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Patient assessment
Published in Michael Parker, Charlie James, Fundamentals for Cosmetic Practice, 2022
Filaggrin is a fascinating protein, which not only helps in regulating homeostasis and terminal differentiation of corneocytes but also aids in barrier formation, helps retain water within the epidermis and helps maintain a normal skin pH. Should filaggrin not function correctly, then the normal protective epidermal barrier can become inflamed and break down due to either a direct failure of the barrier itself or through the effects of pH imbalance or dehydration. The resultant inflammation it itchy, and this almost inevitably results in further barrier degradation due to patients inadvertently scratching afflicted areas. Breaks in the skin barrier expose the more delicate deep epidermis and dermis to irritants and opportunistic microbes, further potentiating the inflammatory response. It is hypothesised that allergens which manage to penetrate the damaged skin barrier can trigger an immunoglobulin E (IgE)–mediated allergic response, not only potentiating the localised inflammation but also propelling the development of other atopic sequelae such as asthma and hay fever.
Food allergies and eosinophilic gastrointestinal diseases
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Cathryn Nagler, Glenn T. Furuta
The heritability of the predisposition to allergic disease suggests a genetic basis, but susceptibility genes for food allergy are as yet largely unidentified. Common (atopy) and unique (food allergy) genetic risk factors may contribute to allergic responses to food. Genome-wide association studies have identified intriguing candidates that may provide new insight into disease pathogenesis, particularly for EoE. The first genome-wide association study for EoE showed that eotaxin-3, a prominent eosinophil-recruiting chemokine, was the most upregulated gene in the esophageal epithelia of children with EoE. Further work has identified an epithelial cluster of EoE-associated genes, including filaggrin, an epidermal barrier protective protein. Loss-of-function variants in filaggrin are associated with atopic dermatitis in some patients. This finding is particularly relevant to EoE, since the esophagus (like the skin) is lined by squamous epithelium. If epithelial barrier function is impaired, as may occur with loss of filaggrin function, luminal allergens could enter the lamina propria and initiate an allergic response. Finally, variants in the epithelial cell alarmin TSLP have been implicated in susceptibility to EoE. The disease model that emerges involves a series of genes related to epithelial barrier defects, eosinophil chemotaxis, and predisposition to a TH2 phenotype (Figure 35.6).
The skin
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
In atopic eczema there is a complex interplay between skin barrier dysfunction, deficiencies in the innate immune system and an excessive response to the cutaneous microenvironment. Genetic factors are important, in particular loss of function mutations in filaggrin have been demonstrated as a predisposing factor. Filaggrin is a protein in terminally differentiated keratinocytes that forms a vital component of the cornified envelope. Absence of filaggrin leads to defective skin barrier function with both increased transepidermal water loss and decreased antimicrobial peptides.
Peanut allergy: risk factors, immune mechanisms, and best practices for oral immunotherapy success
Published in Expert Review of Clinical Immunology, 2023
Jyothi Tirumalasetty, Suzanne Barshow, Laurie Kost, Lu Morales, Reyna Sharma, Carlos Lazarte, Kari C. Nadeau
Unlike allergy to some foods, such as milk and egg, peanut allergy resolves naturally in only approximately 29% of children by age 6 [10]. While much is unknown about the development of peanut allergy, several intrinsic and extrinsic risk factors have been identified. Atopic dermatitis, particularly early onset and severe atopic dermatitis, is one of the best established risk factors for the development of peanut allergy [11]. The filaggrin gene (FLG) mutation, which is strongly associated with atopic dermatitis, has also been linked with food allergy risk. FLG codes for an epidermal protein and a defect in this single gene leads to skin barrier dysfunction [12]. The FLG mutation was significantly associated with an increased incidence of peanut allergy in several different groups; however in populations with a low occurrence of FLG mutations, a significant association between FLG mutations and peanut allergy was not found, even after controlling for atopic dermatitis [13,14]. In a pediatric Italian population with atopic dermatitis, children who carried FLG mutations were at 8.9 times higher risk of developing severe food allergy compared to those with no mutation [15].
Baricitinib for the treatment of atopic dermatitis
Published in Journal of Dermatological Treatment, 2022
Amelia Melo, Jose Manuel Carrascosa, Tiago Torres
People suffering from AD have a genetically impaired skin barrier function, leading to an increase in transepidermal water loss, with a greater severity of the condition associated with higher levels of water loss (35–37). Imbalances between stratum corneum protease (such as kallikrein) and antiprotease activity (such as LEKTI), abnormalities in tight junctions, microbial colonization of the skin and pro-inflammatory cytokines are all factors that can lead to skin barrier disruption (38). In addition, there are structural proteins (such as filaggrin or regulatory enzymes) that, through interactions with keratinocytes on the skin surface, maintain its permeability. Mutations or deficiencies of filaggrin appear to be a key factor to an abnormal skin barrier (2,39). Indeed, there is an association between early-onset AD and asthma in the context of AD with filaggrin mutations (40). A process through which filaggrin defects can promote inflammation is by the secretion of epithelial cell-derived cytokines, such as IL-25, IL-33 and TSLP, that are up-regulated in patients with AD (41–44). Nevertheless, only 30% of European individuals with AD have filaggrin mutations which, despite being associated with the development of AD, raises the question of whether there are other genetic variants that may also account for AD pathogenesis (45).
Vehicles for atopic dermatitis therapies: more than just a placebo
Published in Journal of Dermatological Treatment, 2022
Simon G. Danby, Zoe D. Draelos, Linda F. Stein Gold, Amy Cha, Bonnie Vlahos, Laraine Aikman, Paul Sanders, Dan Wu-Linhares, Michael J. Cork
Beyond skin moisturization, humectants appear to help accelerate skin barrier repair. Although some of this effect can be attributed to their humectant activity, they also display distinct molecular effects. Glycerol, for instance, significantly accelerates skin barrier recovery when applied to the skin following disruption (62,63). Urea, but not glycerol, appears to strengthen the skin barrier and protect against surfactant induced irritation (64,65). This effect has been attributed to the ability of urea to stimulate the expression of keratinocyte differentiation-dependent genes such as the one encoding the structural protein filaggrin (49,66). Filaggrin gene defects in particular are a strong predisposing factor for AD (67). Lactic acid promotes the expression of genes involved in ceramide synthesis (68). As mentioned above, the skin of patients with AD is characterized by abnormal differentiation, which predominantly includes reduced expression of filaggrin, and altered lipid metabolism leading to reduced ceramide levels (5,51).