Date Published: May 2, 2018
Author(s): Danuta Nowicka, Ewelina Grywalska.
Atopic dermatitis (AD) is a condition with a complex and not fully understood etiology. In patients with AD, acute skin lesions are colonized by a greater number of Staphylococcus aureus (S. aureus) bacteria than chronic lesions, clinically unchanged atopic skin, or the skin of healthy people. Mechanisms promoting skin colonization by S. aureus include complex interactions among several factors. Apart from increased adhesion of S. aureus in atopic skin, defects of the innate immune response resulting in the lack of restriction of the growth of microorganisms also contribute to susceptibility to colonization by and infection with S. aureus. A deficiency in the endogenous antimicrobial peptides may be partly responsible for the susceptibility to colonization by and skin infection with S. aureus in patients with AD. Majority of isolated S. aureus stains are able to produce exotoxins, which act as superantigens. Moreover, anti-S. aureus-specific IgE was identified and measured in patients with AD, revealing that its level corresponds to the severity of the disease. This review of the literature attempts to identify factors that are involved in the pathogenesis of AD-related S. aureus skin colonization. In the light of presented mechanisms, a reduction of colonization may become both causative and symptomatic treatment in AD.
Atopic dermatitis (AD) is a condition with a complex and, up till now, not fully understood etiology. The first reports of the disease date back to ancient times; however, the first reports in the literature and its presence in medical practice dates back to 1808 when Wilian made his pioneer “clinical” description of prurigo and of a prurigo-like condition with the special emphasis on the itchiness which is a characteristic for atopic dermatitis . After many years of observation and experience, the term atopic dermatitis was introduced and described only in 1933 by Fred Wise and Marion Sulzberger [2, 3].
In AD, defects in skin barrier structure as well as impairment in functional integrity and reduced ability for self-renewal seem to play a role in releasing both an immune response and nonspecific inflammatory reaction [12, 13]. Increasingly, skin barrier defects are mentioned as one of the factors facilitating bacterial colonization. Skin barrier minimizes water loss from the epidermis and deeper parts of the skin as well as protects against environmental factors such as warmth or cold, penetration of potentially harmful substances, and colonization of pathological bacteria. The good condition of the epidermal barrier assures a healthy appearance and the proper functioning of the skin. In many diseases, the structure and, subsequently to it, the functioning of the epidermal barrier become altered.
Epidermal barrier damage by an inflammatory process facilitates colonization by microorganisms. Mechanical damage by scratching, environmental factors, and contact with detergents contribute to bacterial colonization as well. In the atopic skin, elevated pH is observed on the surface of the epidermis. Its value often reaches up to 8.00 [24, 25]. The structure of the epidermis along with presentation of mutual associations among epidermal barrier damage and immune dysregulations in atopic dermatitis is presented in Figure 1.
In patients with AD, acute skin lesions are colonized by a greater number of S. aureus bacteria than chronic lesions, clinically unchanged atopic skin, or the skin of healthy people. Mechanisms promoting skin colonization by S. aureus include complex interactions among several factors. They encompass the dysfunction of the skin barrier, an elevated synthesis of S. aureus adhesion molecules in the extracellular matrix, decreased lipid content in the skin, changes in the pH of the skin surface in the direction of alkalinity, and defective innate immune responses due to decreased production of endogenous antimicrobial peptides [4, 12, 28, 29].
S. aureus is able to form a biofilm composed of a hydrated matrix of polysaccharides and proteins, which facilitates cell adhesion . Adhesion of S. aureus takes place mainly in the stratum corneum in the epidermis, and it is mediated by fibronectin and fibrinogen. It was shown that adhesion of S. aureus to the surface of the skin is increased in patients with AD in comparison to healthy people. In AD, the inflammatory process is caused by allergens and leads to a damage of the skin barrier and as a result, to the exposure of the extracellular matrix to S. aureus. The extracellular matrix adhesins of the S. aureus cell membrane include dermal and epidermal fibronectin and laminin which become exposed in the skin with lesions and, in this way, increase adhesion of S. aureus. Scratching also increases binding of S. aureus cells though disturbances in the skin barrier and release of cytokines which regulate expression of extracellular matrix adhesins for S. aureus. Additionally, the skin of AD patients shows an increased deposition of fibronectin in the stratum corneum. This factor may increase S. aureus binding to the skin.
Apart from increased adhesion of S. aureus in atopic skin, defects of the innate immune response resulting most of all in the lack of restriction of the growth of microorganisms also contribute to susceptibility to colonization by and infection with S. aureus. Comparison between AD (Th2-mediated inflammatory disease) and psoriasis (Th1-mediated inflammation) showed that about 30% of patients with AD suffered from skin infections, while only 6.7% patients with psoriasis had skin infection despite impaired skin barrier functioning in both groups of patients . This discovery suggests that inflammatory lesions in the skin caused by Th2, but not by Th1, may be associated with defects of the innate immune response.
Superantigens are a group of bacterial and viral peptides recognized for their ability to stimulate a large number of various clones of T cells to produce cytokines . After processing and presentation by antigen-presenting cells via molecules of major histocompatibility complex (MHC) class II, traditional peptide antigens recognize and bind to those of T cells which have 5 specific variable elements (Vβ, Dβ, Jβ, Vα, and Jα) within T cell receptors (TCR). So the amount of T lymphocytes activated with conventional peptide antigens accounts for approximately 0.01 to 0.1% of the total T lymphocyte population. In contrast to conventional peptide antigens, superantigens do not require processing and antigen presentation by antigen-presenting cells. Superantigens bind directly to the variable β-domain of the β chain (Vβ) of the TCR molecule (TCRVβ) and the MHC class II on the surface of antigen-presenting cells outside the groove binding the peptic antigen of the MHC. They recognize and stimulate T lymphocytes with specific TCRVβ domains, which results in activation of huge amounts of polyclonal T cells—up to 15–20% of the total population of T lymphocytes, hence the term “superantigen” .
Skin colonization by S. aureus in the course of AD, as a cause of an overreaction of the immune system to the presence of those bacteria, exerts a toxic effect on keratinocytes, stimulates lymphocytes to secrete IFN, and as a consequence, leads to the development of a chronic type of the disease. The bacteria itself and their metabolites induce activation of T lymphocytes, macrophages, and antigen-presenting cells which lead to increased production of IgE and IgG among others. The elevated level of IgE is one of the characteristic symptoms of the immune response to allergen. Anti-S. aureus-specific IgE was identified and measured in patients with AD. Its level corresponds to the severity of the disease [54, 55].
Many mechanisms facilitate S. aureus colonization on the surface of the epidermis, and simultaneously, many processes induced by those microorganisms exacerbate the course of the disease. Thus, S. aureus colonization is both the cause and consequence of the disease. This condition translates into treatment of AD and a major role for both topical and systemic antibiotics. Unfortunately, more and more often, S. aureus becomes resistant to the most commonly used preparations. In the study conducted by Bessa et al., the frequency of fusidic acid and mupirocin resistant strains was low; however, the high rate of neomycin and bacitracin resistance is alarming as those antibiotics are common in clinical practice .