Severe eczema, also known as atopic dermatitis, is a chronic
inflammatory skin condition that is driven by an allergic reaction. In a study
published in Journal of Experimental Medicine, researchers at La Jolla
Institute reveal an important player that promotes skin inflammation in atopic
dermatitis and the characteristic thickening of the skin.

Their work demonstrates that LIGHT, a member of the tumour
necrosis factor (TNF) super family, directly controls the hyperproliferation of
keratinocytes as well as the expression of periostin, a  protein that contributes to the clinical features of atopic dermatitis as well
as other inflammatory skin diseases such as scleroderma.

“Periostin is being used in the clinic as a marker for
allergic diseases such as asthma as well as atopic dermatitis,” explains senior
author Michael Croft, PhD, professor and head in the Division of Immune
Regulation. “The fact that LIGHT acts upstream of periostin and is controlling
its production really reinforces the idea that this is potentially a very good
clinical target for treatment of atopic dermatitis and other inflammatory skin

In fact, a therapeutic antibody that neutralizes the
activity of LIGHT successfully suppressed disease symptoms after they first
appeared, suggesting that therapies based on blocking LIGHT may add a valuable
treatment option for patients suffering from severe eczema, an often
debilitating disease.

LIGHT is a cytokine primarily produced by T cells and exerts
its function through two receptors, HVEM and LTβR. In an earlier study, Rana
Herro, PhD, an instructor in the Croft lab and lead author on both studies, had
shown that LIGHT plays a key role in skin inflammation in scleroderma, an
autoimmune disease that results in the overproduction of collagen leading to
the thickening and scarring of tissue. But whether LIGHT signalling is also
involved in other types of skin inflammation was unknown.

To find out whether LIGHT contributes to skin inflammation
in atopic dermatitis, Herro used an experimental model for atopic dermatitis
that replicates the human disease. Her experiments revealed that
LIGHT-deficient mice only displayed minimal clinical symptoms compared to
normal control mice. The same was true for animals that only lacked the
LIGHT-receptor HVEM in keratinocytes, the predominant cell type in the
outermost layer of the skin. “This is the important part of the study,” says
Herro. ”Specifically deleting the receptor in keratinocytes was enough to
abrogate disease.”

A closer look revealed that LIGHT stimulates the
proliferation of keratinoyctes and thus the structural remodelling of the skin.
It also showed that LIGHT strongly induces the expression of periostin. This
protein is highly expressed in the skin of patients with atopic dermatitis and
scleroderma, and animal studies have found it is essential for skin inflammation,
although exactly how it functions is still being debated.

“We knew that LIGHT acts as a pro-inflammatory molecule on
immune cells but we were able to implicate, for the first time in a disease
setting, that this molecule acts on non-immune cells like the structural cells
of the skin,” says Herro. “LIGHT directly drives fibrosis, a structural remodelling
process that leads to the thickening and hardening of the skin.”

The researchers then went back and used an existing
therapeutic antibody to block the interaction of LIGHT with its receptor, HVEM,
after disease had already manifested. The antibody treatment suppressed
inflammation and strongly reduced epidermal thickening. “That’s great news for
patients suffering from eczema,” says Herro. “Our findings suggest that
therapies that block LIGHT signalling might halt atopic dermatitis in humans
and maybe even reverse disease symptoms.”


Reference: Herro
R, et al. LIGHT-HVEM Signaling in Keratinocytes Controls Development of
Dermatitis. Journal of Experimental Medicine, January 2018. DOI: