Background Plasma cells (PCs) are heterogeneous in terms of function and lifespan. Long-lived PCs are not depleted by B-cell depletion therapy for autoimmune disorders and therefore likely to be responsible for lack of clinical response in a significant proportion of patients. Until recently , the phenotype of long-lived PCs was not known. Understanding the biological features of long-lived PCs could greatly facilitate identification of therapeutic targets. Long-lived PCs contribute to humoral memory, and may represent the cell of origin for myeloma while neoplastic PCs are generally distinguished by lack of CD19 expression. However, polyclonal CD19Neg PCs constitute approximately 15–35% of total PCs in people aged over 50 years. Here we further characterize normal CD19Neg PC populations in the context of normal and therapeutically perturbed bone marrow.
Objectives To establish the phenotypic and functional differences between normal CD19Pos and CD19Neg human PCs
Methods Extensive phenotyping of surface and intracellular proteins of normal and myeloma PCs were performed by flow cytometry. The regeneration of normal PCs was monitored following bone marrow ablation for myeloma  and B-cell depletion with alemtuzumab  in a series of clinical trials. The immunoglobulin heavy chain variable (IGHV) region of normal CD19Pos and CD19Neg human PCs were sequenced as described previously  to identify phylogenetic relationships.
Results CD19Neg PCs are phenotypically distinct from normal CD19Pos plasma cells with weaker CD95 (p<0.0001) and stronger (p<0.0001) BCL2 expression. Normal CD19Neg PCs share some characteristics with neoplastic PCs including variable expression of CD28, CD56, and CD45, but neoplastic PCs are reliably distinguished from normal CD19Neg PCs by differential expression of CD27, CD81 and CD117 as well as CD56 in some cases. After effective myeloablation for myeloma CD19Pos PCs recovered in 74 out of 80 samples, while CD19Neg PCs remained at less than 1% of total PCs in 30 out of 80 samples. Therapeutic B-cell depletion with alemtuzumab for chronic lymphocytic leukaemia results in loss of CD19Pos PCs (p<0.0001) whereas CD19Neg PCs persist. There was little overlap between the IGHV repertoire with only 2.1 to 3.7% of unique IGHV@ rearrangements shared between the CD19Pos and CD19Neg fractions, suggestive of a largely discrete immunoglobulin repertoire in the two fractions at steady state.
Conclusions CD19Pos and CD19Neg PCs are biologically distinct with different immunoglobulin repertoires and production kinetics consistent with CD19Neg PCs having greater potential lifespan. Identifying the developmental pathway of normal CD19Neg PC is likely to allow selectively targeting PC compartments for autoimmune disorders.
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Disclosure of Interest None declared
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