Atopic Dermatitis (AD) presents a multifaceted pathogenesis involving different interactions between epidermal barrier dysfunction, immune dysregulation, and dysbiosis. This article will expand on how these factors influence each other and explore potential strategies to modulate their effects. This strategic emphasis is grounded in the rationale that targeting immunological systems provides a more accessible and druggable avenue compared to conventional approaches aimed at repairing the skin barrier or rectifying dysbiosis.
Epidemiology Overview
The epidemiology landscape of AD is dynamically shifting, particularly in countries underdoing urbanization. The surge in AD incidence is linked to environmental pressures through the comprehensive concept of the exosome. From conception to the end of life, every environmental exposure contributes to epidermal barrier dysfunction.
The urbanization phenomenon accentuates this correlation, evident in the escalating prevalence of AD in rapidly industrializing nations like China, South Africa, and South America. Urban settings bring forth a multitude of toxic environmental exposures, ranging from tobacco smoke to diesel fumes and microparticles, all exerting either epigenetic manifestations or direct pressure on the skin barrier. The focus is on the consequential damage to the stratum corneum, that can be driven through the aryl hydrocarbon (AhR) receptor, which is currently under investigation as a druggable receptor in clinical trials. The AhR, a xenobiotic receptor, regulates skin barrier function and differentiation; it is a growable target that strings together the barrier, the microbiome, and the environment. This interconnected web amplifies stressors on the skin barrier, contributing significantly to its breakdown and the manifestation of AD.
Introducing Filaggrin (FLG)
Approximately 15 years ago, Dr. Irvine began his research on FLG, a protein that constitutes a substantial 70% of the dry weight of the stratum corneum. Found predominantly beside basal keratinocytes, FLG is a molecular anchor, crucial for the integrity of the skin. This specialized region of the skin serves as our line of defense, continuously responding to environmental changes. Essentially, the stratum corneum acts as the final differentiated barrier, adapting to transitions from dry to wet environments of shifts from neutral to extreme conditions. It is imperative to grasp that the skin, particularly through the stratum corneum, serves as our conduit for sensing and interacting with the environment—an intricate organ that orchestrates our responses to the ever-changing environment.
FLG Mutations
The stakes are high when it comes to the molecular workings of the skin barrier, particularly in the context of FLG. Mutations in FLG can lead to loss of function, a concern emphasized by earlier research indicating that certain mutations result in a significant reduction of one or both alleles, translating to a loss of 50% to 100% of FLG production. The implication of such mutations extends beyond the skin, as evidenced by an elevated risk of allergic disease throughout one’s lifetime. Individuals with FLG mutations exhibit a remarkable susceptibility to conditions such as peanut allergy, with 5 times increase, a 3.5 times higher likelihood of developing AD, and a 1.5 times higher risk of asthma, particularly when initially presented with AD. Severity of these effects is underscored by how rare it is for a single gene mutation to cause such a significant disease impact. Importantly, these mutations are not confined to specific populations; they are prevalent in regions across Asia, South Asia, South America, North America, and Europe, affecting approximately 8 to 10% of individuals outside of Africa. It is significant to note that FLG mutations are relatively uncommon in black Africans (particularly sub-Saharan Africans). This underscores the global significance of understanding and addressing the molecular intricacies of the skin barrier in the context of atopic allergic diseases.
In conclusion, the scientific exploration of the relationship between skin barrier dysfunction and AD reveals a complex interplay of factors influencing its pathogenesis. From the molecular details of FLG to the dynamic response of the stratum corneum, this article brings to light the critical role of the skin barrier in protecting us against environmental changes. Urbanization, as a significant contributor to AD prevalence, highlights the broader impact of the exposome on skin health. The profound consequences of FLG mutations emphasize the far-reaching impact on allergic diseases throughout an individual’s lifetime. This exploration does not only enhance our understanding of AD but also provides a foundation for developing targeted treatments and interventions that address the nature of epidermal barrier dysfunction.
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About the Author
Alan D. Irvine, MD, DSc
A key leader in dermatology research, he is a professor of Dermatology at Trinity College in Ireland. Dr. Irvine is the founding president of the Irish Skin Foundation and the International Eczema Council. His research focuses on molecular genetics of skin disease including rare skin disorders.
