Georgakis Spiros, Ioannidou Kalliopi, Mora Bernat Bramon, Orfanakis Michail, Brenna Cloe, Muller Yannick D, Del Rio Estrada Perla M, Sharma Ashish A, Pantaleo Giuseppe, de Leval Laurence, Comte Denis, Gottardo Raphael, Petrovas Constantinos
Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland.
Biomedical Data Science Center, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland.
Front Immunol. 2025 Feb 13;16:1530327. doi: 10.3389/fimmu.2025.1530327. eCollection 2025.
Systemic lupus erythematosus (SLE) is characterized by dysregulated humoral immunity, leading to the generation of autoreactive B cells that can differentiate both within and outside of lymph node (LN) follicles.
Here, we employed spatial transcriptomics and multiplex imaging to investigate the follicular immune landscaping and the transcriptomic profile in LNs from SLE individuals.
Our spatial transcriptomic analysis revealed robust type I IFN and plasma cell signatures in SLE compared to reactive, control follicles. Cell deconvolution revealed that follicular T cell subsets are mainly affected by the type I IFN fingerprint of SLE follicles. Dysregulation of T differentiation was documented by i) the significant reduction of Bcl6 T cells, ii) the reduced cell density of potential IL-4 producing T cell subsets associated with the impaired transcriptomic signature of follicular IL-4 signaling and iii) the loss of their correlation with GC-B cells. This profile was accompanied by a marked reduction of Bcl6 B cells and an enrichment of extrafollicular CD19CD11cTbet, age-associated B cells (ABCs), known for their autoreactive potential. The increased prevalence of follicular IL-21 cells further reveals a hyperactive microenvironment in SLE compared to control.
Taken together, our findings highlight the altered immunological landscape of SLE follicles, likely fueled by potent inflammatory signals such as sustained type I IFN and/or IL-21 signaling. Our work provides novel insights into the spatial molecular and cellular signatures of SLE follicular B and T cell dynamics, and points to druggable targets to restore immune tolerance and enhance vaccine responses in SLE patients.
系统性红斑狼疮（SLE）的特征是体液免疫失调，导致自身反应性B细胞的产生，这些B细胞可在淋巴结（LN）滤泡内外分化。
在此，我们采用空间转录组学和多重成像技术来研究SLE患者淋巴结中的滤泡免疫格局和转录组特征。
我们的空间转录组分析显示，与反应性对照滤泡相比，SLE中存在强大的I型干扰素和浆细胞特征。细胞反卷积分析表明，滤泡T细胞亚群主要受SLE滤泡的I型干扰素特征影响。T细胞分化失调表现为：i）Bcl6 + T细胞显著减少；ii）潜在产生IL-4的T细胞亚群的细胞密度降低，这与滤泡IL-4信号传导的转录组特征受损有关；iii）它们与生发中心B（GC-B）细胞的相关性丧失。这种特征伴随着Bcl6 + B细胞的显著减少以及滤泡外CD19 + CD11c + Tbet + 、具有自身反应潜能的年龄相关B细胞（ABC）的富集。与对照相比，SLE中滤泡IL-21 + 细胞的患病率增加进一步揭示了其活跃的微环境。
综上所述，我们的研究结果突出了SLE滤泡免疫格局的改变，这可能是由持续的I型干扰素和/或IL-21信号等强效炎症信号驱动的。我们的工作为SLE滤泡B细胞和T细胞动态的空间分子和细胞特征提供了新的见解，并指出了可用于恢复免疫耐受和增强SLE患者疫苗反应的药物靶点。
