皮膚エリテマトーデスの病態に「細胞老化」が関与～老化細胞が免疫細胞の攻撃性を高めるメカニズムを解明～

2025-07-24 北海道大学,札幌医科大学,東京大学医科学研究所

老化細胞はI型インターフェロンを産生して、正常細胞のHLA-Iの発現を高め、細胞傷害性T細胞の攻撃性を高める。

<関連情報>

• https://www.hokudai.ac.jp/news/2025/07/post-1991.html
• https://www.hokudai.ac.jp/news/pdf/250724_pr2.pdf
• https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.43244

HLA-クラス Iの発現を低下させた老化表皮基底細胞が皮膚エリテマトーデス病変を形成するHLA class I-downregulated senescent epidermal basal cells orchestrate skin pathology in cutaneous lupus erythematosus

Sena Yamamoto MS, Yuki Saito PhD, Tsukasa Sato MS, Seina Nakano BS, Dain Kasseki BS, Ayaka Nagao BS, Norihiro Miura MS, Kentaro Nagaoka MD, Arisa Kita MD,PhD …
Arthritis & Rheumatology  Published: 19 May 2025
DOI:https://doi.org/10.1002/art.43244

Abstract

Objective

To investigate the role of senescent epidermal basal cells in cutaneous lupus erythematosus (CLE) pathogenesis using skin samples from patients with CLE and a mouse model of systemic lupus erythematosus (SLE).

Methods

Cellular senescence profiling utilized datasets from the NCBI Gene Expression Omnibus database and Accelerating Medicines Partnership® (AMP®) Phase 1-Metro. Gene array data from GSE184989 (CLE: n = 68, control: n = 4), single-cell RNA sequencing data from GSE186476 (CLE: n = 7, control: n = 14), and AMP® Phase 1-Metro (SLE: n = 17) were utilized. In vitro experiments further examined the expression of p21^WAF1/CIP1, type I interferon (IFN), human leukocyte antigen class I (HLA-I), and epidermal growth factor receptor (EGFR) signalling. Pharmacological clearance of senescent cells was performed using the senolytic drug fisetin in the SLE mouse model.

Results

p21^WAF1/CIP1-high senescent epidermal basal cells in patients with CLE exhibit high type I IFN expression. These cells enhance IFN signalling in surrounding normal epidermal basal cells, leading to increased HLA-I expression. In contrast, senescent epidermal cells upregulate EGFR signalling, which downregulates HLA-I expression, allowing them to evade immune surveillance. This heterogeneity of HLA-I expression promotes CD8-positive T-mediated toxicity against normal epidermal basal cells, resulting in their apoptosis. Pharmacological clearance of senescent epidermal basal cells improved SLE-like skin lesions.

Conclusion

Senescent cells create a microenvironment that directs cytotoxic T-cell-mediated responses against normal epidermis in CLE, contributing to disease pathology. Targeting senescent cells and their signalling pathways may offer novel therapeutic strategies for CLE and SLE skin lesions.