Dual cellular targeting of complement receptor 2 (CR2/CD21) synergistically suppresses autoreactive germinal center activity and autoimmunity in lupus

Authors

Rattan, A., Zhu, D., Oleinika, K., Ma, M., Carroll, M. C.

Abstract

Pathogenic germinal center (GC) activity persists in systemic lupus erythematosus (SLE) because current B cell-targeting therapies do not consistently eliminate the resilient GC niche that sustains autoimmunity. Complement receptor 2 (CR2/CD21) presents a unique bicellular therapeutic target to impede GC-associated autoimmune disease. For B cells, it has been previously shown to lower the threshold for B cell activation, and for follicular dendritic cells (FDCs), it sustains the GC response. Using a CD21-blocking antibody in a spontaneous lupus-prone mouse model, we demonstrate that dual CD21 blockade on both B cells and FDCs synergistically inhibited GC B cell responses and suppressed autoantibody production, memory recall, and renal antibody deposition. Mechanistically, B cell-specific blockade impaired GC entry by limiting initial activation, whereas FDC-specific blockade disrupted GC architecture and curtailed ongoing responses. Further, dual blockade uniquely reshaped immunological memory by promoting accumulation of a CD21low/-CD38+ memory B cell subset with attenuated antibody-secreting cell (ASC) recall potential. These findings identify CD21 blockade as a precision immunomodulatory strategy capable of suppressing pathogenic humoral immunity without complete B cell depletion.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 14 Nov 2026.

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