Cellular and Molecular Determinants Mediating the Dysregulated Germinal Center Immune Dynamics in Systemic Lupus Erythematosus

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2025 Mar 12

PMID 40070830

Authors

Spiros Georgakis

Kalliopi Ioannidou

Bernat Bramon Mora

Michail Orfanakis

Cloe Brenna

Yannick D Muller

Perla M Del Rio Estrada

Ashish A Sharma

Giuseppe Pantaleo

Laurence de Leval

Denis Comte

Raphael Gottardo

Constantinos Petrovas

Affiliations

Soon will be listed here.

Abstract

Introduction: 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.

Methods: Here, we employed spatial transcriptomics and multiplex imaging to investigate the follicular immune landscaping and the transcriptomic profile in LNs from SLE individuals.

Results: 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.

Discussion: 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.

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