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bioRxiv · 10.1101/2025.01.14.632971

IL-21-STAT3 axis negatively regulates LAIR1 expression in B cells

Yoshida, K.·Kurata-Sato, I.·Atisha-Fregoso, Y.·Aranow, C.·Diamond, B.
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Abstract

LAIR1 is an inhibitory receptor broadly expressed on human immune cells, including B cells. LAIR1 has been shown to modulate BCR signaling, however, it is still unclear whether its suppressive activity can be a negative regulator for autoreactivity. In this study, we demonstrate the LAIR1 expression profile on human B cells and prove its regulatory function and relationships to B cell autoreactivity. We show that both the frequency and level of LAIR1 expression decreases during B cell differentiation. LAIR1 expressing (LAIR1+) switched memory (SWM) B cells have a transcriptional profile less differentiated toward a plasma cell (PC) phenotype, harbor more autoreactive B cells and exhibit less PC differentiation in vitro than the LAIR1 negative (LAIR1-) counterpart. These data suggests that LAIR1 functions as a B cell tolerance checkpoint. We confirm previous data showing that patients with systemic lupus erythematosus (SLE) express less LAIR1 on B cells, implying a breakdown of the checkpoint, consistent with the enhanced PC differentiation seen in SLE. We further demonstrate that LAIR1 expression is down-regulated through the IL-21/STAT3 pathway which is known to be upregulated in SLE. These data suggest therapeutic targets that might decrease the aberrant PC differentiation observed in SLE.

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Yoshida, K., Kurata-Sato, I., Atisha-Fregoso, Y., Aranow, C., Diamond, B.. 2025-01-18. IL-21-STAT3 axis negatively regulates LAIR1 expression in B cells. https://doi.org/10.1101/2025.01.14.632971

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