조재현 (UCSF Department of Dermatology)

한빛사논문

조회395

UCSF Department of Dermatology

CV File 153 kb

Sci. Immunol., Jan 26 2024, 9 (91) | https://doi.org/10.1126/sciimmunol.adi2848 A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response

David Wu ¹, Ashley A Hailer ^{1 2}, Sijia Wang ^{1 2 3}, Michelle Yuan ¹, Jamie Chan ⁴, Abdullah El Kurdi ⁵, David Han ⁵, Hira Ali ⁵, Blaize D'Angio ⁵, Aaron Mayer ⁵, Maha Rahim ⁶, Ayano Kondo ⁶, Daniel Klufas ¹, Esther Kim ⁷, A Hunter Shain ¹, Jaehyuk Choi ⁸, Tina Bhutani ¹, Gregory Simpson ⁹, Roy C Grekin ¹, Roberto Ricardo-Gonzalez ¹, Elizabeth Purdom ¹⁰, Jeffrey P North ⁴, Jeffrey B Cheng ^{1 2 † *}, Raymond J Cho ^{1 † *}

¹Department of Dermatology, University of California, San Francisco, San Francisco, CA 94107, USA.

²Dermatology Service, San Francisco Veterans Administration Health Care System, San Francisco, CA 94121, USA.

³Department of Dermatology, Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710004, China.

⁴Dermatopathology Service, University of California, San Francisco, San Francisco, CA 94107, USA.

⁵Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.

⁶Enable Medicine, Menlo Park, CA 94025, USA.

⁷Department of Plastic Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.

⁸Departments of Dermatology and Biochemistry and Molecular Genetics, Feinberg School of Medicine, Chicago, IL 60611, USA.

⁹Department of Dermatology, University of California, Fresno, CA 93701,USA.

¹⁰Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA.

^†These authors contributed equally
^*Corresponding authors: correspondence to Jeffrey B Cheng or Raymond J Cho

Abstract

Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17-producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade-responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17-induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-31)
연구진국외 연구진
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