UV rays may trigger lupus formation through inflammation, researchers detail

11 May 2022 --- Normal-appearing skin in lupus patients contains the same inflammatory signals that are recognized when the skin develops a rash – sometimes at even greater levels, according to researchers from the US-based University of Michigan.

“This data will reinforce the need to be vigilant regarding inflammation triggers in the skin, with the most obvious one being ultraviolet light or sun exposure,” Michelle Kahlenberg, associate professor of Internal Medicine and Dermatology, University of Michigan, tells PersonalCareInsights.

“As the non-lesional skin is primed for inflammation in lupus patients, it doesn’t take much to push patients into a florid rash with the proper trigger.”

Lupus patients have overactive immune systems that target their tissue, causing widespread inflammation. Approximately 70-80% of lupus patients will develop skin disease as part of their condition.

Investigating changes within skin cells
Previous studies of lupus patients’ blood have had difficulty identifying potential biomarkers for disease flares.

Michelle Kahlenberg, associate professor of Internal Medicine and Dermatology, University of Michigan.Knowing that monocytes become more inflammatory when they go to the skin, Kahlenberg believes that the same process could cause systemic immune flares in other lupus organs, including the kidney and brain.

“This paper studies cells straight out of the skin and gives us new insights into how having lupus changes the skin, even when it doesn’t look any different from a healthy person’s,” adds Kahlenberg. “In addition, it shows that the skin cells themselves are playing a vital role in driving and perpetuating inflammation.”

“In future studies, we will want to look at these target organs to understand what’s going on.”

“These cells transformed so robustly when they migrated into the skin it suggests that if we look for biomarkers only in the blood, we will likely miss what is happening in the organs,” she explains.

UV sensitivity and the skin
The researchers evaluated biopsies (an examination of tissue samples) of both normal-appearing skin and skin from rashes of seven lupus patients using single-cell RNA-sequencing analysis.

The findings show that higher interferon signals, a protein linked to UV sensitivity, were found in all lupus biopsies compared to healthy control skin, with the strongest signal coming from the healthy-looking skin rather than the inflamed skin.

These interferon-rich inflammatory properties were found in cells apart from keratinocytes, which make up the skin’s epidermis. The same inflammatory alterations were observed in the fibroblasts that produce the skin’s connective tissue.

“This is important because we have a new drug that can block interferon signaling in lupus, and people are trying to figure out how best to use that medication,” adds Kahlenberg. “So, validating this abnormality in the interferon pathway could be essential for determining the best course of treatment for scores of lupus patients.”

“Anifrolumab is an antibody to the type I interferon receptor that is now approved for use in the US and Japan for moderate to severe lupus with good efficacy in the skin,” explains Kahlenberg. “In addition, JAK inhibitors (used to help treat cancer and inflammatory diseases) block interferon signaling as well.”

“These drugs allow us to block interferons to modulate skin inflammation and interrupt the interferon cycle that drives inflammation and photosensitivity.”

Analyzing skin cells and inflammation
The researchers also obtained blood samples from the same patients to see how immune cells contribute to lupus-related skin inflammation as part of the study.

In lupus patients, immune cells moving from the bloodstream to the skin undergo an inflammatory change (Credit: Justine Ross, Michigan Medicine).Their findings indicate that a subset of monocytes, which are essential members of the innate immune system, are escaping the bloodstream and entering the skin of lupus patients. They undergo a dramatic inflammatory transformation when they enter the skin.

The lupus skin environment – specifically, the interferon in the skin – appears to alter monocytes so that the rest of the immune system is activated.

The innate immune system relies heavily on interferon. It alerts cells about harmful invaders like viruses. However, in many autoimmune diseases, interferon is overproduced in the absence of an actual threat, altering the behavior of immune cells.

“These interferon-educated immune cells seem to be priming many different cell types in the skin to overreact to stimuli with excessive inflammatory responses, manifesting as disfiguring skin lesions,” details Allison C. Billi, a dermatologist at the University of Michigan Health.

“We don’t yet know all of the stimuli that can tip the balance and precipitate these rashes, but UV light certainly appears to be one.”

Understanding cellular alterations, according to Billi, would enable precision medicine in lupus patients, which will use tailored analysis to guide medical decisions and treatment alternatives.

“Research has been hampered by how differently lupus presents across individuals. By focusing on patients with lupus affecting a single organ – the skin – we have insight into which cells are orchestrating lupus inflammation and how,” she explains.

In an interview with PersonalCareInsights, a Renovatio Bioscience exec pegged phenolics as “holy grail” antioxidants for their potential in reducing cellular inflammations and encouraging skin regeneration.

By Nicole Kerr