveeno Dermexa Fast & Long-Lasting Balm (Johnson & Johnson, New Brunswick, NJ) in infants with a parent with allergic disease, demonstrated decreased cumulative incidence and decreased prevalence of atopic dermatitis (AD) at age 12 months. OBJECTIVE: In the STOP AD study, we aimed to identify skin biomarkers that are associated with risk of development of AD. METHODS: Skin swabs were collected from the cheek and antecubital fossa (AF) at baseline, age 8 weeks, and age 12 months from subsets of study participants from the intervention arm (n = 43 of 119) and control arm (n = 43 of 138) and were analyzed for specific cytokines (CCL27, CXCL2, human ß-defensin-1 [hBD-1], IL-18, IL-8, IL-1α, IL-1 receptor antagonist [IL-1RA], IL-1ß, S100A8/9, and IL-36γ) by ELISA. RESULTS: Higher titers of S100A8/9 at the AF at age 8 weeks in infants with the filaggrin wild-type genotype (FLGwt), but not in those with filaggrin loss-of-function mutation (FLGmut), predicted (1) development of AD in the first year of life (P = .033), (2) presence of AD at ages 6 or 12 months (P = .009 and .035, respectively), (3) persistence of AD between ages 6 and 12 months (P < .001), and (4) development of AD with the emollient intervention. CONCLUSION: Increased titers of S100A8/9 from skin swabs of the AF in high-risk infants at age 8 weeks with FLGwt were predictive of AD development in the first year of life and other AD features. These findings suggest that there are different molecular pathways leading to AD in individuals with FLGmut and in individuals with FLGwt. Early identification of infants who are likely to develop AD will allow more targeted interventions.

Frequent oil baths and skin barrier during infancy in the PreventADALL study.

BACKGROUND: In the general population randomized controlled trial PreventADALL, frequent emollient bath additives from 2 weeks of age did not prevent atopic dermatitis, while the effect on skin barrier function throughout infancy is not established. OBJECTIVES: The primary aim of this exploratory substudy was to assess the effect of mineral-based oil baths on transepidermal water loss (TEWL) and dry skin through infancy, and secondarily to explore if filaggrin (FLG) mutations modified the effect. METHODS: Overall, 2153 infants were included and randomized to either the 'Skin intervention' (SI) group (n = 995) (oil bath 4 times weekly from 2 weeks through 8 months) or 'No skin intervention' (NSI) group (n = 1158), with TEWL measurements at 3, 6 and/or 12 months of age. Information on FLG mutation status was available for 1683 of these infants. Effects of the skin intervention on TEWL and dry skin through infancy were assessed by mixed-effects regression modelling. Background characteristics and protocol adherence were collected from electronic questionnaires, birth records and weekly diaries. RESULTS: The TEWL (95% confidence interval) was on average 0.42 g m-2 h-1 (0.13-0.70, P = 0.004) higher in the SI group compared with the NSI group through the first year of life, with significantly higher levels at 3 months [8.6 (8.3-9.0) vs. 7.6 (7.3-7.9)], but similar at 6 and 12 months. Dry skin was observed significantly more often in the NSI group compared with the SI group at 3 months (59% vs. 51%) and at 6 months of age (63% vs. 53%), while at 12 months of age, the difference was no longer significant. At 3 months, the TEWL of FLG mutation carriers was similar to the TEWL in the SI group. No interaction between SI and FLG mutation was found in the first year of life. CONCLUSIONS: Infants given frequent oil baths from 2 weeks of age had reduced skin barrier function through infancy compared with controls, largely attributed to higher TEWL at 3 months of age, while the skin at 3 and 6 months appeared less dry in infants subjected to the skin intervention.

Atopic dermatitis (AD) affects approximately 20% of children in industrialized countries. AD causes dry, itchy skin and can increase the chance of infections. This study was a substudy of the large Scandinavian PreventADALL trial, including 2394 infants, recruited from the general population between 2014 and 2016. Children in this trial were allocated randomly to receive either a skin intervention, food intervention, combined intervention, or no intervention. Children were examined at 3, 6 and 12 months of age. The examinations involved an investigation of the skin, to evaluate dry skin and skin barrier function by transepidermal water loss (TEWL) in the outer layers of the skin (higher TEWL suggests decreased skin barrier function). The skin intervention consisted of oil baths at least 4 times per week from 2 weeks of age through 8 months of age, and have previously not been shown to prevent AD by 1 and 3 years of age. We aimed to investigate whether frequent oil baths had any effect on TEWL and dry skin. We found that the skin intervention increased TEWL in the first year of life, especially at 3 months of age. Dry skin was less common in the skin intervention groups compared with the groups with no skin intervention. Infants with mutations in the gene coding for a skin barrier protein, called filaggrin, were associated with increased TEWL; however, in the skin intervention group, TEWL was similar among the infants with or without filaggrin mutations. Our findings suggest that oil baths several times per week from early infancy transiently decreases skin barrier function.

Association between polymorphisms and atopic dermatitis susceptibility: A systematic review and meta-analysis.

AIM: Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease that is closely linked to genetic factors. Previous studies have revealed numerous single nucleotide polymorphisms (SNPs) that been related to susceptibility to AD; however, the results are conflicting. Therefore, a meta-analysis was conducted to assess the associations of these polymorphisms and AD risk. MATERIAL AND METHODS: PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure databases were retrieved to identify eligible studies, with selected polymorphisms being reported in a minimum of three separate studies. The Newcastle-Ottawa Scale (NOS) was used to evaluate study quality. Review Manager 5.3 and STATA 14.0 were used to perform the meta-analysis. RESULTS: After screening, 64 studies involving 13 genes (24 SNPs) were selected for inclusion in the meta-analysis. Nine SNPs were positively correlated with AD susceptibility [filaggrin (FLG) R501X, FLG 2282del4, chromosome 11q13.5 rs7927894, interleukin (IL)-17A rs2275913, IL-18 -137 G/C, Toll-like receptor 2 (TLR2) rs5743708, TLR2 A-16934 T, serine protease inhibitor Kazal type-5 (SPINK5) Asn368Ser, interferon-γ (IFN-γ) T874A] and one was negatively associated with AD susceptibility (IL-4 -1098 T/G). The 14 remaining SNPs were not significantly associated with AD susceptibility. CONCLUSIONS: Nine SNPs that may be risk factors and one SNP that may be a protective factor for AD were identified, providing a reference for AD prediction, prevention, and therapy.

Influence of household pet ownership and filaggrin loss-of-function mutations on eczema prevalence in children: A birth cohort study.

BACKGROUND: The association between pet exposure in infancy, early childhood eczema, and FLG mutations remains unclear. METHODS: This was a birth cohort study performed in Tokyo, Japan. The primary outcome was current eczema based on questionnaire responses collected repeatedly from birth to 5 years of age. Generalized estimating equations and generalized linear modeling were used to evaluate the association. RESULTS: Data from 1448 participants were used for analyses. Household dog ownership during gestation, early infancy, and 18 months of age significantly reduced the risk of current eczema. Household cat ownership also reduced the risk of current eczema, albeit without statistical significance. The combined evaluation of children from households with pets, be it cats, dogs or both, the risk of current eczema at 1-5 years of age was lower in those with household pet exposure ownership during gestation (RR = 0.59, 95 % CI 0.45-0.77) and at 6 months (RR = 0.49, 95 % CI 0.36-0.68). , Reduced risks of eczema were also observed at 2-5 (RR = 0.52, 95 % CI 0.37-0.73) and 3-5 years of age (RR = 0.50 95 % CI 0.35-0.74) when the respective household pet ownership were evaluated at 18 months and 3 years of age. These protective associations of reduced risk of eczema were only observed in children without FLG mutations. CONCLUSIONS: Household dog and pet (dog, cat, or both) ownership was protective against early childhood eczema in a birth cohort dataset. This protective association was observed only in children without FLG mutations, which should be confirmed in studies with larger cohorts.

Decreased TET2/5-hmC reduces the integrity of the epidermal barrier via epigenetic dysregulation of filaggrin in psoriatic lesions.

BACKGROUND: TET2 participates in tumor progression and intrinsic immune homeostasis via epigenetic regulation. TET2 has been reported to be involved in maintaining epithelial barrier homeostasis and inflammation. Abnormal epidermal barrier function and TET2 expression have been detected in psoriatic lesions. However, the mechanisms underlying the role of TET2 in psoriasis have not yet been elucidated. OBJECTIVE: To define the role of TET2 in maintaining epithelial barrier homeostasis and the exact epigenetic mechanism in the dysfunction of the epidermal barrier in psoriasis. METHODS: We analyzed human psoriatic skin lesions and datasets from the GEO database, and detected the expression of TET2/5-hmC together with barrier molecules by immunohistochemistry. We constructed epidermal-specific TET2 knockout mice to observe the effect of TET2 deficiency on epidermal barrier function via toluidine blue penetration assay. Further, we analyzed changes in the expression of epidermal barrier molecules by immunofluorescence in TET2-specific knockout mice and psoriatic model mice. RESULTS: We found that decreased expression of TET2/5-hmC correlated with dysregulated barrier molecules in human psoriatic lesions. Epidermal-specific TET2 knockout mice showed elevated transdermal water loss associated with abnormal epidermal barrier molecules. Furthermore, we observed that TET2 knockdown in keratinocytes reduced filaggrin expression via filaggrin promoter methylation. CONCLUSION: Aberrant epidermal TET2 affects the integrity of the epidermal barrier through the epigenetic dysregulation of epidermal barrier molecules, particularly filaggrin. Reduced TET2 expression is a critical factor contributing to an abnormal epidermal barrier in psoriasis.

Infant lung function and early skin barrier impairment in the development of asthma at age 3 years.

BACKGROUND: Largely unexplored, we investigated if lower lung function, impaired skin barrier function by transepidermal water loss (TEWL), eczema, and filaggrin (FLG) mutations in infancy were associated with asthma in early childhood. METHODS: From the factorially designed randomized controlled intervention study PreventADALL, we evaluated 1337/2394 children from all randomization groups with information on asthma at age 3 years, and at age 3 months either lung function, TEWL, eczema, and/or FLG mutations. Lower lung function was defined as the time to peak tidal expiratory flow to expiratory time (tPTEF /tE ) <0.25, and skin barrier impairment as a high TEWL >9.50 g/m2 /h. Eczema was clinically observed, and DNA genotyped for FLG mutations. Asthma was defined as asthma-like symptoms (≥3 episodes of bronchial obstruction) between age 2-3 years as well as a history of doctor-diagnosed asthma and/or asthma medication use. Associations were analyzed in logistic regression models, presented with adjusted ORs (aOR) and 95% confidence intervals (CI). RESULTS: Lower lung function and skin barrier impairment were associated with asthma in general; aOR (95% CI) 5.4 (2.1, 13.7) and 1.6 (1.1, 2.5), while eczema and FLG mutations were associated with asthma in children with atopic dermatitis or allergic sensitization only. Stratifying for sex, the risk of asthma was only increased in boys with lower lung function; aOR (95% CI) 7.7 (2.5, 23.6), and in girls with FLG mutations; aOR (95% CI) 3.5 (1.5, 8.2). CONCLUSION: Lower lung function and impaired skin barrier function in infancy may increase the risk of asthma at age 3 years.

Filaggrin and beyond: New insights into the skin barrier in atopic dermatitis and allergic diseases, from genetics to therapeutic perspectives.

Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide, affecting 20% of children and 5% of adults. One critical component in the pathophysiology of AD is the epidermal skin barrier, with its outermost layer, the stratum corneum (SC), conferring biochemical properties that enable resilience against environmental threats and maintain homeostasis. The skin barrier may be conceptualized as a key facilitator of complex interactions between genetics, host immunity, the cutaneous microbiome, and environmental exposures. The key genetic risk factor for AD development and persistence is a loss-of-function mutation in FLG, with recent advances in genomics focusing on rare variant discovery, establishment of pathogenic mechanisms, and exploration of the role of other epidermal differentiation complex gene variants in AD. Aberrant type 2 inflammatory responses down-regulate the transcription of key epidermal barrier genes, alter the composition of SC lipids, and induce further injury through a neurocutaneous feedback loop and the itch-scratch cycle. The dysbiotic epidermis exhibits reduced bacterial diversity and enhanced colonization with Staphylococcus and Malassezia species, which contribute to both direct barrier injury through the action of bacterial toxins and perpetuation of the inflammatory cascades. Enhanced understanding of each of the pathogenic mechanisms underpinning barrier disruption has led to the development of novel topical and systemic molecules, including interleukin (IL)-4Ra, IL-13, PDE4, and Janus-associated kinase inhibitors, whose clinical effectiveness exceeds conventional treatment modalities. In this narrative review, we aim to summarize the current understanding of the above-mentioned pathophysiological and therapeutic mechanisms, with a focus on the genetic, cellular, and molecular mechanisms underpinning AD development.

Inflammation-related proteins in blood after dermal exposure to some common chemicals depend on the skin barrier gene filaggrin - a human experimental study.

Filaggrin (FLG), a skin barrier protein, is associated with higher dermal uptake of some chemicals in carriers of loss-of-function (null) mutations. This study investigates FLG mutations and systemic effects following dermal exposure to chemicals. Individuals (n = 23 FLG null, n = 31 FLG wt) were simultaneously exposed to pyrimethanil, pyrene, oxybenzone, and nickel ions for 4 h. Pre- and post-exposure, 25-hydroxyvitamin D3 (25(OH)D3, LC-MS/MS) and 92 inflammation-related proteins (proximity-extension assay) were measured. FLG null carriers exhibited significantly higher 25(OH)D3 concentrations than wt carriers, both pre- and post-exposure. Eleven proteins differed in abundance post- vs pre-exposure among FLG null carriers, and 22 proteins among wt carriers (three proteins overlapped). Twelve proteins showed median differences (post- vs pre-exposure) between FLG null and wt carriers. Overall, FLG null carriers showed an increase, while FLG wt carriers showed a decrease in inflammation-related proteins. These findings suggest FLG-dependent differences in susceptibility to systemic effects following simultaneous dermal chemical exposure.

Identification of eczema clusters and their association with filaggrin and atopic comorbidities: analysis of five birth cohorts.

BACKGROUND: Longitudinal modelling of the presence/absence of current eczema through childhood has identified similar phenotypes, but their characteristics often differ between studies. OBJECTIVES: To demonstrate that a more comprehensive description of longitudinal pattern of symptoms may better describe trajectories than binary information on eczema presence. METHODS: We derived six multidimensional variables of eczema spells from birth to 18 years of age (including duration, temporal sequencing and the extent of persistence/recurrence). Spells were defined as consecutive observations of eczema separated by no eczema across 5 epochs in five birth cohorts: infancy (first year); early childhood (age 2-3 years); preschool/early school age (4-5 years); middle childhood (8-10 years); adolescence (14-18 years). We applied Partitioning Around Medoids clustering on these variables to derive clusters of the temporal patterns of eczema. We then investigated the stability of the clusters, within-cluster homogeneity and associated risk factors, including FLG mutations. RESULTS: Analysis of 7464 participants with complete data identified five clusters: (i) no eczema (51.0%); (ii) early transient eczema (21.6%); (iii) late-onset eczema (LOE; 8.1%); (iv) intermittent eczema (INT; 7.5%); and (v) persistent eczema (PE; 11.8%). There was very-high agreement between the assignment of individual children into clusters when using complete or imputed (n = 15 848) data (adjusted Rand index = 0.99; i.e. the clusters were very stable). Within-individual symptom patterns across clusters confirmed within-cluster homogeneity, with consistent patterns of symptoms among participants within each cluster and no overlap between the clusters. Clusters were characterized by differences in associations with risk factors (e.g. parental eczema was associated with all clusters apart from LOE; sensitization to inhalant allergens was associated with all clusters, with the highest risk in the PE cluster). All clusters apart from LOE were associated with FLG mutations. Of note, the strongest association was for PE [relative risk ratio (RRR) 2.70, 95% confidence interval (CI) 2.24-3.26; P < 0.001] followed by INT (RRR 2.29, 95% CI 1.82-2.88; P < 0.001). CONCLUSIONS: Clustering of multidimensional variables identified stable clusters with different genetic architectures. Using multidimensional variables may capture eczema development and derive stable and internally homogeneous clusters. However, deriving homogeneous symptom clusters does not necessarily mean that these are underpinned by completely unique mechanisms.