Research – published in a recent issue of the journal JCI Insight – has discovered a cause of the dry, inflamed and itchy skin that plagues eczema patients. A team led by Donald Leung, MD, Ph.D. at National Jewish Health learned that an immune system skewed toward allergy alters the lipids in the skin. The altered lipids allow the skin to crack, water to leave and irritants to enter, setting the stage for eczematous lesions to develop.
“We have long known that an activated immune system and a defective skin barrier are both important factors in eczema, but not how they are related and which one drives the disease,” says Dr. Leung. “We have now shown that the allergic immune response shortens lipids in the skin, making them less effective at maintaining moisture and more susceptible to irritants.”
The researchers first examined skin from eczema patients and found lipids that were shorter than lipids in the skin of participants with no disease. Lipids are waxy substances vital to healthy skin. They help keep allergens, irritants and infections out, while keeping moisture in. Lipids with longer carbon chains are stronger and more water repellent. The shorter lipids prevalent on eczema patients’ skin protect the skin less effectively. Patients’ skin cells also produced fewer of the enzymes that lengthen lipid chains. When they added cytokines IL-4 and IL-13 to cultured human skin cells, the allergic immune response kicked into high gear and lipids became shorter.
Treatment with those pro-allergic enzymes also reduced expression of lipid-lengthening enzymes. Blocking the activity of IL-4 and IL-13 in the cultured skin cells resulted in an abundance of long-chain lipids. “Our findings demonstrate how the pro-allergic, type 2 immune response alters lipid formation in the skin, leading to a defective skin barrier and the dry, cracked and itchy skin in eczema,” said Dr. Leung.
New Study Identifies A Natural Brake In Allergic Attacks
Eczema – known as atopic dermatitis – is a chronic skin disease that afflicts an estimated 35 million Americans. It is characterized by patches of itchy, dry and cracked skin, which can profoundly impact patients’ lives. Although symptoms mostly involve the skin, an allergic immune response has long been recognized as an important component of the disease. Eczema affects about 17 percent of children in developed countries and is often the gateway to food allergy and asthma, initiating an “atopic march” toward broader allergic sensitization. There are treatments such as steroid creams and a recently approved biologic, but they are expensive or have side effects.
A recent study in Science Immunology suggests a different approach to eczema, one that stimulates a natural brake on the allergic attack. The skin inflammation of eczema is known to be driven by “type 2” immune responses. These are led by activated T helper 2 (TH2) cells and type 2 innate lymphoid cells (ILC2s), together known as effector cells. Another group of T cells, known as regulatory T cells or Tregs, are known to temper type 2 responses, thereby suppressing the allergic response. If you examine an eczema lesion, the numbers of Tregs are unchanged.
Tregs comprise only about five percent of the body’s T cells, but up to 50 percent of T cells in the skin. “Our question was, is there something special about the Tregs that reside in the skin?” says Raif Geha, MD, chief of the Division of Immunology at Boston Children’s Hospital and the senior author of the study. Geha led an investigation using two separate mouse models of eczema, each recreating a separate pathway leading to allergic skin inflammation. The team purified Tregs from the animals’ skin and blood and compared the genes they express.
The Double Whammy
Several genes were especially likely to be turned on in the skin Tregs. One encodes retinoid-related orphan receptor alpha (ROR?), a transcription factor that itself regulates multiple other genes. “We then used a genetic trick to remove ROR? only from Tregs,” says Geha. “Without ROR?, allergic inflammation went crazy in both our mouse models.” The team saw a three-fold increase in the influx of inflammatory cells, and ILC2s and TH2 cells were at the center of the action.”
Why did the Tregs stop working when ROR? was removed? Geha and colleagues discovered that the cells made less of a receptor for a cytokine called TNF ligand-related molecule 1, or TL1A. TL1A is released by skin cells known as keratinocytes, and activates not only Tregs but also ILC2 and TH2 effector cells. “The two kinds of immune cells are competing for TL1A,” Geha explains. “If Tregs don’t have this receptor, they can’t ‘see’ TL1A. Not only are they not activated, but more TL1A is available to activate the effector cells. So you have a double whammy.”
Testing human samples, the team documented higher expression of ROR? in skin Tregs compared with those in blood, similar to mice. Geha now wants to see if ROR? is expressed less in human eczema and whether it’s important in the atopic march. If so, he sees several possible treatment approaches. One is to boost ROR?’s level or activity with compounds that act as ROR? agonists, perhaps given in a topical cream. Geha’s lab also plans to look for factors in the skin that drive ROR? activity, which could present other targets for intervention. Finally, the study showed that ROR? regulates the expression of several genes important for Treg cell migration and function; those pathways could be potential targets too.
Reasons For Eczema Susceptibility
Scientists have uncovered evidence that a deficiency in the skin’s barrier is key to triggering eczema. The team at Newcastle University, in collaboration with scientists at Stiefel, have identified how a key skin barrier protein called filaggrin impacts on other proteins and pathways in the skin, which in turn drive the development of eczema. This also lead them to identify potential targets for future drug development which could treat the underlying cause rather than treating the symptoms.
The research builds on the discovery by scientists in Dundee which showed that lack of the protein filaggrin in the skin caused an inherited dry skin condition known as ichthyosis vulgaris that is strongly linked to the development of atopic eczema, as well as other allergic diseases such as hayfever and asthma. Nick Reynolds, Professor of Dermatology at Newcastle University and who works within the Newcastle Hospitals NHS Foundation Trust, is the lead investigator of the study. “We have shown for the first time that loss of the filaggrin protein alone is sufficient to alter key proteins and pathways involved in triggering eczema,” Reynolds said. “This research reinforces the importance of filaggrin deficiency leading to problems with the barrier function in the skin and predisposing someone to eczema.”
More Pivotal Research
Publishing in the Journal of Allergy and Clinical Immunology(JACI), researchers at Newcastle University, in collaboration with scientists at Stiefel, reported on their development of a human model system. In this, the upper layer of skin (epidermis) was modified, using molecular techniques, to become filaggrin-deficient, directly mimicking the situation observed in the skin of patients with atopic eczema.
This model enabled the team to discover proteins and signaling pathways directly down-stream of filaggrin, and most importantly, identified a number of key regulatory mechanisms. These included regulators of inflammatory signaling, cell structure, barrier function and stress response. These pathways were found to map to those networks observed in the skin of people with active eczema. This mapping provides researchers with new understanding of the mechanisms involved and suggests targets for future drug development.
“This latest research from Newcastle is crucial as it expands on our knowledge of how filaggrin impacts on other proteins and pathways in the skin, which in turn trigger the disease,” says Nina Goad of the British Association of Dermatologists. “This type of research allows scientists to develop treatments that target the actual root cause of the disease, rather than just managing its symptoms. Given the level of suffering eczema causes, this is a pivotal piece of research.”
Can You Improve Children’s Eczema With Silk Clothing?
No significant differences were observed in eczema severity for children with moderate to severe eczema who wore silk garments compared with those who wore their usual clothing, according to a randomized controlled study published in PLOS Medicine by Kim Thomas from University of Nottingham, UK, and colleagues. Clothing may play a role in either exacerbating or soothing eczema, and patients often avoid wool garments and turn to cotton and other fine weave fabrics, including silk.
In the study, 300 children ages one to 15 years with moderate to severe eczema were recruited from five United Kingdom centers covering a range of rural and urban settings. The participants were randomly divided into two groups. Half the children received the standard of care and the other half received the standard of care plus silk garments that are claimed to be beneficial for eczema.
After six months, there was no significant difference in eczema severity based on the Eczema Area and Severity Index. There was also no difference in quality of life or medication use between the groups. The researchers report that the garments are unlikely to be cost-effective even if the small differences between groups were genuine, with a computed cost per quality. A limitation of the study is that the use of an objective outcome measure – an eczema severity score assessed by research nurses – may underestimate changes in symptoms. “The results of this trial suggest that silk garments are unlikely to provide additional clinical or economic benefits over standard care for children with moderate to severe eczema,” the authors added.