The relationship between skin barrier dysfunction and immune dysregulation in atopic dermatitis (AD) is well established and has been extensively studied. The immune system has evolved to respond to various pathogens through 3 types of immunity, with AD falling under type 2, an inflammation disease.
Skin Barrier Dysfunction and Immune Dysregulation Interplay
When the skin barrier is stressed, it releases Thymic Stromal Lymphopoietin (TSLP), leading to type 2 polarization. This creates a vicious cycle of amplification within the skin, which is a significant aspect of AD. Inflammation primarily occurs in the skin, making peripheral signals less important. These peripheral signals, which include cytokines and cells, merely leak out from the skin, and can be detected in the blood, but the core issue remains within the skin itself. This process generates muscle amplification as a repercussion when the body’s alarm systems are triggered. The result is an amplification of the entire circuit, leading to further breakdown of filaggrin and other skin barrier components, which in turn drives more inflammation.
The key cytokines involved in AD are IL-13, and IL-4, which signal through the Janus Kinas/signal transducers and activators of transcription (JAK/STAT) pathway. Additionally, there is a second barrier, the stratum granulosum which acts as an antigen barrier. Type 2 cytokines dissolve this barrier, allowing dendritic cells to reach out and sense external antigens, leading to allergic sensitization. This barrier is active, lying on immune-active dendritic cells in the dermis and epidermis. The epidermis plays a crucial role in driving immune activation and forming long-term allergy memories.
Brian Kim’s research emerged after various molecules had been put through trials and even approved. He demonstrated a new immune pathway involving IL-3, IL-13, IL-4, IL-31, and other cytokines signaling through the JAK-STAT pathway, which is crucial for pathogen or parasite elimination. This research spans from non-lesional skin and preclinical abnormalities to the lesional and chronic lesional stages of AD, showing how these factors drive each other.
The only targetable aspect here is filaggrin deficiency, which is challenging to address through gene therapy. Currently, the most viable clinical target is immune access. When immune access is targeted, barrier function under dysbiosis tends to improve. Many pharmaceutical companies have validated this concept, showing that both barrier function and microbiome health improve when immune access is addressed.
Effects of Topical Corticosteroids
A study examined infants under 1 year with AD who were treated with topical corticosteroids for 6 weeks. The study focused on their skin barrier function and systemic cytokines. While transepidermal water loss improved, the natural moisturizing factor of the skin did not show significant improvement. This indicates that while inflammation reduction allows the skin to repair itself, it does not address the underlying genetic issues, much like putting out a fire in a house does not repair the damage.
The study also observed a reduction in innate type 2 angiogenesis biomarkers in the stratum corneum with corticosteroid treatment. Interestingly, plasma biomarker also decreased significantly, suggesting a systemic effect of the topical corticosteroids over the 6-week period. This supports the idea that cytokines are leaching out of the skin into the peripheral blood, consistent with the nature of AD as a skin disease.
Another study investigated the normalization of the microbiome following topical corticosteroid treatment. It found a significant reduction of staphylococcus aureus levels. This aligns with the concept that targeting the immune axis can correct some bio-abnormalities and begin to normalize the microbiome.
Dupilumab: Mechanism of Action
Dupilumab targets the IL-4 and IL-13 receptors. According to Emma Guttman’s work, this treatment affects the duration and normalization of skin morphology, skin biome morphology, and the expression of skin differentiation markers. By switching off the type 2 signal, Dupilumab allows the skin barrier to restore itself, effectively putting out the inflammatory “fire” and enabling the skin to begin its repair process.
Can Barrier Protection Prevent AD?
A large meta-analysis examined whether barrier protection could prevent AD in high-risk infants. The results were mixed: while some smaller studies suggested a lower incidence of AD, larger studies did not support this finding, and their greater weight in the meta-analysis led to inconclusive results.
This suggests that the concept of using moisturizers to prevent AD may require more advanced formulations or might not be effective at all. There is some interest in ceramide-based bio-repair as a potential solution. However, based on current evidence, population-level interventions involving moisturizing to prevent AD cannot be recommended.
To conclude, barrier dysfunction is a cardinal feature of AD, driven by genetics and environmental factors (the exposome) from conception onwards. The microbiome plays a crucial role, both positively and negatively, and is connected to the Staphylococcus aureus signal. This connection is influenced by topical drugs and systemic therapy. Manipulating the microbiome is highly complex, and there is still much to learn in this area. The process of skin barrier repair is poorly understood, including how moisturizers affect the skin and their potential interference with barrier function.
Want to learn more about skin barrier dysfunction in AD? Follow the link to access the full webinar: https://inderostg.wpenginepowered.com/skin-barrier-dysfunction-atopic-dermatitis-and-beyond/
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. His research focuses on molecular genetics of skin disease including rare skin disorders.
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