How Lupus Skin Reacts Differently to Sunlight

THE LAMP delivered graded doses of ultraviolet B (UVB) light, from 10 up to 80 millijoules per square centimeter, to small patches of skin on the upper buttock, a spot that rarely sees the sun. Skin biopsies taken a day after a controlled dose of ultraviolet light suggest that lupus skin answers with a more inflammatory chain of events than healthy skin does, one that starts in the outermost skin cells and runs through to recruited immune cells leaning toward inflaming rather than calming. That is the picture from skin samples of eight patients with lupus and seven healthy volunteers, analyzed one cell at a time in a study in Science Translational Medicine. Sun avoidance and sunscreen are still the only preventive tools patients have, which makes the cell-by-cell detail worth a closer look.

Photosensitivity is common, with up to 93% of lupus patients who have skin lesions affected, and for them even moderate sun can bring on rashes and flares that reach beyond the skin. By the team’s account, no earlier study had laid out the response cell by cell across both layers of skin.

Ultraviolet B light is mostly absorbed by the basal layer of the epidermis, the skin’s outer shell, so whatever alarm gets raised has to be passed down to the dermis beneath, where blood vessels, fibroblasts (the cells that build connective tissue) and immune cells live. Lupus skin arrives already tilted. Even before any light lands, its cells show signs of interferon activity (interferons are the immune system’s alarm proteins), and that activity climbed further after exposure. In healthy controls, melanocytes, fibroblasts and the cells lining blood vessels showed that interferon signature rising at 24 hours.

Same Cells, Different Conversations

Same light, different skin. Inflammatory keratinocytes, a stressed-looking outer-skin cell state, expanded after exposure in both groups, and you might expect them to behave alike, but software that predicts which cells signal to which put them at the center of the conversation with deeper skin in lupus, while in healthy skin they stayed relatively quiet and Langerhans cells and a subset of melanocytes did most of the talking.

The lupus versions switched on interferon-driven genes and chemokines (signals that call in other cells), where the healthy versions leaned on stress-response genes and a more regulated, calming profile. Software that infers the upstream drivers of those gene patterns flagged mTORC2, a protein complex involved in switching on interferon genes, as the top suspect in lupus. Hence the one wet-lab test in the paper: in cultured keratinocytes (cells grown in a dish) from six patients with lupus, the drug rapamycin, given for 24 hours before UVB exposure, blunted the activity of the interferon beta gene, while a one-hour dose did not, and keratinocytes from healthy donors showed no such effect.

Michelle Kahlenberg, vice chair of research in the Department of Internal Medicine at University of Michigan Health, whose lab ran the study, says the recruited immune cells and their inflammatory skewing “may be an important step in causing lupus rashes.” That is a hedge worth noticing, because the study stopped at a single time point, a day after exposure, and so cannot watch a rash form.

Dendritic Cells Take a Different Route

Of all the immune cells recorded, only monocyte-derived dendritic cells (immune cells that arrive from the blood and present scraps of other cells to the rest of the immune system) rose as a share of the total 24 hours after exposure, and they did so in lupus and healthy skin alike. And where they ended up differed. Under the microscope, a larger share of them sat within 100 micrometers of the boundary between the outer and deeper skin layers in lupus than in healthy samples, and spatial maps of biopsies from four patients with lupus put them closest to the inflammatory keratinocytes after exposure.

More of the lupus ones also carried RNA from keratinocyte genes, a hint (no more than that) that they had swallowed dying skin cells, which could hand the immune system fresh self-material to react to. Pathway analysis tagged the lupus versions as inflammatory and interferon-driven, whereas the healthy versions leaned toward calming, housekeeping programs, and computational trajectories linking blood cells to skin cells suggested a different parentage, classical monocytes for the healthy cells and nonclassical monocytes for the lupus ones, which, if it holds up, would mean two different recruitment routes into the same patch of sun-struck skin.

Still, that family tree comes from computation rather than from following cells through time, and the sample is small: eight patients with lupus, seven controls, one time point, nonlesional skin from people whose skin disease was mild or inactive. The sequencing method missed neutrophils, they are early responders to ultraviolet light, and it missed another dendritic cell type, the plasmacytoid kind, as well, and because interferon genes were expressed at such low levels the team could not say which cells actually make the interferon.

What the Release Leaves Out

The university’s release goes a step further than the paper in two places: it describes the response as centered on too much interferon production, though the team inferred interferon activity from gene signatures and could not say which cells make it, and it says the work identifies pathways that can be targeted to prevent photosensitivity, though no treatment was tested in patients. Fair hopes, not findings.

When the team compared the sun-recruited dendritic cells with cells from lupus rashes sampled in earlier work, the two overlapped in the genes they switched on, and trajectory analysis put the sun-recruited cells upstream of the rash ones. That is an inference from a computer model, not a lineage trace. Still, if it holds, the cells would make a tidy link between one dose of sun and the rash that follows, and a candidate target for prevention alongside the interferon signals that seem to feed them. The release adds that Kahlenberg’s lab will keep building on the approach to improve lupus care.

Meanwhile, sunscreen and sun avoidance remain the only preventive options patients have, and compliance with them is low, per the paper’s own introduction. Ask whether a drug aimed at these cells could do better, and the honest answer is that this study was never built to say.

FAQ