Atopic dermatitis
Atopic dermatitis (AD), also known as atopic eczema, is a chronic inflammatory skin disease. The common characteristics for all forms of AD and the development of eczematous skin are, especially, skin barrier damage together with environmental factors (climate, diet, smoking, etc.) and changes in the immune system.
Atopic dermatitis is a multifactorial disease, which firstly occurs in childhood, but symptoms may develop in adults. The symptoms and course of AD are different and change depending on age and individuals.
The skin barrier and its structure
The skin is a highly specialised and effective barrier protecting the body against the entry of harmful substances and microorganisms as well as limiting harmful external effects. Skin desquamation (peeling) is also part of the regulation of transepidermal water loss (TEWL), i.e. skin hydration. The main parts of the skin barrier are skin cells – keratinocytes, corneocytes, keratin and filaggrin proteins, and lipids.The highest layer of the skin, called the stratum corneum, is constantly renewed through the keratinization process. In this process, the keratin protein, which gives protection to the skin, accumulates in the surface layers of the skin. During keratinization, the skin cells (keratinocytes) are transformed into the cells of the top part of the skin (corneocytes). Then these cells are slowly exfoliated (desquamation) and new cells from the lower layers of the skin rise. This entire process of skin restoration takes about 28-30 days.
Corneocytes are flattened and detached (enucleated) skin cells. Corneocytes have a cover made from sebum, perspiration, and other disintegrated corneocytes. This cover prevents transepidermal water loss (TEWL) and keeps a constant acidic environment (pH 4-6) that inhibits microbial growth. Corneocytes are filled with solid fibres formed by keratin. During the production of corneocytes, these fibres are arranged into organised bundles by means of the protein filaggrin – one of the key proteins of the skin barrier.
Corneocytes also produce a natural moisturising factor (NMF), which grows from the degradation of filaggrin. NMF is very important in keeping skin hydrated. Water bound within NMF gives skin elasticity and a healthy look. It also ensures the proper functioning of the hydrolytic enzymes involved in skin peeling (desquamation). NMF levels in the skin decrease with age. The decrease in NMF is associated with the lowered synthesis of filaggrin and the weakening of the skin barrier in aged persons.
The symptoms of both the acute and late stages of the disease can be mitigated by consistent and effective skin care, the elimination of risk factors, and an appropriate comprehensive treatment.
During their production, corneocytes are regularly arranged by means of direct joints (corneodesmosomes). Space arises between cells that is filled with specific lipids, helping to protect the skin. Up to 50% of the lipid component is formed by ceramides along with cholesterol and unsaturated fatty acids. The number of direct joints and their size naturally decrease as the corneocytes get close to the top layer of the skin with the help of proteases (enzymes splitting proteins), enabling corneocyte desquamation. The skin repairing process is shown in the figure below.
The quality of the skin barrier depends on a wide range of processes. Disorders in these processes result in a decrease in the amount of lipids and NMF and an increase in transepidermal water loss (TEWL ). This is followed by dehydration of the skin, increase in skin pH, decrease in the activity of hydrolytic enzymes, and deteriorating of the peeling process (and thus skin restoration). This results in a failure of the skin barrier, which adds to the growth of atopic dermatitis.
Components of the stratum corneum (SC) and their disorders
There are several known deformities which may add to the failure of the skin barrier:1. Filaggrin gene mutation
2. Decreased ceramide content and total lipid levels in the outer layer of skin (stratum corneum)
3. Higher activity of serine proteases
Filaggrin
Filaggrin (FLG) is shown as the key protein of the skin barrier and adds to skin stability. Filaggrin is arranged as a polymer pro-filaggrin comprised of repetitive units of filaggrin. With the step-by-step process of keratinization, pro-filaggrin is split into filaggrin by specific enzymes (proteases). The keratin fibers produced by the progress of keratinization are bonded with the help of filaggrin into bundles and are formed into a flattened corneocyte structure.
In the outer layers of the skin (stratum corneum), filaggrin is, on the other hand, separated from the keratin fibers and broken down into substances forming a natural moisturising element (NMF). The balance between the production and breaking down of filaggrin is vital for maintaining a stable environment in the stratum corneum (SC) and providing an effective skin barrier.
People who have mutations in the filaggrin gene have decreased levels of NMF and a higher degree of TEWL. Decreased filaggrin production in the skin, or the loss of its function due to a mutation in the filaggrin gene (FLG), leads to an increased skin pH and the development of atopic eczema.
Ceramides
Ceramides are lipid molecules, which are part of the lipid bilayer in the SC, and therefore are an important part of the outer layer of skin. The function of ceramide is to strengthen and keep the integrity of the SC, control the flow of water and nutrients in the epidermis, and stop the entry of foreign substances and microorganisms.
Keratinocytes in the stratum granulosum release the first molecules (precursors) of lipids, which are then enzymatically changed into ceramides, cholesterol, and free acids. These substances then make up the lipid bilayer in the SC.
In healthy skin, ceramides make up 50% of the lipids, but in individuals suffering from AD, lower levels of ceramidds and a change in their composition have been found. These abnormalities may lead to the flawed activity of enzymes involved in lipid metabolism in the SC, a change in pH, and an increase in serine protease activity.
Serine proteases
Serine proteases belong to a group of proteases which split proteins. Kallikrein (KLK5, KLK7, and KLK14) is an important protease which is vital for the exfoliation of dead skin cells. The activity of these proteases is dependent on the pH value – a higher pH level increases proteases activity. In addition to the pH value, protease activity is regulated by the LEKTI inhibitor (a protein regulating the process of desquamation) as a reduction in activity inhibits proteases.
A break of the balance between proteases and their inhibitors, due to genetic mutation, leads to deformities in the process of desquamation and to an interruption of the skin barrier. In addition, because of the increased pH and the activity of serine proteases, the inflammatory response is stronger and increases the pathological changes in the SC described above. Thus, many interconnected mechanisms occur simultaneously influencing each other.
Antimicrobial peptides
The skin and its protection mechanisms are the first defense against pathogens (germs). The skin barrier (epidermis) stops the entry of foreign elements and gives the primary protection against infection. Urgent reaction is mediated by antimicrobial peptides (AMPs), which represent a defensive mechanism of congenital immunity. AMPs are small proteins made, in addition to keratinocytes, by other cells of the immune system (mast cells, phagocytes, etc.). The properties of AMPs allow them to break the membranes of the pathogens, thereby eliminating the threat.
In atopic dermatitis, a decrease in AMP along with a broken skin barrier of the SC increases the risk of accumulated pathogens (e.g. Staphylococcus aureus, Malassezia furfur, etc.) on the skin. These pathogens, in addition to a heightened risk of infection, cause higher IgE levels and persistent allergic hypersensitivity.
Elevated immunoglobulin E (IgE) levels and their role in AD
Atopic dermatitis (AD) is 50-85% connected with elevated immunoglobulin E (IgE) levels. IgE is a type of antibody produced by white blood cells connected to the surface of immune system cells, which fight against infections. Elevated IgE levels are associated with early hypersensitivity when an allergic reaction occurs within a short time after contact with an allergen (e.g. asthma, atopy, parasitic infection, and food allergies). The exact role of IgE in atopic dermatitis continues to be researched and analysed. Genetic factors which may cause the dysfunctional regulation of IgE, atopy, and higher IgE levels have already been identified.
Based on elevated serum IgE levels, two forms of AD are analysed:
Extrinsic
Identifying specific IgE antibodies (i.e. sensitivity to an allergen) is conducted by a simple prick test – a needle prick of the presumed allergen into the skin. Another method involves the application of the suspected allergen on the skin for 48 hours. Note, in 50-80% of cases, the reaction of increased IgE levels is due to a sensitivity to airborne and/or food allergens.
Intrinsic
At normal IgE levels, specific IgE antibodies are not produced, and thus allergens do not apply.
However, the clinical demonstrations of AD are the same in both forms.
