Category: Dermatology

Exploring the Mechanism behind Drug Eruptions in the Skin

Skin cell (keratinocyte). This normal human skin cell was treated with a growth factor that triggered the formation of specialised protein structures that enable the cell to move. We depend on cell movement for such basic functions as wound healing and launching an immune response.
Credit: Torsten Wittmann, University of California, San Francisco

Millions of people worldwide suffer from unpredictable drug toxicities every year. In particular, drug eruptions which manifest through symptoms such as redness, blisters, and itching on the skin, are quite common. Severe drug eruptions can become life-threatening and can have long-lasting consequences.

Previous studies have identified specific variants of certain genes as potential causal agents of drug eruptions. Scientists believe that the genes encoding the human leukocyte antigen (HLA), a protein expressed on the surface of leucocytes known to play an important role in the immune system, are involved in the onset of drug eruption. But current theories cannot explain why HLA-related drug eruptions typically manifest on the skin rather than in multiple organs throughout the body.

To address this knowledge gap, a research team including Lecturer Shigeki Aoki, Kousei Ito, and Akira Kazaoka from the Graduate School of Medical and Pharmaceutical Sciences, Chiba University, conducted an in-depth study on the link between HLA and drug eruptions. Their findings were published in PNAS Nexus.

The researchers first conducted a series of experiments on mice keratinocytes. These keratinocytes, the most common type of skin cell, were engineered to express a specific variant of the HLA gene called HLA-B*57:01, which specifically bind to the antiviral drug abacavir. Then, they validated these findings in genetically modified mice expressing HLA-B*57:01, that were exposed to abacavir.

The researchers found that HLA-B*57:01-expressing keratinocytes that were exposed to abacavir exhibited endoplasmic reticulum (ER) stress responses, such as immediate release of calcium into the cytosol and elevated expression of heat shock protein 70 (HSP70). They also observed an increased production of cytokines and immune cell migration. Abacavir exposure triggered HLA misfolding in the ER, leading to ER stress. Moreover, the researchers observed that the ER stress could be reduced by using 4-phenylbutyrate (4-PB). By alleviating this stress, they managed to suppress the onset of severe drug eruption symptoms. This newfound knowledge could form the basis for innovative treatment options for management of drug eruptions.

HLAs – secondary players for the immune system

But how does this new information contrast with what was already known about HLA? “HLA molecules are an integral component of our immune system, that typically present foreign antigens to white blood cells, which judge these antigens as self or non-self. In this established role, HLAs are usually secondary players,” explains Dr Aoki. “However, our research highlights a novel function of the HLA molecule within skin cells. We revealed that a specific HLA genotype in keratinocytes can recognise certain drugs as foreign, triggering an endoplasmic reticulum stress response.”

Taken together, the findings of this study uncover a new role of HLA proteins in sensing and responding to potential threats in skin cells. Thus, their functions may extend well beyond mere antigen presentation for the immune system. Moreover, considering that the variant of HLA possessed by an individual can be determined through genetic testing, this study could help develop preventive measures and diagnostics against severe adverse drug reactions.

According to Dr Aoki, this is in line with current research directions and trends in medical science.

“In 10 years, we anticipate entering the ‘whole genome era,’ where personalised medicine based on individual genomes will become a standard practice,” he comments. He further adds, “Building on the findings of this study, we believe that a comprehensive understanding of the mechanism underlying HLA-dependent adverse drug reactions will enable the delivery of safe medical care, allowing patients to avoid unnecessary suffering due to side effects.”

Future research might minimise the occurrence of drug eruptions and save people from potentially fatal adverse drug reactions.

Source: Chiba University

Among Black Men, Study Finds Increased Mortality from Melanoma Diagnoses

Photo by Nsey Benajah on Unsplash

Melanoma is often detected later in people with darker skin complexions – and the consequences can be devastating, according to the results of a Mayo Clinic study published in the Journal of Surgical Oncology.

While melanoma may be found less frequently in people with darker complexions than fair ones, this aggressive form of skin cancer, accounting for 75% of all skin-cancer-related deaths, can strike anyone. The study, which consisted of 492 597 patients with melanoma, suggests that added vigilance in early screening is particularly needed for Black men, whose cancers are often found at later stages, leading to worse outcomes compared to white patients or Black women.

“We compared non-Hispanic Black patients to white patients and saw striking differences in how patients presented with the disease,” says surgical oncologist Tina Hieken, MD, senior author of the study and a researcher at Mayo Clinic Comprehensive Cancer Center. “We saw more extremity melanoma, and more later-stage disease.”

Extremity melanoma refers to skin cancer that can develop on the arms, legs, hands and feet. Various factors, including social risk factors and biological components, could be at play, but further research is needed to help determine why these differences exist.

Revealing differences in sex-based immune response

The research found that Black female patients with melanoma fared better than Black male patients. Men tended to be older at diagnosis and more likely to have cancer that had spread to their lymph nodes compared to women. This translated to worse survival rates: the five-year survival for Black men with stage 3 melanoma was only 42% chance, compared to 71% for Black women.

Most research on melanoma hasn’t focused on how race and sex affect outcomes and hasn’t looked at the influence of race and ethnicity across all groups. Dr Hieken says the study highlights the need to understand these differences better, noting that this is the first large study to confirm that sex-based differences in melanoma outcomes exist within the non-Hispanic Black population.

“When we talk about later-stage melanoma patients who are female versus male in that non-Hispanic Black patient cohort who ended up doing worse, some biological things may be going on here that are interesting,” says Dr Hieken.

One theory centres on variations in immune response.

“Several immune signals suggest that women may respond better to some immunotherapies than males,” says Dr Hieken.

Researchers note that more studies focused on melanoma in a broader range of people, including more Black participants in clinical trials, is key to bridging this knowledge gap and potentially identifying more effective treatments.

Healthcare professionals should screen carefully

Dr Hieken notes that this study is a wake-up call for everyone battling to diagnose and cure melanoma, regardless of the patient’s sex or skin tone.

She emphasises that healthcare professionals should carefully examine areas like palms, soles and under fingernails, where melanoma might be more challenging to spot on darker skin.

“We can incorporate screening for skin lesions or lesions under the nails into the visit for patients as part of their regular checkups,” says Dr Hieken. “What we want to do is elevate care for our patients.”

Source: Mayo Clinic

New Index Improves Targeting of Skin Blemishes with Laser Treatment

Photo by Cottonbro on Pexels

To improve the efficacy of treating skin blemishes with laser treatment while reducing complications, an Osaka Metropolitan University-led research group has developed an index of the threshold energy density, known as fluence, and the dependent wavelength for picosecond lasers. The use of this indicator, described in Lasers in Surgery and Medicine, is expected to help set irradiation conditions in clinical practice and reduce complications.

Picosecond lasers have in recent years been used to remove pigmented lesions. These lasers deliver energy beams in pulses that last for about a picosecond – a trillionth of a second. The lasers target melanosomes, which produce, store, and transport the melanin responsible for pigment.

Postdoctoral Fellow Yu Shimojo of OMU’s Graduate School of Medicine and Specially Appointed Professor Toshiyuki Ozawa and Professor Daisuke Tsuruta of the school’s Department of Dermatology were among the researchers who developed this first picosecond laser index for each of the wavelengths used in clinical practice in treating pigmented lesions.

Using a mathematical model based on the thresholds, the researchers quantitatively evaluated irradiation parameters for 532-, 730-, 755-, 785-, and 1064-nm picosecond laser treatments.

A suspension of melanosomes extracted from pig eyes was irradiated using picosecond lasers with varying fluence. The mean particle size of the irradiated melanosomes was measured by dynamic light scattering, and their disruption was observed by scanning electron microscopy to determine the disruption thresholds. A mathematical model was developed, combined with the threshold obtained and Monte Carlo light transport to calculate irradiation parameters required to disrupt melanosomes within the skin tissue.

The numerical results quantitatively revealed the relationship between irradiation wavelength, incident fluence, and spot size required to disrupt melanosomes distributed at different depths in the skin tissue. Comparing previously reported clinical studies, the researchers confirmed that clinical results showing low complication rates and high efficacy can be explained based on these wavelength-dependent indicators.

“The use of this indicator is expected to play an important part in setting irradiation conditions in clinical practice,” Postdoc Fellow Shimojo said. “In addition, the implementation of picosecond laser therapy based on scientific evidence, rather than relying solely on physicians’ experience, is expected to improve the safety and effectiveness of the treatment.”

Source: Osaka Metropolitan University

Hyaluronic Acid Can Reverse Photoaging Effects, Study Shows

Picture by Macrovector on Freepik

Chronic exposure of human skin to ultraviolet light causes premature aging, or photoaging. As the skin undergoes photoaging, type I collagen bundles, which are found in the dermis beneath the top layer of the skin and provide strength and support to skin, become fragmented. This leads to wrinkles, fragility and loss of support and elasticity.

“The best way to prevent damage to type I collagen by sunlight is to wear sunscreen consistently, daily if possible and particularly when spending time outdoors,” said Frank Wang, MD, the William B. Taylor Endowed Professor of Clinical Dermatology at U-M Medical School.

Experts observed in a new study that injection of the most popular type of dermal filler, cross-linked hyaluronic acid, into photoaged skin could reverse the dermal changes associated with photoaging.

These fillers are typically injected into the skin to reduce lines and wrinkles.

They are thought to provide clinical improvement by adding volume to the skin, but researchers have found that cross-linked hyaluronic acid also stimulates production of new type I collagen in the dermis.

The filler does so rapidly, stimulating collagen production within several weeks of injection, and is long-lasting, promoting the accumulation of more collagen over the course of a year.

These findings indicate how the filler improves the appearance of skin in the short-term – a combination of space-filling and collagen.

Additionally, since newly formed dermal collagen lasts many years, the findings also provide insight into how the filler can promote long-term clinical improvement, months or even a year after injection.

“A single injection of cross-linked hyaluronic acid dermal filler can lead to rapid and long-lasting improvement of skin by stimulating collagen deposition, and furthermore, repeat injections may add more collagen, eventually reducing the need for re-treatment,” Wang said.

Source: Michigan Medicine – University of Michigan

New Therapy Eliminates ‘Problematic’ T Cells in Skin Autoimmune Diseases

Photo: CC0

In a groundbreaking study published in Science, researchers discovered distinct mechanisms controlling different types of immune cells, and found that, by precisely targeting these mechanisms, they could selectively eliminate ‘problematic cells’ and reshape the skin’s immune landscape.

The skin is packed with specialised immune cells that protect against infections and cancer and promote healing. These cells, called tissue-resident T cells or TRM cells, stay in place to fight infections and cancerous cells in the skin.

However, when not controlled properly, some of these skin TRM cells can contribute to autoimmune diseases, such as psoriasis and vitiligo.

Researchers, led by University of Melbourne’s Professor Laura Mackay, a Laboratory Head and Immunology Theme Leader at the Peter Doherty Institute of Infection and Immunity (Doherty Institute), found a way to redress this imbalance.

University of Melbourne’s Dr Simone Park, an Honorary Research Fellow and former Postdoctoral Fellow in the Mackay Lab at the Doherty Institute, and lead first author of the study, said that this research is the first to describe the unique elements that control various types of skin TRM cells in animal models, offering precise targets for potential treatment strategies.

“Specialised immune cells in our skin are diverse: many are critical to prevent infection and cancer, but others play a big role in mediating autoimmunity,” said Dr Park.

“We discovered key differences in how distinct types of skin T cells are regulated, allowing us to precisely edit the skin’s immune landscape in a targeted way.”

University of Melbourne’s Dr Susan Christo, Senior Research Officer in the Mackay Lab at the Doherty Institute and co-first author of the study, explained how these discoveries could advance efforts to treat skin disease.

“Most autoimmune therapies treat the symptoms of the disease rather than addressing the cause. Conventional treatments for skin disorders often impact all immune cells indiscriminately, meaning that we could also be wiping out our protective T cells,” said Dr Christo.

“Until now, we didn’t know how to pick apart ‘bad’ T cells in the skin from the ‘good’ protective ones. Through this research, we discovered new molecules that allow us to selectively remove disease-causing T cells in the skin.”

The research team harnessed this new knowledge to eliminate ‘problematic’ cells that can drive autoimmune disorders, while preserving the ‘good’ ones that are essential to maintain protective immunity.

University of Melbourne’s Professor Laura Mackay, senior author of the study, explained that these findings could pave the way for more precise and long-lasting therapies for skin disease.

“Skin conditions like psoriasis and vitiligo are difficult to treat long-term. The T cells driving disease are hard to remove, so patients often need life-long treatment. Our approach has the potential to revolutionise the way we treat these skin disorders, significantly improving outcomes for people dealing with challenging skin conditions,” said Professor Mackay.

With the study demonstrating successful removal of specific skin T cells in animal models, further research is necessary to validate the efficacy of these strategies in human subjects.

Dr Park hopes the study will inspire the development of new treatments for skin disease.

“These discoveries bring us one step closer to developing new drugs that durably prevent autoimmune skin disorders without compromising immune protection,” said Dr Park.

Source: The Peter Doherty Institute for Infection and Immunity

Skin Bacteria may Hold New Weapons against Antibiotic-resistant Bacteria

Methicillin resistant Staphylococcus aureus (MRSA) – Credit: CDC

Antibiotic-resistant bacteria are a growing global problem, but of the solution may lie in copying the bacteria’s own weapons. Researchers in the Norwegian city of Tromsø has found a new bacteriocin, in a very common skin bacterium, which they describe in Microbiology Spectrum. Bacteriocin inhibits the growth of antibiotic-resistant bacteria that are often the cause of disease and can be difficult to treat.

One million deaths each year

The fact that we have medicines against bacterial infections is something many people take for granted. But increasing resistance among bacteria means that more and more antibiotics do not work. When the bacteria become resistant to the antibiotics we have available, we are left without a treatment option for very common diseases. Over one million people die each year as a result of antibiotic resistance.

The first step in developing new antibiotics is to look for substances that inhibit bacterial growth.

Sami name for an exciting discovery

The research group for child and youth health at UiT The Arctic University of Norway has studied substances that the bacteria themselves produce to inhibit the growth of competitors. These substances are called bacteriocins. Through the work, they have discovered a new bacteriocin, in a very common skin bacterium. Bacteriocin inhibits the growth of antibiotic-resistant bacteria that can be difficult to treat with common antibiotics.

The researchers have called the new bacteriocin Romsacin, after the Sami name for Tromsø, Romsa. The hope is that Romsacin can be developed into a new medicine for infections for which there is currently no effective treatment.

Long way to go

At the same time, researcher Runa Wolden at the Department of Clinical Medicine at UiT emphasizes that there is a long way to go before it is known whether Romsacin will be developed and taken into use as a new medicine. Because that’s how it is with basic research; you cannot say in advance when someone will make use of the results you produce.

“This discovery is the result of something we have been researching for several years. Developing Romsacin – or other promising substances – into new antibiotics is very expensive and can take 10-20 years,” says Wolden, who is part of the research group for child and youth health.

Effective against bacterial types

Before new antibiotics can be used as medicines, one needs to make sure that they are safe to use. Currently, researchers do not know how the bacteriocin works in humans. A further process will involve comprehensive testing, bureaucracy and marketing.

“This naturally means that there is a long way to go before we can say anything for sure. What we already know, however, is that this is a new bacteriocin, and that it works against some types of bacteria that are resistant to antibiotics. It’s exciting,” says Wolden.

The new bacteriocin is produced by a bacterium called Staphylococcus haemolyticus. The bacteriocin is not produced by all S. haemolyticus, but by one of the 174 isolates that the researchers have available in the freezer.

“We couldn’t know that before we started the project, and that’s one of the things that makes research fun,” says Wolden.

She says that ten years ago the researchers collected bacterial samples from healthy people when they wanted to compare S. haemolyticus in healthy people with those found in patients in hospital.

“Subsequently, we have done many experiments with these bacteria, and this is the result from one of our projects,” says Wolden.

Source: UiT The Arctic University of Norway

Researchers Stumble on Haemoglobin in the Epidermis

Image by macrovector on Freepik

Researchers have shown for the first time that haemoglobin, a protein found in red blood cells where it binds oxygen, is also present in the epidermis. The study, which appears in the Journal of Investigative Dermatology, published by Elsevier, provides important insights into the properties of the skin’s protective external layer.

This research was driven by a curiosity about the protective role of the epidermis and what unexpected molecules are expressed in it. Researchers discovered the haemoglobin α protein in keratinocytes of the epidermis and in hair follicles. This unexpected evidence adds a new facet to the understanding of the workings of the skin’s defence mechanisms.

Lead investigator of the study Masayuki Amagai, MD, PhD, Department of Dermatology, Keio University School of Medicine, Tokyo, and Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, explains: “The epidermis consists of keratinised stratified squamous epithelium, which is primarily composed of keratinocytes. Previous studies have identified the expression of various genes with protective functions in keratinocytes during their differentiation and formation of the outer skin barrier. However, other barrier-related genes escaped prior detection because of difficulties obtaining adequate amounts of isolated terminally differentiated keratinocytes for transcriptome analysis.”

Haemoglobin binds gases such as oxygen, carbon dioxide, and nitric oxide, and it is an iron carrier via the heme complex. These properties make epidermal haemoglobin a prime candidate for antioxidant activity and potentially other roles in barrier function.

Professor Amagai continues: “We conducted a comparative transcriptome analysis of the whole and upper epidermis, both of which were enzymatically separated as cell sheets from human and mouse skin. We discovered that the genes responsible for producing haemoglobin were highly active in the upper part of the epidermis. To confirm our findings, we used immunostaining to visualise the presence of haemoglobin α protein in keratinocytes of the upper epidermis.”

Professor Amagai concludes: “Our study showed that epidermal haemoglobin was upregulated by oxidative stress and inhibited the production of reactive oxygen species in human keratinocyte cell cultures. Our findings suggest that haemoglobin α protects keratinocytes from oxidative stress derived from external or internal sources such as UV irradiation and impaired mitochondrial function, respectively. Therefore, the expression of haemoglobin by keratinocytes represents an endogenous defence mechanism against skin aging and skin cancer.”

Source: EurekAlert!

New Synthetic Melanin Cream Could Boost Skin’s Natural Healing Process

The synthetic melanin is being applied to inflamed skin. Just under the surface of the skin are green free radicals, also known as reactive oxygen species (ROS). Credit: Yu Chen, Northwestern University

Imagine a skin cream that heals damage occurring throughout the day when your skin is exposed to sunlight or environmental toxins. That’s the potential of a synthetic, biomimetic melanin developed by scientists at Northwestern University.

In a new study, published in Nature npj Regenerative Medicine, the scientists show that their synthetic melanin, mimicking the natural melanin in human skin, can be applied topically to injured skin, where it accelerates wound healing. These effects occur both in the skin itself and systemically in the body.

When applied in a cream, the synthetic melanin can protect skin from sun exposure and heals skin injured by sun damage or chemical burns, the scientists said. The technology works by scavenging free radicals, which are produced by injured skin such as a sunburn. Left unchecked, free radical activity damages cells and ultimately may result in skin aging and skin cancer.

Melanin in humans and animals provides pigmentation, protecting cells from sun damage with increased pigmentation in response to sunlight. That same pigment in skin also naturally scavenges free radicals in response to damaging environmental pollution from industrial sources and automobile exhaust fumes.

Everyday skin injury

“People don’t think of their everyday life as an injury to their skin,” said co-corresponding author Dr. Kurt Lu, the Eugene and Gloria Bauer Professor of Dermatology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine dermatologist. “If you walk barefaced every day in the sun, you suffer a low-grade, constant bombardment of ultraviolet light. This is worsened during peak mid-day hours and the summer season. We know sun-exposed skin ages versus skin protected by clothing, which doesn’t show age nearly as much.”

The skin also ages due to chronological aging and external environmental factors, including environmental pollution.

“All those insults to the skin lead to free radicals which cause inflammation and break down the collagen,” Lu said. “That’s one of the reasons older skin looks very different from younger skin.”

When the scientists created the synthetic melanin engineered nanoparticles, they modified the melanin structure to have higher free radical scavenging capacity.

“The synthetic melanin is capable of scavenging more radicals per gram compared to human melanin,” said co-corresponding author Nathan Gianneschi, the Jacob and Rosaline Cohn Professor of Chemistry, Materials Science & Engineering, Biomedical Engineering and Pharmacology at Northwestern. “It’s like super melanin. It’s biocompatible, degradable,nontoxic and clear when rubbed onto the skin. In our studies, it acts as an efficient sponge, removing damaging factors and protecting the skin.”

Once applied to the skin, the melanin sits on the surface and is not absorbed into the layers below.

“The synthetic melanin stabilises and sets the skin on a healing pathway, which we see in both the top layers and throughout the body,” Gianneschi said.

Both Lu and Gianneschi are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Topical cream quiets immune system

The scientists, who have been studying melanin for nearly 10 years, first tested their synthetic melanin as a sunscreen.

“It protected the skin and skin cells from damage,” Gianneschi said. “Next, we wondered if the synthetic melanin, which functions primarily to soak up radicals, could be applied topically after a skin injury and have a healing effect on the skin? It turns out to work exactly that way.”

Lu envisions the synthetic melanin cream being used as a sunscreen booster for added protection and as an enhancer in moisturiser to promote skin repair.

“You could put it on before you go out in the sun and after you have been in the sun,” Lu said. “In both cases, we showed reduction in skin damage and inflammation. You are protecting the skin and repairing it simultaneously. It’s continuous repair.”

The cream could also potentially be used for blisters and open sores, Lu said.

Gianneschi and Lu discovered that the synthetic melanin cream, by soaking up the free radicals after an injury, quieted the immune system. The stratum corneum, the outer layer of mature skin cells, communicates with the epidermis below. It is the surface layer, receiving signals from the body and from the outside world. By calming the destructive inflammation at that surface, the body can begin healing instead of becoming even more inflamed.

“The epidermis and the upper layers are in communication with the entire body,” Lu said. “This means that stabilising those upper layers can lead to a process of active healing.”

The scientists used a chemical to create a blistering reaction to a human skin tissue sample in a dish. The blistering appeared as a separation of the upper layers of the skin from each other.

“It was very inflamed, like a poison ivy reaction,” Lu said.

They waited a few hours, then applied their topical melanin cream to the injured skin. Within the first few days, the cream facilitated an immune response by initially helping the skin’s own radical scavenging enzymes to recover, then by halting the production of inflammatory proteins. This initiated a cascade of responses in which they observed greatly increased rates of healing. This included the preservation of healthy skin layers underneath. In samples that did not have the melanin cream treatment, the blistering persisted.

“The treatment has the effect of setting the skin on a cycle of healing and repair, orchestrated by the immune system,” Lu said.

Melanin could protect from toxins including nerve gas

Gianneschi and Lu are studying melanin as part of US government-funded research, which has included looking at melanin as a dye for clothing that would also act as an absorbent for toxins in the environment, particularly nerve gas. They showed they could dye a military uniform black with the melanin, and that it would absorb the nerve gas.

Melanin also absorbs heavy metals and toxins. “Although it can act this way naturally, we have engineered it to optimise absorption of these toxic molecules with our synthetic version,” Gianneschi said.  

The scientists are pursuing clinical translation and trials testing for efficacy of the synthetic melanin cream. In an initial step, the scientists recently completed a trial showing that the synthetic melanins are non-irritating to human skin.

Given their observation that melanin protects biologic tissue from high energy radiation, they surmise that this could be an effective treatment for skin burns from radiation exposure.

The promising work may well provide treatment options for cancer patients in the future, undergoing radiation therapy.

Source:

Study Reveals a Touchy Secret in Hair Follicles

Photo by Tobias Aeppli

Imperial researchers have discovered a hidden mechanism within hair follicles that allows the sensation of touch. Previously, touch was thought to be detected only by nerve endings present within the skin and surrounding hair follicles. This new research from Imperial College London has found that that cells within hair follicles (the structures surrounding the hair fibre) are also able to detect the sensation in cell cultures.

The researchers also found that these hair follicle cells release the neurotransmitters histamine and serotonin in response to touch. These findings, published in Science Advances, might help us in future to understand histamine’s role in inflammatory skin diseases like atopic dermatitis.

Lead author of the paper Dr Claire Higgins, from Imperial’s Department of Bioengineering, said: “This is a surprising finding as we don’t yet know why hair follicle cells have this role in processing light touch. Since the follicle contains many sensory nerve endings, we now want to determine if the hair follicle is activating specific types of sensory nerves for an unknown but unique mechanism.”

A touchy subject

We feel touch using several mechanisms: sensory nerve endings in the skin detect touch and send signals to the brain; richly innervated hair follicles detect the movement of hair fibres; and sensory nerves known as C-LTMRs, that are only found in hairy skin, process emotional, or ‘feel-good’ touch.

Now, researchers may have uncovered a new process in hair follicles. To carry out the study, the researchers analysed single cell RNA sequencing data of human skin and hair follicles and found that hair follicle cells contained a higher percentage of touch-sensitive receptors than equivalent cells in the skin.

They established co-cultures of human hair follicle cells and sensory nerves, then mechanically stimulated the hair follicle cells, finding that this led to activation of the adjacent sensory nerves.

They then decided to investigate how the hair follicle cells signalled to the sensory nerves. They adapted a technique known as fast scan cyclic voltammetry to analyse cells in culture and found that the hair follicle cells were releasing the neurotransmitters serotonin and histamine in response to touch.

When they blocked the receptor for these neurotransmitters on the sensory neurons, the neurons no longer responded to the hair follicle cell stimulation. Similarly, when they blocked synaptic vesicle production by hair follicle cells, they were no longer able to signal to the sensory nerves.

They therefore concluded that in response to touch, hair follicle cells release that activate nearby sensory neurons.

The researchers also conducted the same experiments with cells from the skin instead of the hair follicle. The cells responded to light touch by releasing histamine, but they didn’t release serotonin.

Dr Higgins said: “This is interesting as histamine in the skin contributes to inflammatory skin conditions such as eczema, and it has always been presumed that immune cells release all the histamine. Our work uncovers a new role for skin cells in the release of histamine, with potential applications for eczema research.”

The researchers note that the research was performed in vitro, and will need to be replicated in vivo The researchers also want to determine if the hair follicle is activating specific types of sensory nerves. Since C-LTMRs are only present within hairy skin, they are interested to see if the hair follicle has a unique mechanism to signal to these nerves that we have yet to uncover.

Source: Imperial College London

When This Itch Cytokine ‘Talks’, Neurons Respond

Photo by FOX

Scratching an itch can be a relief, but for many patients it can get out of control, becoming a serious health problem. So what normally stops this progression?

A paper published in Science Immunology reports a breakthrough that could transform how doctors treat conditions from atopic dermatitis to allergies, they have discovered a feedback loop centred on a single immune protein called IL-31 that both causes the urge to itch and dials back nearby inflammation.

The findings, by Scientists at UC San Francisco, lay the groundwork for a new generation of drugs that interact more intelligently with the body’s innate ability to self-regulate.

Previous approaches suggested that IL-31 signals itch and promotes skin inflammation. But the UCSF team discovered that nerve cells, or neurons, that respond to IL-31, triggering a scratch, also prevent immune cells from overreacting and causing more widespread irritation.

“We tend to think that immune proteins like IL-31 help immune cells talk to one another, but here, when IL-31 talks to neurons, the neurons talk right back,” said Marlys Fassett, MD, PhD, UCSF professor of dermatology and lead author of the study. “It’s the first time we’ve seen the nervous system directly tamp down an allergic response.”

The discovery could eventually change how asthma, Crohn’s and other inflammatory diseases are treated, due to IL-31’s presence throughout the body.

“IL-31 causes itch in the skin, but it’s also in the lung and in the gut,” said Mark Ansel, Ph.D., UCSF professor of immunology and senior author of the study. “We now have a new lead for fighting the many diseases involving both the immune and nervous systems.”

More than an itch

IL-31 is one of several “itch cytokines” because of its ability to instigate itch in animals and people. Fassett, a dermatologist and a researcher, has wanted to know why since she arrived at UCSF in 2012, a few years after its discovery. She reached out to Ansel, a former colleague and asthma expert who welcomed her into his lab.

First, Fassett removed the IL-31 gene from mice and exposed them to the house dust mite, a common, itchy allergen.

“We wanted to mimic what was actually happening in people who are chronically exposed to environmental allergens,” Fassett said. “As we expected, the dust mite didn’t cause itching in the absence of IL-31, but we were surprised to see that inflammation went up.”

Why was there inflammation but no itching? Fassett and Ansel found that a cadre of immune cells had been called into action in the absence of the itch cytokine. Without IL-31, the body was blindly waging an immunological war.

IL-31 brings balance to the forces

Ansel and Fassett then homed in on the nerve cells in the skin that received the IL-31 signal. They saw that the same nerve cells that spurred a scratch also dampened any subsequent immune response. These nerve cells were integral to keeping inflammation in check, but without IL-31, they let the immune system run wild.

The findings squared well with what dermatologists were increasingly seeing with a new drug, nemolizumab, which blocked IL-31 and was developed to treat eczema. While clinical trial patients found that the dry, patchy skin of their eczema receded on the drug, other skin irritation, and even inflammation in the lungs, would sometimes flare up.

“When you give a drug that blocks the IL-31 receptor throughout the whole body, now you’re changing that feedback system, releasing the brakes on allergic reactions everywhere,” Ansel said.

Fassett and Ansel also found that these neurons released their own signal, called CGRP, in response to the itch signal, which could be responsible for dampening the immune response.

“The idea that our nerves contribute to allergy in different tissues is game changing,” Fassett said. “If we can develop drugs that work around these systems, we can really help those patients that get worse flares after treatment for itch.”

Fassett recently founded her own lab at UCSF to tease apart these paradoxes in biology that complicate good outcomes in the clinic. And Ansel is now interested in what this itch cytokine is doing beyond the skin.

“You don’t itch in your lungs, so the question is, what is IL-31 doing there, or in the gut?” Ansel asked. “But it does seem to have an effect on allergic inflammation in the lung. There’s a lot of science ahead for us, with immense potential to improve therapies.”

Source: