Cellular and molecular determinants mediating the dysregulated germinal center immune dynamics in systemic lupus erythematosus.
Details
Serval ID
serval:BIB_998DDC606A6D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Cellular and molecular determinants mediating the dysregulated germinal center immune dynamics in systemic lupus erythematosus.
Journal
Frontiers in immunology
ISSN
1664-3224 (Electronic)
ISSN-L
1664-3224
Publication state
Published
Issued date
2025
Peer-reviewed
Oui
Volume
16
Pages
1530327
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
Abstract
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 in situ 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 <sub>FH</sub> differentiation was documented by i) the significant reduction of Bcl6 <sup>hi</sup> T <sub>FH</sub> cells, ii) the reduced cell density of potential IL-4 producing T <sub>FH</sub> 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 <sup>hi</sup> B cells and an enrichment of extrafollicular CD19 <sup>hi</sup> CD11c <sup>hi</sup> Tbet <sup>hi</sup> , age-associated B cells (ABCs), known for their autoreactive potential. The increased prevalence of follicular IL-21 <sup>hi</sup> 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 <sub>FH</sub> cell dynamics, and points to druggable targets to restore immune tolerance and enhance vaccine responses in SLE patients.
Here, we employed spatial transcriptomics and multiplex imaging to investigate the follicular immune landscaping and the in situ 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 <sub>FH</sub> differentiation was documented by i) the significant reduction of Bcl6 <sup>hi</sup> T <sub>FH</sub> cells, ii) the reduced cell density of potential IL-4 producing T <sub>FH</sub> 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 <sup>hi</sup> B cells and an enrichment of extrafollicular CD19 <sup>hi</sup> CD11c <sup>hi</sup> Tbet <sup>hi</sup> , age-associated B cells (ABCs), known for their autoreactive potential. The increased prevalence of follicular IL-21 <sup>hi</sup> 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 <sub>FH</sub> cell dynamics, and points to druggable targets to restore immune tolerance and enhance vaccine responses in SLE patients.
Keywords
Lupus Erythematosus, Systemic/immunology, Lupus Erythematosus, Systemic/genetics, Humans, Germinal Center/immunology, Female, B-Lymphocytes/immunology, B-Lymphocytes/metabolism, T Follicular Helper Cells/immunology, Adult, Transcriptome, Gene Expression Profiling, Middle Aged, Male, Cell Differentiation/immunology, Lymph Nodes/immunology, Interferon Type I/metabolism, Plasma Cells/immunology, Plasma Cells/metabolism, IL-4, T follicular helper cells (TFH), age-associated B cells, germinal center response, systemic lupus erythematosus (SLE), type I IFN
Pubmed
Open Access
Yes
Create date
14/03/2025 13:31
Last modification date
15/03/2025 7:18