Cellular and molecular determinants mediating the dysregulated germinal center immune dynamics in systemic lupus...

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_FH differentiation was documented by i) the significant reduction of Bcl6^hi T_FH cells, ii) the reduced cell density of potential IL-4 producing T_FH 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^hi B cells and an enrichment of extrafollicular CD19^hiCD11c^hiTbet^hi, age-associated B cells (ABCs), known for their autoreactive potential. The increased prevalence of follicular IL-21^hi 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_FH cell dynamics, and points to druggable targets to restore immune tolerance and enhance vaccine responses in SLE patients.