He Jiayu, Guo Yuanning, Chen Jiamin, Xu Jinhua, Zhu Xiaohua
Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
Department of Genetics and Developmental Biology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
J Autoimmun. 2025 May;153:103393. doi: 10.1016/j.jaut.2025.103393. Epub 2025 Mar 26.
Lupus erythematosus (LE) comprises various autoimmune inflammatory diseases, with significant overlap between cutaneous LE (CLE) and systemic LE (SLE). A key feature of both CLE and SLE is UV photosensitivity, particularly in UV-exposure-related skin inflammation. Despite this, reliable and objective UVB photosensitivity indicators closely correlating with LE activity have yet to be identified, and the underlying cellular and molecular mechanisms linking UVB sensitivity with LE onset and progression remain unclear. We discovered that ultraviolet B minimal erythema dose (UVB-MED), a quantitative photosensitivity measure, is a significant and independent risk factor for SLE activity, demonstrating a negative correlation with SLEDAI (r = -0.58, P < 0.0001). Comprehensive transcriptomic analyses of large-scale CLE and SLE samples (5918 in discovery and 7242 in validation datasets) revealed more pronounced and extensive UVB-response gene dysregulation in skin tissues compared to blood. Additionally, 14 lupus activity-correlated, UVB-response genes (UVBACGs) were identified, including eight type I interferon-stimulated genes (IRF7, ISG20, ISG15, IFI44, IFITM1, MX1, LY6E, OASL) and others (JUN, PTTG1, HLA-F, CAV1, HOPX, RPL3), with dysregulation evident in skin, blood, and affected organs (e.g., kidney and synovium). Immunocytes serve as the primary carriers of this dysregulation. Conventional LE therapies and type I interferon-targeted therapies were found to be associated with these genes and can potentially regulate them, thereby contributing to therapeutic effects. These findings highlight the role of UVB in triggering autoimmune inflammation in the skin, which may subsequently spread to systemic inflammation via immune cells and factors. UVBACGs play a critical role in this process and may serve as targets for precise therapies, providing insight into the link between UVB photosensitivity and LE pathogenesis.
红斑狼疮（LE）包括多种自身免疫性炎症性疾病，皮肤型红斑狼疮（CLE）和系统性红斑狼疮（SLE）之间存在显著重叠。CLE和SLE的一个关键特征是紫外线光敏性，尤其是在与紫外线暴露相关的皮肤炎症方面。尽管如此，尚未确定与LE活动密切相关的可靠且客观的中波紫外线（UVB）光敏性指标，并且将UVB敏感性与LE发病和进展联系起来的潜在细胞和分子机制仍不清楚。我们发现，紫外线B最小红斑剂量（UVB-MED）作为一种定量光敏性指标，是SLE活动的一个显著且独立的危险因素，与系统性红斑狼疮疾病活动指数（SLEDAI）呈负相关（r = -0.58，P < 0.0001）。对大规模CLE和SLE样本（发现队列中有5918个样本，验证数据集中有7242个样本）进行的综合转录组分析显示，与血液相比，皮肤组织中UVB反应基因的失调更为明显和广泛。此外，还鉴定出了14个与狼疮活动相关的UVB反应基因（UVBACGs），包括8个I型干扰素刺激基因（IRF7、ISG20、ISG15、IFI44、IFITM1、MX1、LY6E、OASL）和其他基因（JUN、PTTG1、HLA-F、CAV1、HOPX、RPL3），在皮肤、血液和受累器官（如肾脏和滑膜）中均存在失调。免疫细胞是这种失调的主要载体。发现传统的LE治疗方法和I型干扰素靶向治疗方法与这些基因相关，并且可能潜在地调节它们，从而产生治疗效果。这些发现突出了UVB在引发皮肤自身免疫性炎症中的作用，这种炎症随后可能通过免疫细胞和因子扩散至全身炎症。UVBACGs在这一过程中起关键作用，可能成为精准治疗的靶点，为深入了解UVB光敏性与LE发病机制之间的联系提供了思路。
