Origins and diversity of pan-isotype human bone marrow plasma cells

Bone marrow plasma cells (BMPCs) produce durable, infection-resistant IgM, IgG, and IgA antibodies, but in some cases, pro-allergic IgE. Despite this, BMPC sources are unclear. We charted single BMPC transcriptional and clonal heterogeneity in peanut-allergic and non-allergic humans across CD19 protein expression—due to CD19's inverse correlation to BMPC longevity. Transcriptional and clonal diversity revealed distinct functional modules. Additionally, distributions of somatic hypermutation and intraclonal antibody sequence variance suggest CD19low and CD19high BMPCs arise from recalled memory and germinal center B cells, respectively. Most IgE BMPCs were from peanut-allergic individuals; some bound peanut and potently prevented peanut-driven anaphylaxis in a mouse model. These findings shed light on BMPC origins and identify the bone marrow as a likely source for long-lived pathogenic IgE in peanut allergy. Overall design: Human bone marrow samples were obtained from the iliac crest of food-allergic or non-allergic controls. Samples were RBC-lysed, magentically-erniched for CD138+ cells, and FACS sorted (DAPI-, IgD-, CD3-, CD14-, CD138+, CD38+). Some samples were further FACS-sorted into CD19low and CD19mid/high populations. Some samples also contain B cells magnetically-enriched with positive selection CD19 beads from peripheral blood.