Why are certain body parts more vulnerable to skin diseases than others?

Two latest UC Davis Health studies explored how differences in skin composition may result in dermatological conditions, similar to psoriasis and atopic dermatitis.

“Skin doesn’t have a uniform composition throughout the body,” said Emanual Maverakis, professor of dermatology, molecular medical microbiology at UC Davis and senior creator on each studies. “Different skin characteristics at different body sites may affect the skin’s susceptibility to certain diseases.”

Skin diseases affect about 84.5 million Americans. Aging, trauma, and environmental and genetic aspects can result in a big selection of skin conditions.

Body site determines skin structure and performance and disease susceptibility

The skin is the biggest organ within the body. It has a median area of about 20 square feet – that is the scale of a 4′ by 5′ room! Its outermost layer (epidermis) has a lipid matrix composed of free fatty acids, cholesterol and ceramides (a family of waxy lipid molecules).

This layer must meet the environmental challenges specific to every area of the body. For instance, the skin of the face must be thin and versatile to accommodate facial expressions. The skin covering the heel of the foot needs to be thick and rigid to face up to force and protect it from objects we step on.

Skin composition is determined by multiple aspects, including the structure of the skin barrier, the cell types, and the genes they express.

Until recently, little was known in regards to the cellular and molecular processes behind these differences. In the primary study, researchers showed the mechanisms that lead to those structural changes within the skin.

The epidermis has a “brick and mortar” structure: molecules like ceramides, cholesterol and fatty acids make up the “mortar,” and cells called keratinocytes are the “bricks.”

The researchers used single-cell sequencing to characterize how the keratinocytes differ at different body sites. In addition they used targeted molecular profiling to characterize the molecules that form the “mortar” between the keratinocytes. They then examined how these differences in gene expression matched the compositional differences within the lipid and protein structures across body sites. These experiments explained why the skin looks so different at different body sites.

The compositional differences within the skin’s lipids and proteins across different body sites may explain why different skin diseases are found at different body sites. While characterizing the precise lipid alterations related to various skin diseases, the researchers discovered that lipids stuck to a bit of tape applied to the skin were sufficient to diagnose a patient with a specific skin disease.

“These discoveries will result in non-diagnostic tests for common dermatologic disease” said co-lead creator, Project Scientist Alexander Merleev.

“These differences are also relevant to the long run design of skincare products,” said Stephanie Le, dermatology resident and co-lead creator of the study. “They exhibit how skincare products must be specifically formulated to match the actual body site that they will likely be applied to.”

Psoriasis and the immune system

Within the second study, the research team studied how skin cells interact with the immune system.

Previously, it was known that keratinocytes could secrete substances that each increase and reduce inflammation. Using single-cell sequencing to research each keratinocyte individually, the researchers observed that these immune-modulating molecules were expressed in certain layers of the epidermis.

Keratinocytes at the bottom layer of the epidermis secrete immune-attracting and immune anti-inflammatory molecules. That is to draw immune cells to the skin and park them in place to attend patiently to fight off any pathogenic microbe or parasite which may break through the physical barrier of the skin. In contrast, they found that the keratinocytes within the outer layer of the epidermis secrete proinflammatory molecules, particularly IL-36.

IL-36 is a most important mediator of a subtype of psoriasis, an inflammatory skin disease. The team found that the quantity of IL-36 within the skin was regulated by one other molecule called PCSK9 and that individuals with variations of their PCSK9 gene were predisposed to developing psoriasis.

“Our discovery that different layers of the skin secrete different immune mediators is an example of how the skin is very specialized to interact with the immune system. Some people develop skin diseases, similar to psoriasis, when there may be an imbalance within the molecules secreted by different layers of the skin.” said UC Davis research fellow Antonio Ji-Xu, co-lead creator of the study.

Each studies were published in JCI Insight.

Source:

University of California – Davis Health

Journal reference:

10.1172/jci.insight.159762