Langerhans Cells Protect Skin Against Photosensitivity in Lupus, Researchers Find

Langerhans Cells Protect Skin Against Photosensitivity in Lupus, Researchers Find

A type of immune cell found in the outer layer of the skin, called Langerhans cells, seem to be essential to protect the skin against photosensitivity in cutaneous and systemic forms of lupus.

The study, “A protective Langerhans cell–keratinocyte axis that is dysfunctional in photosensitivity,” was published in Science Translational Medicine.

It is estimated that photosensitivity, or extreme skin sensitivity to ultraviolet radiation (UVR), leading to severe skin rashes and blistering, affects 30 to 60 percent of patients diagnosed with lupus. While it is a common feature among several autoimmune and dermatologic disorders, its basis is still poorly understood.

“Photosensitivity is poorly understood, and we launched the study to gain insight into the underlying cause,” Theresa Lu, MD, PhD, lead investigator and associate scientist in the Autoimmunity and Inflammation Program at Hospital for Special Surgery (HSS), said in a press release. “Current treatment consists mainly of sun avoidance and sunscreen to prevent the skin rash. A better understanding of the cellular mechanisms involved in photosensitivity could lead to improved treatment.”

The researchers focused their efforts on Langerhans cells (LCs) with the belief that they could play an important role in protecting the skin against photosensitivity.

Keratinocytes, the predominant type of cells found in the epidermis, or outer layer of the skin, rely on epidermal growth factor family (EGF) molecules to remain healthy. In normal conditions, LCs express metalloprotease 17 (ADAM17), a molecule that is activated by UV light and activates EGF molecules.

However, when researchers analyzed the skin of mice that lacked LCs, they found the mice developed photosensitivity. The same happened when they deleted ADAM17 from LCs.

“We knew that [Langerhans cells] were immune cells that protect against infection, so this is a new role for them in terms of protecting the health of the skin exposed to UV light,” Lu said. “We’re excited about these findings because they provide new insight into photosensitivity, and we now have a potential pathway of molecules and cells to target for a possible treatment down the road.”

They also demonstrated that human and mice LCs grown in a lab dish protected keratinocytes from UVR. They also showed that UVR induces the activation of ADAM17 and the production of EGFR (EGF receptor) ligands in LCs, indicating that LCs may protect keratinocytes from UVR damage.

Lu’s team also showed that in photosensitive mouse models for systemic lupus erythematosus (SLE) and in skin samples from patients that this chain of events was not working well. There was a significant reduction in EGF activation, accompanied by LC defects.

“Our laboratory study found that Langerhans cells played an important role in protecting the skin from UV light-induced injury. In models of lupus, LCs express less of the ADAM17 molecule, so they are less effective at activating the EGF family cytokines that play a role in protecting the skin. In other words, the cellular pathway is not working as it should,” Lu explained.

Topical application of EGFR ligands reduced skin photosensitivity in the SLE mouse model, suggesting that EGFR stimulation could be used to treat photosensitivity.

“Our data suggest that topical EGFR stimulation could be a treatment to prevent the development of photosensitive cutaneous lesions in lupus erythematosus. … topical EGF is being investigated for rashes associated with the use of EGFR inhibitors to treat lung cancer patients who are most likely immunocompromised (CinicalTrials.gov; trials NCT03051880 and NCT03047863),” the authors wrote.

The findings suggested that LCs protect the skin against photosensitivity, uncovered its mechanistic basis and indicated that EGFR stimulation could be a promising treatment for lupus erythematosus and other autoimmune and dermatologic conditions.

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