Patient assessment
Michael Parker, Charlie James in 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.
Skin Barrier Repair in Atopic Dermatitis Therapy
Donald Rudikoff, Steven R. Cohen, Noah Scheinfeld in Atopic Dermatitis and Eczematous Disorders, 2014
During the transformation of basal layer keratinocytes to stratum corneum corneocytes, the intracellular structural protein profilaggrin is first converted to filaggrin by dephosphorylation and later to free amino acids through proteolysis (Rawlings and Matts 2005). These free amino acids, together with carboxylic, urocanic, and lactic acids, urea, sugars, and other intracellularly derived molecules, constitute the so-called natural moisturizing factor (NMF) (Rawlings and Harding 2004). Filaggrin is thought to aggregate keratin filaments, the main structural proteins in basal keratinocytes, into tight bundles. This causes progressive flattening of the cells as they transform into corneocytes (Candi et al. 2005). In addition, keratinocytes synthesize lipid bilayers in their Golgi apparatus from ceramides, cholesterol, and fatty acids, which are then extruded as lamellar bodies into the intercellular spaces of the stratum granulosum (Fig 8.2). This process is modulated by hyaluronic acid and water content gradients between the stratum granulosum and the cornified layer (Pasonen-Seppänen et al. 2003, Maytin et al. 2004).
Structure and function of skin
Roger L. McMullen in Antioxidants and the Skin, 2018
The major component of the keratohyalin granules is the polyprotein profilaggrin, which is the precursor for the protein, filaggrin. Profilaggrin is essentially a polymer of filaggrin proteins, separated by links. During the transition from a granular to a cornified cell, profilaggrin is converted to filaggrin by proteolysis of the linkages and dephosphorylation of the entire molecule. Filaggrin is an important component of the amorphous phase of the keratinocyte, which aligns KIFs in a direction parallel to the surface of the skin, providing the stratum corneum with a planar cell. Hence the name filaggrin, or filament aggregating protein. K1 and K10 are still present in the stratum granulosum; however, they may undergo proteolysis and phosphorylation to K2 and K11. Keratohyalin granules also contain intermediate filaments and loricrin, a chief component of the cell envelope.
The Epidermal Barrier Structure and Function of Re-Harvested Skin from Non-Scalp Donor Sites
Published in Journal of Investigative Surgery, 2023
Bohan Zhang, Peng Luo, Jiachen Sun, Dawei Li, Zhaoxing Liu, Xinzhu Liu, Hongqing Zhao, Zhisheng Li, Xiaoye Xie, Jianqiu Yang, Chuan’an Shen
The structural proteins of CE include filaggrin, loricrin, involucrin, SPRR, etc., which play a key role in providing resistance to external mechanical tension, preventing the invasion of pathogens and allergens, and preventing excessive water loss in the body.11 Filaggrin is mainly expressed in the granular layer and the transparent layer of the epidermis, which interacts with keratin intermediate filaments and aggregates to form dense keratin fiber bundles, thereby forming a flat and tough scaffold structure of keratinocytes.12 With the participation of SPRR, loricrin and involucrin cross-link with each other to form an abnormally water-insoluble CE, wrapping keratin fiber bundles and forming the unique stratum corneum barrier structure of the epidermis.12 In this study, these proteins were analyzed by IHC staining. The results revealed that the expression of CE structural proteins in the skin tended to decrease as the skin was re-harvested. As a result, the connection between keratin proteins was weakened, thus impairing the barrier function.
Immunohistochemical markers for eosinophilic esophagitis
Published in Scandinavian Journal of Gastroenterology, 2020
Katarzyna Zdanowicz, Magdalena Kucharska, Joanna Reszec, Dariusz Marek Lebensztejn, Urszula Daniluk
Filaggrin interacts with the intermediate filaments and retains the function of an epithelial barrier. Mutations in the filaggrin gene have been detected in atopic disorders such as asthma or eczema. In vitro gene silencing studies have shown that a loss of filaggrin expression promotes esophageal epithelial barrier dysfunction in EoE. In addition, IL-13, a proinflammatory cytokine which is upregulated in EoE, had an inhibitory effect on the expression of filaggrin in esophageal mucosa [30]. IHC staining of fillagrin in esophageal biopsies of children showed a low detection of this protein in EoE compared to healthy controls and GERD, with a noticeable restoration of expression after topical steroid treatment in a significant proportion of EoE cases [22,32]. Similar results were reported in studies with adult patients with EoE [30].
Variation of asthma characteristics with atopic march, gastroesophageal reflux, and ENT pathologies
Published in Journal of Asthma, 2023
Norane Shehab, Jobayer Hossain, Ejaz Yousef
Atopic dermatitis is one of the most common chronic pediatric diseases. It is thought to affect 15–30% of children and is particularly common in industrialized countries (15). AD is mostly diagnosed in the first months of life, before the development of FA, AR, and asthma. Atopic dermatitis likely results from disruption of the skin barrier due to intrinsic defects of epithelial cells associated with AD and development of FA, AR, or asthma by 5 years of age (16). The classic atopic march starts with AD and FA in infancy to gradual development into allergic asthma and AR in childhood (17). Multiple studies have been conducted to show an association between AD and asthma. The link between asthma, AD, and other atopic syndromes is related to IgE-mediated response. Atopic asthma is characterized by the development of a persistent Th2-type inflammatory response after exposure to certain inhaled allergens leading to the synthesis of specific IgE antibodies in the serum (18). Similarly, AD is associated with high IgE levels and eosinophilia. Atopic dermatitis is associated with Filaggrin gene mutation, which is one of the most crucial factors in skin- barrier function. Mutation or loss of function leads to impairment of epidermal-barrier function, leading to allergens penetrating the skin resulting in allergic sensitization and high-IgE phenotype (19).
Related Knowledge Centers
- Chromosome 1
- Epidermis
- Epithelium
- Keratin
- Protease
- Protein
- Stratum Granulosum
- Cellular Differentiation
- Epidermal Differentiation Complex
- Stratum Corneum