W133 - Mechanisms Driving Dysregulated Germinal Center Dynamics in Systemic Lupus Erythematosus

Abstract Text: Systemic lupus erythematosus (SLE) disrupts humoral immunity, promoting the development of autoreactive B cells within and outside lymph node (LN) follicles. This study combines spatial transcriptomics and multiplex imaging to dissect the immune landscape and transcriptomic features of LNs in SLE. Our analysis revealed prominent type I interferon (IFN) and plasma cell signatures in SLE compared to reactive control follicles. Cell deconvolution demonstrated that follicular T cell subsets are predominantly influenced by the type I IFN signature characteristic of SLE follicles.A closer look at T follicular helper (TFH) cells revealed significant alterations, including reduced numbers of Bcl6hi TFH cells and diminished representation of IL-4-producing TFH subsets alongside compromised IL-4 signaling in follicles. Additionally, the correlation between TFH and GC-B cell densities was lost in SLE. These changes coincided with a decline in Bcl6hi GC-B cells and an accumulation of extrafollicular CD19hiCD11chiTbethi age-associated B cells (ABCs), which are known for their autoreactivity. Additionally, SLE follicles exhibited increased IL-21+ cell densities, indicative of a highly inflammatory microenvironment.
These findings highlight the profound disruption of follicular immune regulation in SLE, likely driven by sustained inflammatory signals such as type I IFN and IL-21. This study provides critical insights into the cellular and molecular dynamics of SLE-affected LNs, identifying potential therapeutic avenues to restore immune balance and improve vaccine efficacy in SLE patients.