PracticalDermatology

Atopic dermatitis (AD) is a complex and heterogeneous skin disorder with a multifactorial etiology. The underlying mechanisms of AD are incompletely defined as the condition involves a diverse interplay of genetic and environmental factors that contribute to the pathophysiology of the skin.1 Rather than being a single disease entity, it likely represents a group of skin disorders that cause chronic pruritus and inflammation. This review aims to explore the etiology of AD by examining the impact of genetics and various environmental factors on the development and progression of the disease. By understanding the different causes of AD, we can improve both prognosis and guidance for patients. Precision medicine can provide more personalized therapeutics for AD patients, with improved efficacy, safety, and tolerability. Thus, a better understanding of the disease mechanism is crucial for advancing treatment options in the new era of personalized medicine.

GENETIC FACTORS

Filaggrin (FLG) mutations are widely recognized as a significant genetic risk for AD due to potential water loss and pH imbalance.1 This essential skin protein and its downstream products help maintain the stratum corneum, regulate the passage of water and solutes, control skin pH, and inhibit the penetration of allergens. Damage to the skin barrier can lead to inflammation and dry skin—key features of AD. Furthermore, AD associated with FLG mutations is related to distinct clinical findings such as increased risk of asthma, elevated IgE, and family history of atopy.2 However, it is important to note that only 10% to 40% of AD patients have FLG loss-of-function mutations, and those who have homozygous FLG mutations do not always have AD. Other genetic pathways, such those regulating serine proteases and tight junctions, have further been implicated in the involvement of abnormal enzyme processing resulting in skin barrier dysfunction, underscoring the fact that AD is truly not a single disorder. (Table 1.)1

The skin also acts as a microbial barrier and hosts a complex microbiome. The genetic risks discussed above may predispose AD patients to dysbiosis and subsequent greater colonization by Staphylococcus aureus, which further comprises the skin barrier and exacerbates AD symptoms.4 S. Aureus is found on both lesional and nonlesional AD skin. However, the density and rate of colonization has been related to AD flares and overall severity of disease. Toxins released by this pathogen mediate the dissolution of the stratum corneum and directly drive T-cell mediated inflammation in the skin.

Overactivation of TH2-mediated immune responses is a typical finding in AD and relates to the immune dysregulation that underlies AD pathogenesis.3 The skewing of TH2 lymphocytes produces high levels of IL-4 and IL-13. These cytokines activate IgE antibodies and eosinophils that promote more inflammation and damage to the epithelium. This process simultaneously reduces filaggrin expression and allows for further expansion of S. Aureus, creating a vicious cycle of disease. Additionally, IL-4 and IL-13 directly affect sensory nerves, contributing to the “itch” sensation and scratching.5 This produces another parallel cycle of inflammation and skin barrier disruption (Figure 1).

Figure 1. Inflammatory loop involving interactions between immune system, skin colonization, and pruritus.⁵

IMPACT OF THE ENVIRONMENT

Environmental exposures to chemicals and pollutants may initiate or worsen both innate and adaptive immune pathways involved in AD progression.1 Substances including airborne formaldehyde, benzene, and preservatives have been reported as agents that may lead to cell damage and inflammation. Prenatal and childhood exposures to environmental tobacco smoke also have the potential to cause epigenetic changes via methylation of a TSLP candidate gene. This generates a TH2 dominant skew, increasing the likelihood of developing AD.

Moreover, we need to assess the rural and urban divide of AD prevalence. The incidence of AD has steadily increased over the past several decades, particularly affecting individuals living in urban settings of wealthier, industrialized countries.6 The hygiene hypothesis might offer insight into the disproportionate impact of AD on urban societies. Early-life exposure to microbes could help develop the immune system in a way that provides important protection against autoimmunity and allergy.7 One proposed mechanism is the limited production of regulatory cytokines (eg, IL-10 and TGF-Β) as a consequence of decreased immune activation. Several studies have demonstrated the relationship of maternal exposure to farm animals during pregnancy and reduced risk of childhood AD and allergic disease. However, the results have indicated greater protection against asthma and respiratory allergies.

A study in South Africa compared plasma samples of 152 children with and without AD from rural farming areas or urban townships.8 Independent of AD status, individuals from rural environments had the highest levels of cytokines with no particular TH skewing reflecting environmental influence on immune development. Additionally, higher IL-4 and IL-13 levels in urban children with AD were correlated with less animal exposure, age of solid food introduction, and greater antibiotic and acetaminophen use within the first year of life. This suggests the importance of antigenic stimulation for protection against TH2 polarization.

Pollutants in the post-industrial environment may also provide another explanation in the steep rise and gap of AD prevalence between urban and rural environments. A recent study examined the role of environmental toxins and reported a strong association of diisocyanates and AD diagnoses.9 Methylene diphenyl diisocyanate and toluene diisocyanate are frequently used for the manufacture of common products, including couch cushions, paint, nylon, and polyurethane, and isocyanates are present in the exhaust from vehicles. Although the exact mechanism remains unclear, diisocyanates may contribute to the disruption of commensal skin microbiota and lead to dysbiosis that triggers immune-mediated pathways of AD. After obtaining data on diagnoses of AD and environmental pollutant exposure in US zip codes, they found the strongest correlation for AD diagnosis to be with exposure to diisocyanates. These results implicate a prominent impact of environmental hazards on the pathogenesis of AD. However, further research needs to be conducted using more precise tools to measure concentrations of pollutants as well as a longitudinal examination of their impact.

CONCLUSION

The origin of AD involves a complex interaction of compromised skin barriers, immune dysregulation, skin dysbiosis, and environmental factors. We have summarized some of the proposed immune mechanisms that modulate skin inflammation and pruritus. New therapeutics rely on the knowledge of identifying specific etiology of AD subtypes. Recently, powerful targeted topical and systemic medications have improved outcomes of AD.10 Unfortunately, not all patients respond to these medications, and adverse effects may prevent people from using any drug. Formulating precise pharmacological targets based on detailed mechanisms could offer promising results with greater efficacy and limited adverse outcomes. Further research is necessary, particularly using a more diverse pool of patients across different ages, ethnicities, and environments to cover the breadth of AD pathophysiology.

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8. Lunjani N, Tan G, Dreher A, et al. Environment-dependent alterations of immune mediators in urban and rural South African children with atopic dermatitis. Allergy. 2022 Feb;77(2):569-581. doi:10.1111/all.14974

9. Zeldin J, Chaudhary PP, Spathies J, et al. Exposure to isocyanates predicts atopic dermatitis prevalence and disrupts therapeutic pathways in commensal bacteria. Sci Adv. 2023 Jan 6;9(1):eade8898. doi:10.1126/sciadv.ade8898

10. Halling AS, Loft N, Silverberg JI, Guttman-Yassky E, Thyssen JP. Real-world evidence of dupilumab efficacy and risk of adverse events: A systematic review and meta-analysis. J Am Acad Dermatol. Epub 2020 Aug 18. PMID: 32822798. 2021 Jan;84(1):139-147. doi:10.1016/j.jaad.2020.08.051