# Distinct autoreactive CD19– plasma cell subsets accumulate in lupus-prone mice

## TL;DR

The study identifies a specific type of plasma cell linked to lupus in mice, suggesting current treatments targeting CD19 may not be fully effective.

## Contribution

The discovery of distinct autoreactive CD19– plasma cell subsets in lupus-prone mice provides new insights into SLE pathogenesis and therapy.

## Key findings

- CD19– plasma cells expand in lupus-prone mice and show unique gene expression profiles.
- CD19– plasma cells originate from CD19+ plasma cells in a unidirectional manner.
- Elevated CD19– plasma cells are found in peripheral blood of SLE patients.

## Abstract

Plasma cells (PC) participate in the pathogenesis of systemic lupus erythematosus (SLE) through sustained autoantibody and inflammatory cytokine secretion. Current PC-depleting therapies risk eliminating protective long-lived PCs, highlighting the need to identify pathogenic subsets for selective targeting. Here, using single-cell RNA sequencing, B cell receptor repertoire analysis, and genetic models, we identify disease- and organ-specific PCs in lupus-prone mice. We find a substantial expansion of autoreactive CD19– PCs, particularly class-switched CXCR3⁺ and phosphatidylcholine-specific B-1–derived subsets, which exhibit unique gene expression profiles. We show that CD19– PCs originate from CD19+ PCs in a unidirectional manner. Peripheral blood from SLE patients shows elevated frequencies of CD19– PCs, implicating these cells in sustaining pathogenic activity. Our findings highlight the emergence of autoreactive CD19– PCs as a critical feature of lupus pathogenesis in mice and underscore the need for therapeutic approaches that extend beyond CD19-targeting to improve treatment strategies in SLE.

Plasma cells (PC) contribute to the pathogenesis of autoimmune diseases by secreting autoantibodies. Strategies to target pathogenic PCs are thus required. Here, the authors profile different PC subsets in naïve and lupus-prone mice and report the emergence and expansion of a CD19– PC subset in diseased mice that could compromise the effectiveness of CD19-targeting therapies.