MSGID: 1:317/3 627201c6   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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   
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   People with lupus have overactive immune systems that attack their own   
   tissue, causing inflammation throughout the body.   
      
      
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   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.   
      
      
      
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   "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.   
      
      
      
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   "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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