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.

Emollient application from birth to prevent eczema in high-risk children: the BEEP RCT.

Background: Atopic eczema is a common childhood skin problem linked with asthma, food allergy and allergic rhinitis that impairs quality of life. Objectives: To determine whether advising parents to apply daily emollients in the first year can prevent eczema and/or other atopic diseases in high-risk children. Design: A United Kingdom, multicentre, pragmatic, two-arm, parallel-group randomised controlled prevention trial with follow-up to 5 years. Setting: Twelve secondary and four primary care centres. Participants: Healthy infants (at least 37 weeks' gestation) at high risk of developing eczema, screened and consented during the third trimester or post delivery. Interventions: Infants were randomised (1 : 1) within 21 days of birth to apply emollient (Doublebase Gel®; Dermal Laboratories Ltd, Hitchin, UK or Diprobase Cream®) daily to the whole body (excluding scalp) for the first year, plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). Families were not blinded to allocation. Main outcome measures: Primary outcome was eczema diagnosis in the last year at age 2 years, as defined by the UK Working Party refinement of the Hanifin and Rajka diagnostic criteria, assessed by research nurses blinded to allocation. Secondary outcomes up to age 2 years included other eczema definitions, time to onset and severity of eczema, allergic rhinitis, wheezing, allergic sensitisation, food allergy, safety (skin infections and slippages) and cost-effectiveness. Results: One thousand three hundred and ninety-four newborns were randomised between November 2014 and November 2016; 693 emollient and 701 control. Adherence in the emollient group was 88% (466/532), 82% (427/519) and 74% (375/506) at 3, 6 and 12 months. At 2 years, eczema was present in 139/598 (23%) in the emollient group and 150/612 (25%) in controls (adjusted relative risk 0.95, 95% confidence interval 0.78 to 1.16; p = 0.61 and adjusted risk difference -1.2%, 95% confidence interval -5.9% to 3.6%). Other eczema definitions supported the primary analysis. Food allergy (milk, egg, peanut) was present in 41/547 (7.5%) in the emollient group versus 29/568 (5.1%) in controls (adjusted relative risk 1.47, 95% confidence interval 0.93 to 2.33). Mean number of skin infections per child in the first year was 0.23 (standard deviation 0.68) in the emollient group versus 0.15 (standard deviation 0.46) in controls; adjusted incidence rate ratio 1.55, 95% confidence interval 1.15 to 2.09. The adjusted incremental cost per percentage decrease in risk of eczema at 2 years was £5337 (£7281 unadjusted). No difference between the groups in eczema or other atopic diseases was observed during follow-up to age 5 years via parental questionnaires. Limitations: Two emollient types were used which could have had different effects. The median time for starting emollients was 11 days after birth. Some contamination occurred in the control group (< 20%). Participating families were unblinded and reported on some outcomes. Conclusions: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children. Emollient use was associated with a higher risk of skin infections and a possible increase in food allergy. Emollient use is unlikely to be considered cost-effective in this context. Future research: To pool similar studies in an individual patient data meta-analysis. Trial registration: This trial is registered as ISRCTN21528841. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/67/12) and is published in full in Health Technology Assessment; Vol. 28, No. 29. See the NIHR Funding and Awards website for further award information.

Eczema is a troublesome itchy skin condition affecting 1 in 5 children and 1 in 10 UK adults. There is no cure and affected children are more likely to develop food allergies. We wanted to see if we could prevent eczema by protecting the skin of babies at higher risk of developing eczema (with an immediate relative with eczema, asthma or hay fever) with moisturisers used to treat dry skin. Previous research suggested that protecting the skin barrier might also prevent food allergy. One thousand three hundred and ninety-four families took part in a study; half of them were asked to apply moisturiser every day to their newborn baby for the first year and half to look after their baby's skin in the normal way. At the age of 2 years, we did not see any difference in how common eczema was between the two groups: 23% had eczema in the moisturiser group and 25% in the normal care group. It did not matter how we defined eczema ­ whether examined by a researcher or parent report. We did not find any differences in related conditions like asthma or hay fever either. We found that children using moisturisers had seen their doctor slightly more often for mild skin infections. There was a hint that food allergy might have been increased in the moisturiser group, but there was not enough data to be sure. We followed up the children to age 5 years, but we still did not find any benefits from using moisturisers in early life. Since this study, other similar research has been done using newer types of moisturisers, but their results are the same. This study shows that using daily moisturisers on healthy babies with a high risk of eczema does not prevent eczema. It is one less thing for busy families to worry about.

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.

Skin colonization by Staphylococcus aureus in hemodialysis patients with pruritus and the effect of Staphylococcus aureus-secreted α-toxin on filaggrin expression.

Staphylococcus aureus (S. aureus) commonly reside on human skin in residents in long-term care facilities, yet its colonization and impact on the skin of hemodialysis (HD) patients have yet to be studied. The aim of the present study was to investigate the colonization of S. aureus on the skin of pruritic and non-pruritic HD patients, and the influence of S. aureus and S. aureus-secreted α-toxin on skin barrier function-related protein expression. In this study, a higher relative S. aureus count in pruritic HD patients compared to non-pruritic HD patients and healthy subjects were revealed by real-time polymerase chain reaction. S. aureus and α-toxin decreased mRNA and protein expression levels of aryl hydrocarbon receptor (AHR), ovo-like transcriptional repressor 1 (OVOL1), and filaggrin (FLG) in keratinocytes. In addition, anti-alpha-hemolysin (anti-hla) was used as an α-toxin neutralizer, and it successfully abrogated S. aureus-induced AHR, OVOL1, and FLG mRNA and protein expression downregulation. Mechanistically, α-toxin could decrease FLG activity by preventing the recruitment of AHR to the FLG promoter region. In conclusion, pruritic HD patients had higher S. aureus colonization, with S. aureus-secreted α-toxin suppressing FLG expression through the AHR-FLG axis.

Ethnic and Racial Disparities in Clinical Manifestations of Atopic Dermatitis.

Atopic dermatitis is a heterogenous inflammatory skin illness that may last for long time and affect people of different racial and ethnic backgrounds. The condition primarily appears in infants and young children. There are people living with atopic dermatitis in every country and every ethnic group, although the frequency of the disease varies greatly. Due to the varied clinical presentations that atopic dermatitis can have, it can be challenging to characterize and diagnose the disease, particularly in adults. Nevertheless, there exists a dearth of information pertaining to the various presentations of atopic dermatitis among individuals from diverse racial and cultural groups. This critical review article offers a succinct and comprehensive overview of the current findings on the epidemiology of atopic dermatitis with regards to ethnic and racial disparities. The findings hold potential significance in advancing the development of targeted treatments for personalized medicine approaches and enhancing the quality of life for patients with atopy.

Evaluation of OVOL1 and Filaggrin immunohistochemical expression and clinical relevance in psoriasis.

BACKGROUND: Psoriasis is a disease of overactive immune system. OVOL1 and Filaggrin have been associated with many inflammatory skin lesions. To the best of our knowledge, the correlation between OVOL1 and Filaggrin in psoriasis was not previously investigated. This work aims to search the immunohistochemical expression and correlation between OVOL1 and Filaggrin in psoriasis. MATERIALS AND METHODS: Slides cut from paraffin blocks of 30 psoriasis cases and 30 control subjects were stained with OVOL1 and Filaggrin. Clinicopathological data were correlated with the results of staining. RESULTS: OVOL1 and Filaggrin expression in epidermis showed a significant gradual reduction from normal skin to peri-lesional and psoriasis biopsies (P < 0.001). In contrast, psoriasis dermis showed a significant overexpression of OVOL1 in inflammatory cells in relation to peri-lesional biopsies (P < 0.002). OVOL1 demonstrated a significant direct correlation with Filaggrin expression in psoriasis (r = 0.568, P < 0.004). OVOL1 and Filaggrin expression in psoriasis skin epidermis demonstrated a statistically significant negative correlation with PASI score. CONCLUSION: OVOL1 and Filaggrin might be involved in psoriasis-associated inflammation and skin hyperproliferation. OVOL1 might have a protective barrier function in the skin and could be used to stratify progressive disease. Filaggrin may play a role in progression of psoriasis. OVOL1 inhibition could be considered in suppression of Filaggrin function. OVOL1 agonists may be beneficial in psoriasis treatment.

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.

Stressors in Atopic Dermatitis.

As with other inflammatory skin disorders, atopic dermatitis has a tendency to cause stress and also be exacerbated by it. Patients with atopic dermatitis have several disease-associated stressors, some of which include physical discomfort due to itching and altered appearance due to flare-ups. These stressors have been shown to effect patients psychosocially by altering sleep patterns, decreasing self-esteem, and interfering with interpersonal relationships. In combination with its direct effect on patients, atopic dermatitis also causes stress for parents and caregivers. Studies suggest that atopic dermatitis is strongly correlated with co-sleeping habits, which can negatively impact the health and mood of parents or caregivers. It has also been reported to interfere with the formation of a strong mother-child relationship. In order to optimize treatment for patients with atopic dermatitis, it is important to note the impact that it has on quality of life. By implementing patient counseling, sleep-targeted therapies, and the use of quality of life (QoL) indices, atopic dermatitis patients and caregivers have the potential to experience greater satisfaction with treatment.

A Novel Recombinant Human Filaggrin Segment (rhFLA-10) Alleviated a Skin Lesion of Atopic Dermatitis.

Atopic dermatitis (AD), a prevalent chronic inflammatory skin disorder, is marked by impaired skin barrier function and persistent pruritus. It significantly deteriorates patients' quality of life, making it one of the most burdensome non-lethal skin disorders. Filaggrin plays a crucial role in the pathophysiology of barrier disruption in AD, interacting with inflammatory mediators. It is an integral part of the extracellular matrix architecture, serving to protect the skin barrier and attenuate the inflammatory cascade. In this study, we engineered a novel recombinant human filaggrin (rhFLA-10) expression vector, which was subsequently synthesized and purified. In vitro and ex vivo efficacy experiments were conducted for AD. rhFLA-10, at low concentrations (5 to 20 µg/mL), was non-toxic to HACaT cells, significantly inhibited the degranulation of P815 mast cells, and was readily absorbed by cells, thereby exerting a soothing therapeutic effect. Furthermore, rhFLA-10 demonstrated anti-inflammatory properties (p < 0.05). In vivo, efficacy experiments further substantiated that rhFLA-10 could effectively ameliorate AD in mice and facilitate the repair of damaged skin (p < 0.001). These findings underscore the considerable potential of rhFLA-10 in the treatment of AD.

The stratum corneum barrier: impaired function in relation to associated lipids and proteins.

The skin is the largest organ of the human body and is widely considered to be the first-line defense of the body, providing essential protection against mechanical, physical, and chemical damage. Keratinocytes are the primary cells of the outer layer of the epidermis, which acts as a mechanical and permeability barrier. The epidermis is a permanently renewed tissue where undifferentiated keratinocytes located at the basal layer proliferate and migrate to the overlying layers. Here we report that some components of keratinocytes affect the formation and differentiation of the stratum corneum, which is the most specialized layer of the epidermis.

Atopic Dermatitis Disease Complications.

This chapter will describe infectious complications of atopic dermatitis, including bacterial, viral, and fungal infections and the evolving understanding of the relationship between atopic dermatitis and infectious disease. The underlying immunological dysregulation and poor skin barrier function associated with atopic dermatitis not only increase the likelihood of infectious complications but also lend atopic dermatitis skin vulnerable to flares induced by environmental triggers. Thus, this chapter will also highlight the impact of common external environmental agents on precipitating flares of disease. Lastly, this chapter will discuss complications that can arise from treatments and the association of atopic dermatitis with more serious conditions such as lymphoma.

Immunolabeling for filaggrin and acidic keratins in the granular layer of mammalian epidermis indicates that an acidic-basic interaction is involved in cornification.

The soft epidermis of mammals derives from the accumulation of keratohyaline granules in the granular layer, before maturing into corneocytes. Main proteins accumulated in the granular layer are pro-filaggrin and filaggrin that determine keratin clumping and later moisturization of the stratum corneum that remains flexible. This soft epidermis allows the high sensitivity of mammalian skin. Presence and thickness of the stratum granulosum varies among different species of mammals and even between different body regions of the same animal, from discontinuous to multilayered. These variations are evident using antibodies for filaggrin, a large protein that share common epitopes among placentals. Here we have utilized filaggrin antibodies (8959 and 466) and an acidic keratin antibody (AK2) for labeling placental, marsupial and monotreme epidermis. AK2 labeling appears mainly to detect K24 keratin, and less likely other acidic keratins. Immunoreactivity for filaggrin is absent in platypus, discontinuous in Echidna and in the tested marsupials. In placentals, it is inconstantly or hardly detected in the thin epidermis of bat, rodents, and lagomorphs with a narrow, mono-stratified and/or discontinuous granular layer. In contrast, where the granular layer is continuous or even stratified, both filaggrin and AK2 antibodies decorate granular cells. The ultrastructural analysis using the AK2 antibody on human epidermis reveals that a weak labeling is associated with keratohyalin granules and filamentous keratins of transitional keratinocytes and corneocytes. This observation suggests that basophilic filaggrin interacts with acidic keratins like K24 and determines keratin condensation into corneocytes of the stratum corneum.

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.

In vitro generation of epidermal keratinocytes from human CD34-positive hematopoietic stem cells.

The epidermis is largely composed of keratinocytes (KCs), and the proliferation and differentiation of KCs from the stratum basale to the stratum corneum is the cellular hierarchy present in the epidermis. In this study, we explore the differentiation abilities of human hematopoietic stem cells (HSCs) into KCs. Cultured HSCs positive for CD34, CD45, and CD133 with prominent telomerase activity were induced with keratinocyte differentiation medium (KDM), which is composed of bovine pituitary extract (BPE), epidermal growth factor (EGF), insulin, hydrocortisone, epinephrine, transferrin, calcium chloride (CaCl2), bone morphogenetic protein 4 (BMP4), and retinoic acid (RA). Differentiation was monitored through the expression of cytokeratin markers K5 (keratin 5), K14 (keratin 14), K10 (keratin 10), K1 (keratin 1), transglutaminase 1 (TGM1), involucrin (IVL), and filaggrin (FLG) on day 0 (D0), day 6 (D6), day 11 (D11), day 18 (D18), day 24 (D24), and day 30 (D30) using immunocytochemistry, fluorescence microscopy, flow cytometry, qPCR, and Western blotting. The results revealed the expression of K5 and K14 genes in D6 cells (early keratinocytes), K10 and K1 genes in D11-D18 cells (mature keratinocytes) with active telomerase enzyme, and FLG, IVL, and TGM1 in D18-D24 cells (terminal keratinocytes), and by D30, the KCs were completely enucleated similar to cornified matrix. This method of differentiation of HSCs to KCs explains the cellular order exists in the normal epidermis and opens the possibility of exploring the use of human HSCs in the epidermal differentiation.

Unraveling the skin; a comprehensive review of atopic dermatitis, current understanding, and approaches.

Atopic dermatitis, also known as atopic eczema, is a chronic inflammatory skin disease characterized by red pruritic skin lesions, xerosis, ichthyosis, and skin pain. Among the social impacts of atopic dermatitis are difficulties and detachment in relationships and social stigmatization. Additionally, atopic dermatitis is known to cause sleep disturbance, anxiety, hyperactivity, and depression. Although the pathological process behind atopic dermatitis is not fully known, it appears to be a combination of epidermal barrier dysfunction and immune dysregulation. Skin is the largest organ of the human body which acts as a mechanical barrier to toxins and UV light and a natural barrier against water loss. Both functions face significant challenges due to atopic dermatitis. The list of factors that can potentially trigger or contribute to atopic dermatitis is extensive, ranging from genetic factors, family history, dietary choices, immune triggers, and environmental factors. Consequently, prevention, early clinical diagnosis, and effective treatment may be the only resolutions to combat this burdensome disease. Ensuring safe and targeted drug delivery to the skin layers, without reaching the systemic circulation is a promising option raised by nano-delivery systems in dermatology. In this review, we explored the current understanding and approaches of atopic dermatitis and outlined a range of the most recent therapeutics and dosage forms brought by nanotechnology. This review was conducted using PubMed, Google Scholar, and ScienceDirect databases.

Adenosine A2B receptor agonist improves epidermal barrier integrity in a murine model of epidermal hyperplasia.

Adenosine regulates multiple physiological processes through the activation of four receptor subtypes, of which the A2B adenosine receptor (A2BAR) has the lowest affinity for adenosine. Being the adenosine receptor subtype most prominently expressed in epidermis, we recently described the antiproliferative and anti-inflammatory effect of the selective A2BAR agonist BAY60-6583 (BAY) in human keratinocytes stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA), so we sought to establish the effect of topical application of BAY in a model of murine epidermal hyperplasia. Topical application of BAY (1 or 10 µg/site) prevented the inflammatory reaction and skin lesions induced by TPA, minimizing hyperproliferation and acanthosis, as well as the expression of specific markers of proliferative keratinocytes. On the other hand, pre-treatment with the selective A2BAR antagonist, PSB-1115 (PSB, 5 or 50 µg/site) reversed these beneficial effects. Additionally, BAY application normalized the expression of epidermal barrier proteins, whose integrity is altered in inflammatory skin diseases, while treatment with the antagonist alone worsened it. Our results, besides confirming the anti-inflammatory and antiproliferative effects of the A2BAR agonist, further demonstrate a role of A2BAR activation to preserve the epidermal barrier. Therefore, the activation of A2BAR may constitute a possible new pharmacological target for the treatment of skin inflammatory diseases such as psoriasis.

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.

Studies Using Antibodies against Filaggrin and Filaggrin 2 in Canine Normal and Atopic Skin Biopsies.

Filaggrin is important for the skin barrier and atopic dermatitis. Another filaggrin-like protein, filaggrin 2, has been described. We evaluated antibodies against both filaggrins in normal and atopic skin biopsies from dogs before and after allergen challenges (D0, D1, D3 and D10). Filaggrins expression was evaluated by immunohistochemistry and Western blot. We used PCR to investigate changes in filaggrin gene expression. Effects of group (p = 0.0134) and time (p = 0.0422) were shown for the intensity of filaggrin staining. Only an effect of group was found for filaggrin 2 (p = 0.0129). Atopic samples had higher intensity of staining than normal dogs [filaggrin on D3 (p = 0.0155) and filaggrin 2 on D3 (p = 0.0038) and D10 (p < 0.0001)]. Atopic samples showed increased epidermal thickness after allergen exposure (D3 vs. D0, p = 0.005), while normal dogs did not. In atopic samples, significant increased gene expression was found for filaggrin overtime but not for filaggrin 2. Western blot showed an increase in filaggrin 2 on D3. A small size band (15 kD) containing a filaggrin sequence was found in Western blots of atopic samples only. We conclude that atopic skin reacts to allergen exposure by proliferating and increasing filaggrin production but that it also has more extensive filaggrin degradation compared to normal skin.

Aspirin-exacerbated respiratory disease is associated with variants in filaggrin, epithelial integrity, and cellular interactions.

Background: Previous studies have determined that up to 6% of patients with aspirin-exacerbated respiratory disease (AERD) have family history of AERD, indicating a possible link with genetic polymorphisms. However, whole exome sequencing (WES) studies of such associations are currently lacking. Objectives: We sought to examine whether WES can identify pathogenic variants associated with AERD. Methods: Diagnoses of AERD were confirmed in patients with nasal polyps and asthma. WES was performed using an Illumina sequencing platform. Human Phenotype Ontology terms were used to define the patients' phenotypes. Exomiser was used to annotate, filter, and prioritize possible disease-causing genetic variants. Results: Of 39 patients with AERD, 41% reported a family history of asthma and 5% reported a family history of AERD. Pathogenic exome variants in the filaggrin gene (FLG) were found in 2 patients (5%). Other variants not known to be pathogenic were detected in an additional 16 patients (41%) in genes related to epithelial integrity and cellular interactions, including genes encoding desmoglein 3 (DSG3), dynein axonemal heavy chain 9 (DNAH9), collagen type VII alpha 1 chain (COL7A1), collagen type XVII alpha 1 chain (COL17A1), chromodomain helicase DNA binding protein-7 (CHD7), TSC complex subunit 2/tuberous sclerosis-2 protein (TSC2), P-selectin (SELP), and platelet-derived growth factor receptor-alpha (PDGFRA). Conclusion: WES identified a monogenic susceptibility to AERD in 5% of patients with FLG pathogenic variants. Other variants not previously identified as pathogenic were found in genes relevant to epithelial integrity and cellular interactions and may further reveal genetic factors that contribute to this condition.

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.