Long-Lived Plasma Cells Are Contained within the CD19−CD38hiCD138+ Subset in Human Bone Marrow

Abstract

Antibody responses to viral infections are sustained for decades by long-lived plasma cells (LLPCs). However, LLPCs have yet to be characterized in humans. Here we used CD19, CD38, and CD138 to identify four PC subsets in human bone marrow (BM). We found that the CD19−CD38hiCD138+ subset was morphologically distinct, differentially expressed PC-associated genes and exclusively contained PCs specific for viral antigens to which the subjects had not been exposed for over 40 years. Protein sequences of measles- and mumps-specific circulating antibodies were encoded for by CD19−CD38hiCD138+ PCs in the BM. Finally, we found that CD19−CD38hiCD138+ PCs had a distinct RNA transcriptome signature and human immunoglobulin heavy chain (VH) repertoire that was relatively uncoupled from other BM PC subsets and likely represents the B cell response’s “historical record” of antigenic exposure. Thus, our studies define human LLPCs and provide a mechanism for the life-long maintenance of anti-viral antibodies in the serum.

Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy

“…8,18 Phenotypic analysis in mice suggests that loss of CD19 expression represents progressive differentiation, marking long-lived PCs. 28 Similar to depletion studies in mice, [5][6][7] significant reductions in the number of CD19 1 PCs in patients' bone marrow have been observed following anti-CD20 therapy without a significant change in the CD19 2 subset, suggesting that the CD19 1 PC subset represents a short-lived population requiring replenishment from CD20 1 B cells.…”

“…Recent data on human PCs suggest that CD19 2 PCs are enriched in bone marrow and may include long-lived cells that give rise to long-lasting humoral immunity. 8,18 We hypothesized that CTL019 would spare the population of CD19 2 PCs, leaving previously established humoral immunity relatively intact. Furthermore, we anticipated that tracking the fate of the PCs in the context of CTL019-induced B-cell aplasia would shed light on the question of CD19 2 PC lifespan and maintenance.…”

Targeting B cells in relapsing–remitting multiple sclerosis: from pathophysiology to optimal clinical management

“…Therefore, the depletion of CD19-expressing cells might offer potential advantages with regard to efficacy by additionally depleting antibodyproducing plasmablasts, but potentially with a higher risk of infections. Mature plasma cells are not directly affected by anti-CD19 treatment [Halliley et al 2015]. The most advanced compound in clinical trials targeting CD19 is MEDI-551, a humanized monoclonal antibody.…”

Long-lived plasma cells in human bone marrow can be either CD19+ or CD19–

“…5,6 We thus examined CD19 expression on vaccinia-specific LLPCs. CD138 1 CD38 high plasma cells were sorted as either CD19…”

“…A few cells escape apoptotic death and are able to mature into LLPCs, a transition that includes downregulation of CD19 expression. 5,6 That both vaccination to and eradication of smallpox occurred decades ago suggest that the vaccinia-specific plasma cells detected in the BM have not migrated there recently. This raises the possibility that differentiation of new vaccinia-specific plasma cells may occur in the BM.…”