For many people, experiences with skin rashes are fleeting, perhaps triggered by heat, chemicals or allergens. However, in individuals suffering from atopic dermatitis (AD)—more commonly known as eczema—persistent itching occurs. AD is often accompanied by dry, red and scaly skin which can greatly impair quality of life. Worldwide, an estimated one in ten adults are affected by AD, with the condition being ten times more prevalent in children than adults.
Scientists have sought to understand the root causes of AD using various mouse models that mimic specific aspects of the disease. “The major challenge in replicating human AD faithfully in mouse models is that there are numerous phenotypes, subtypes and phases that comprise the disease spectrum classified as AD,” said John Common, a Principal Investigator at the Skin Research Institute of Singapore (SRIS). Skin microbes also interact with host immune cells in disease progression, adding another layer of complexity.
Existing mouse models of AD can be broadly divided into three categories: skin surface sensitization, spontaneous AD development and genetically engineered models of AD. Using these, researchers have successfully identified a few major molecular mechanisms involved in AD progression and development. For example, spontaneous recessive mutations in the mouse filaggrin gene produced flaky tail mice with symptoms reminiscent of AD, and similar loss-of-function mutations are the strongest genetic risk factor for AD in human subjects.
Researchers have also found that excessive production of certain interleukins, which activate the arm of the immune response involved in allergic reactions, contribute to AD development. Certain microbes colonizing the skin, such as Staphylococcus aureus, have also been known to influence the production of these interleukins. Less commonly, infection by certain viruses such as herpes can also contribute to AD.
Knowing how AD presents in each patient has given rise to more sophisticated treatment approaches. “These range from improvement in the skin barrier function from birth to prevent early sensitization, all the way through to biologics therapies that neutralize immune pathways,” explained Kenji Kabashima, Chair and Professor in dermatology at Kyoto University, Japan, a co-author on the study. Kabashima concurrently holds Adjunct Professorships at SRIS and the Singapore Immunology Network (SIgN).
“The most advanced of these biologics approaches is the recently-approved Dupilumab that targets the interleukin-4 receptor and blocks the action of interleukins-4 and 13, the prototypical Th2-type cytokines,” Kabashima added.
In the future, patient stratification will be crucial for ensuring the effectiveness of these targeted treatment approaches. “We are currently investigating various phenotypes and endotypes of AD in human patients and mouse models to better understand the contribution of specific microbiome, skin barrier and immune components in this complex disease,” Common concluded.
The A*STAR-affiliated researchers contributing to this research are from the Skin Research Institute of Singapore (SRIS) and the Singapore Immunology Network (SIgN).
