by Charles Bankhead, Staff Writer, MedPage Today
August 10, 2014

CHICAGO — Clinicians have long suspected that physical manifestations of stress include skin problems. Now scientific evidence has accumulated to justify the suspicion.

Decades of puzzling and seemingly anomalous clinical observations have converged with advances in neurochemistry and molecular signaling to build an increasingly persuasive case that the skin can become stressed out along with the rest of the human body, according to a presentation here at the summer meeting of the American Academy of Dermatology.

“I think we have to decide whether the time has come for stress management techniques to be part of what we use to treat skin disorders and what we tell our patients,” said Richard D. Granstein, MD, of Weill Cornell Medical College in New York City. “If so, what do we tell them to do?”

What about a pimple or other blemish that arises just before an important event? Or a spontaneous case of dermatitis? Or worsening of an existing skin condition? Every dermatologist and many other clinicians can cite at least one example of a patient who has a skin problem that occurs in association with stress, Granstein said.

Anecdotal Evidence

One early anecdote about stress-skin relationships involved a man who required knee surgery to remove a torn ligament. The patient had a long history of plaque psoriasis on both knees. In a letter to the editors of Archives of Dermatology, the patient’s physician described how the psoriasis resolved spontaneously after the surgery.

“It would appear that loss of nerve supply resulted in a dramatically prompt reversal of whatever those nerves were contributing to plaque formation … ,” Stephen B. Dewing, MD, wrote. “The remission and relapse relate directly to the cutting of the nerve and to its regeneration, and are not likely to have been accidental coincidences.”

In a 1972 letter to the journal, another physician described how use of “nerve-blocking agents” led to remission of psoriasis, not once, but on multiple occasions.

“Since the first patient treated by lidocaine, I have treated a considerable number of other patients, the subjects of longstanding psoriasis, either with lidocaine or procaine hydrochloride,” wrote Henry Harris Perlman, MD, PharmD. “Many of these patients have had striking remissions in their disease.”

Just 2 years ago, another report in the dermatology journal documented “sustained complete clinical response” of neurogenic rosacea following endoscopic thoracic sympathectomy.

To illustrate the complexity of the relationship, Granstein played devil’s advocate for a moment. Noting that stress is considered immunosuppressive, he asked why stress does not improve immunologically mediated conditions.

The medical literature contains reports of stress-exacerbated psoriasis, atopic dermatitis, acne, and rosacea. Other reports have described improvement in atopic dermatitis and psoriasis in association with stress-reducing interventions.

Beyond Anecdotes

Though intriguing, the anecdotal reports and limited clinical data fail to provide clear evidence of a scientific basis for the observations. Laboratory studies have begun to fill in the gaps.

In particular, preclinical models have proved to be informative. In one mouse model, mice were engineered to express a transcription factor from keratinocytes, resulting in a psoriasiform inflammation (not necessarily psoriatic disease). Denervation of the skin led to resolution of the inflammation.

Historically Langerhans cells have been considered primary antigen-presenting cells and key initiators of immune responses. Recent studies have suggested “probably that’s not true,” Granstein said. Instead, the cells appear to have situation-dependent immunosuppressive effects.

Granstein and others have examined the effects of calcitonin gene-related peptide (CGRP) on Langerhans cells. A neuropeptide found in central and peripheral nerves, CGRP has potent vasodilator activity. More recently, studies have shown that CGRP affects immune function.

The peptide is found in association with Langerhans cells in the esophageal mucosa, particularly in the setting of inflammation. Additionally, studies have shown that CGRP inhibits T-cell proliferation, production of interleukin-2, and certain macrophage functions, including antigen presentation.

Collectively, the evidence suggested that “CGRP might be telling Langerhans cells what to do,” Granstein said. To explore the issue, investigators introduced antigen into CGRP-exposed and unexposed Langerhans cells, injected the cells into mice, and monitored the animals for delayed hypersensitivity response.

The results showed a dose-dependent downregulation of immune response in the cells exposed to CGRP.

In subsequent studies involving human epidermis, investigators found that CGRP-containing nerves followed pathways directly to Langerhans cells, providing additional evidence of neural input into immunologic activity in the skin.

Continued investigation of CGRP led to the observation that CGRP levels increased in mice exposed to stress. Similarly, experiments involving healthy human volunteers also showed that CGRP levels increased in response to simulated stress.

The question of whether stress can worsen existing skin conditions was evaluated in another study involving mice predisposed to develop atopic dermatitis in conventional housing, but not in a specific pathogen-free environment. Animals exposed to simulated stress developed dermatitis in the conventional and pathogen-free housing.

Sympathetic Involvement

Skin responses to stress might also involve activation of the sympathetic nervous system, resulting in the release of neurotransmitters. As a sympathetic co-transmitter, adenosine triphosphate (ATP) could influence stress-related responses in the skin. Granstein and colleagues hypothesized that ATP might be involved in leukocyte recruitment in the skin by means of inducing expression of proinflammatory molecules by endothelial cells.

In a series of laboratory experiments, investigators demonstrated that endothelial cells express receptors for ATP. Treating the cells with ATP induced expression of IL-6, IL-8, and several other proinflammatory molecules. Additionally, ATP induces expression of ICAM-1, a molecule that facilitates cellular adhesion to the endothelium. Pretreatment of the cells with a receptor antagonist inhibited ATP-induced production of the cytokines and chemokines.

Collectively, the studies have led to the hypothesis that in response to stress, sympathetic nerves express ATP, which binds to endothelial cells in the skin. The binding initiates upregulation of ICAM-1 to facilitate leukocyte binding to the endothelium and induces release of the cytokines and chemokines.

“We now have a whole panoply of different mechanisms by which stress and the nervous system can influence immunity in the skin,” Granstein said. “The real question is whether this is relevant to what we see everyday in the clinic. It probably is, but we still have to find out.”