Study finds healthy-appearing lupus skin predisposed to flares, rashes
In patients with lupus, immune cells undergo an inflammatory
transformation when migrating from the blood to the skin

Date:
May 3, 2022
Source:
Michigan Medicine - University of Michigan
Summary:
A new study finds that the normal-appearing skin of lupus patients
contains the same inflammatory signals that are detected when the
skin develops a rash, sometimes at even higher levels. Researchers
say immune cells undergo an inflammatory transformation that primes
the skin without rashes for disease flares.



FULL STORY ========================================================================== People with lupus have overactive immune systems that attack their own
tissue, causing inflammation throughout the body.


========================================================================== Around 70-80% of them will develop skin disease as part of their
condition. And while it's thought that exposure to ultraviolet light
triggers the rashes, scientists are not sure how it ties together with
the systemic inflammation.

A Michigan Medicine study now brings more clarity, as researchers found
that the normal-appearing skin of lupus patients contains the same
inflammatory signals that are detected when the skin develops a rash -- sometimes at even higher levels. The results are published in Science Translational Medicine.

"This really starts to piece the puzzle together of how inflammation seen
in lupus patients may be related to skin exposures such as UV light,"
said J.

Michelle Kahlenberg, M.D., Ph.D., senior author of the study and
rheumatologist at University of Michigan Health. "We were able to see
the properties of normal-appearing skin in unparalleled resolution,
suggesting that the skin is primed for inflammatory reactions." The team
of researchers used single-cell RNA-sequencing analysis to assess the
biopsies of both normal-appearing skin and skin from rashes of seven
lupus patients. The results reveal that elevated signals of interferon,
a protein known to contribute to UV sensitivity, were robustly present in
all lupus biopsies compared to healthy control skin -- with the strongest signal coming from the healthy-appearing skin, not the inflamed skin.

These interferon-rich inflammatory properties weren't just found
in the keratinocytes, the cells that make up the epidermis of the
skin. Researchers saw the same inflammatory changes in the fibroblasts
that generate the connective tissue of the skin.



========================================================================== "This is really 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," said Kahlenberg, who is also an associate professor of rheumatology at U-M Medical School. "So, validating
this abnormality in the interferon pathway could be essential for
determining the best course of treatment for scores of lupus patients."
Cell education The researchers also took blood samples of the same
patients to examine how immune cells are promoting skin inflammation
in lupus. Their data suggest that a subtype of monocytes, important
members of the innate immune system, are exiting the blood into the skin
of lupus patients. Upon moving into the skin, they undergo a striking inflammatory transformation.

Kahlenberg calls it "cell education." The lupus skin environment itself
- - specifically, the interferon within the skin -- appears to change
the monocytes in a way that sets up the rest of the immune system to be
turned on.

Interferon plays a critical role in the innate immune system. It alerts
the cells to dangerous invaders such as viruses. In many autoimmune
diseases, however, interferon is overproduced in the absence of any real threat, changing how immune cells behave.



========================================================================== "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," said Allison
C. Billi, M.D., Ph.D., co-first author of the study, dermatologist
at U-M Health and assistant professor of dermatology at U-M Medical
School. "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
of them." Previous research analyzing the blood of lupus patients has struggled to identify potential biomarkers for disease flares. Knowing
that the monocytes became more inflammatory when traveling to the skin, Kahlenberg believes the same process could also trigger systemic immune
flares in other organs affected by lupus, such as the kidney and brain.

"In future studies, we will want to look at these target organs to
really understand what's going on," she said. "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 really
happening in the organs." Billi says understanding changes at a cellular
level will enable precision medicine in lupus patients, which would employ individualized analysis to guide medical decisions and treatment options.

"Research has been hampered by how differently lupus presents across individuals," she said. "By focusing on patients with lupus affecting
a single organ -- the skin -- we have gained some insight into which
cells are orchestrating lupus inflammation and how." Additional authors include Olesya Plazyo, Ph.D., Mehrnaz Gharaee-Kermani, DVM, Ph.D.,
Rachael Wasikowski, M.S., Grace A. Hile, M.D., Xianying Xing, M.D.,
Christine M. Yee, B.S., Syed M. Rizvi, DVM, M.S., Ph.D., Mitra P. Maz,
Celine C. Berthier, Ph.D., Fen Wen, Ph.D., Lam C. Tsoi, Ph.D., Johann
E. Gudjonsson, M.D., Ph.D., all of Michigan Medicine.

From the University of California Los Angeles: Feiyang Ma, Ph.D., Matteo Pellegrini, Ph.D., Robert L. Modlin, M.D.


========================================================================== Story Source: Materials provided by
Michigan_Medicine_-_University_of_Michigan. Original written by Noah
Fromson. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Allison C. Billi, Feiyang Ma, Olesya Plazyo, Mehrnaz
Gharaee-Kermani,
Rachael Wasikowski, Grace A. Hile, Xianying Xing, Christine
M. Yee, Syed M. Rizvi, Mitra P. Maz, Celine C. Berthier, Fei
Wen, Lam C. Tsoi, Matteo Pellegrini, Robert L. Modlin, Johann
E. Gudjonsson, J. Michelle Kahlenberg. Nonlesional lupus skin
contributes to inflammatory education of myeloid cells and primes
for cutaneous inflammation. Science Translational Medicine, 2022;
14 (642) DOI: 10.1126/scitranslmed.abn2263 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/05/220503083003.htm

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