Plasma cell development and survival

Abstract

Plasma cells have long been recognized as the basis of humoral immunity, yet we are only now beginning to appreciate the complexities of plasma cell development and the fact that not all plasma cells are created equal. In vivo, plasma cells can arise from two developmental routes: one occurring outside the follicle and another within the germinal center. A B cell's decision to follow one of these pathways is in part determined by the phenotypic subset to which it belongs and is also influenced by the nature of the antigen eliciting the response and the affinity of the B-cell receptor for that antigen. Once a plasma cell has chosen one of these pathways, the outcome of differentiation is relatively hard-wired. However, the phenotype of the plasma cells arising from these two pathways is distinct in terms of survival, location, and the quantity and quality of antibody they secrete. The extra-follicular pathway represents a relatively unchecked route to differentiation resulting in the generation of short-lived plasma cells that secrete low-affinity antibody. The germinal center response, however, allows the integration of external signals to delay plasma cell differentiation, eventually generating a plasma cell that secretes high-affinity antibody of an appropriate class, and that persists for a lifetime. The means by which these varying properties are conferred to a developing plasma cell are the subject of intense investigation.

Plasma cells in systemic lupus erythematosus: The long and short of it all

“…Although extrafollicular B cells do not undergo extensive somatic mutation, they may still secrete pathogenic autoantibodies [12,13]. Plasma cells derived from the extrafollicular focus are dependent on BAFF and a proliferationinducing ligand (APRIL) for their immediate survival but they are short-lived, surviving an average of 3-4 days [11,16].B cells with relatively low affinity tend to enter germinal centers; this is mediated through downregulation of EBI2 [14]. Subsequent differentiation into either memory or plasma cells is regulated in part by the strength of the BCR signal [17].…”

“…Plasma cell differentiation also requires expression of complement receptor 2 (CR2) [18]. Plasma cells that are fated to migrate to the BM downregulate CXCR5 (which retains cells in the follicles), and upregulate S1P 1 (which allows egress from peripheral lymphoid tissues), BCMA (a receptor for the survival factors BAFF and APRIL), and CXCR4 (the receptor for CXCL12, the major chemoattractant for circulating plasmablasts) [11].Whether a plasma cell becomes long-lived largely depends on whether it finds a microenvironmental survival niche. These limited and poorly defined survival niches exist in the BM, the spleen, and the inflamed organs, and involve the interaction of plasma cells with stromal cells that provide survival factors such as BAFF, APRIL, and IL-6, adhesion molecules such as VCAM-1 and chemokines such as CXCL12 [11,[19][20][21].…”

“…Plasma cells that are fated to migrate to the BM downregulate CXCR5 (which retains cells in the follicles), and upregulate S1P 1 (which allows egress from peripheral lymphoid tissues), BCMA (a receptor for the survival factors BAFF and APRIL), and CXCR4 (the receptor for CXCL12, the major chemoattractant for circulating plasmablasts) [11].…”

“…Although extrafollicular B cells do not undergo extensive somatic mutation, they may still secrete pathogenic autoantibodies [12,13]. Plasma cells derived from the extrafollicular focus are dependent on BAFF and a proliferationinducing ligand (APRIL) for their immediate survival but they are short-lived, surviving an average of 3-4 days [11,16].…”

“…These limited and poorly defined survival niches exist in the BM, the spleen, and the inflamed organs, and involve the interaction of plasma cells with stromal cells that provide survival factors such as BAFF, APRIL, and IL-6, adhesion molecules such as VCAM-1 and chemokines such as CXCL12 [11,[19][20][21]. In murine lupus, the inflammatory environment, extramedullary hematopoiesis in lymphoid organs, and lymphoid neogenesis in inflamed target organs all provide an expanded number of sites where autoantibody-producing plasma cells can survive.…”