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Distinct Autoreactive CD19– Plasma Cell Subsets Accumulate in Lupus

ABSTRACT: Plasma cells (PCs) play a pathogenic role in autoimmune diseases by secreting autoantibodies and inflammatory cytokines. While PC elimination therapies exist, they risk depleting protective long-lived plasma cells. Using single cell RNA sequencing, including B cell receptor repertoire analysis, and genetic models, we identified disease- and organ-specific PC subsets in systemic lupus erythematosus (SLE) mice. We uncovered a substantial expansion of autoreactive CD19– PCs, particularly switched CXCR3+ and phosphatidylcholine-specific B-1-derived subsets, which exhibit unique gene expression profiles in SLE. Notably, our findings suggest that CD19– PCs originate from CD19+ PCs in a unidirectional manner, complicating the effectiveness of CD19-targeted therapies in advanced disease stages. This study highlights the crucial role of timing in anti-CD19 therapy and the necessity to broaden therapeutic targets beyond CD19+ PCs. The emergence of CD19– subpopulations underscore the need for novel therapeutic strategies that target these elusive PCs, offering new avenues for intervention in SLE treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE275094 | GEO | 2025/10/01

REPOSITORIES: GEO

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Project description:Objective: Production of pathogenic autoantibodies by self-reactive plasma cells (PC) is a hallmark of autoimmune diseases. Investigating the prevalence of PC in autoimmune disease and their relationship with known pathogenic pathways may increase our understanding of the role of PC in disease progression and treatment response. Methods: We developed a sensitive gene expression based method to overcome the challenges of measuring PC using flow cytometry. Whole genome microarray analysis of sorted cellular fractions identified a panel of genes, IGHA, IGJ, IGKC, IGKV, and TNFRSF17, expressed predominantly in PC. The sensitivity of the PC signature score created from the combined expression levels of these genes was assessed through ex vivo experiments with sorted cells. This PC gene expression signature was used for monitoring changes in PC levels following anti-CD19 therapy; evaluating the relationship between PC and other autoimmune disease-related genes; and estimating PC levels in affected blood and tissue from multiple autoimmune diseases. Results: The PC signature was highly sensitive and capable of detecting as few as 300 PCs. The PC signature was reduced over 90% in scleroderma patients following anti-CD19 treatment and this reduction was highly correlated (r = 0.77) with inhibition of collagen gene expression. Evaluation of multiple autoimmune diseases revealed 30-35% of lupus, rheumatoid arthritis, and scleroderma patients with increased PC levels. Conclusion: This newly developed PC signature provides a robust and accurate method to measure PC levels in the clinic. Our results highlight subsets of patients across multiple autoimmune diseases that may benefit from PC depleting therapy. MI-CP200 is a Phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety and tolerability of escalating single IV doses of MEDI-551 in adult subjects with scleroderma. In this study, 5 cohorts of subjects (n=25) received 1 of 5 single IV doses of MEDI-551 (0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo. Twenty-four healthy donor control samples are also included.

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Distinct Autoreactive CD19– Plasma Cell Subsets Accumulate in Lupus

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