Plasma Cells

Abstract

Plasma cells are terminally differentiated B lymphocytes that provide protective immunity through the continuous secretion of antibodies. Antibody‐secreting cells develop in secondary lymphoid tissue following antigen stimulation and may enter a short‐lived plasma cell population that resides primarily in the nonlymphoid area of the spleen or lymph nodes. Alternatively, antibody‐secreting cells can migrate to the bone marrow where the majority enter a long‐lived, nonproliferative population of plasma cells. Within the marrow, plasma cells situate themselves within niches where longevity is supported by factors such as APRIL, IL‐6, and CXCL2, provided by support cells that include CXCL12‐abundant reticular (CAR) cells, eosinophils, megakaryocytes and dendritic cells, among others.

Key Concepts

  • Plasma cells are terminally differentiated cells of the B lymphocyte lineage. They are committed to secreting antibody that provides an organism with protective immunity.
  • Plasma cells may be short‐lived, surviving only 3–5 days. Generally, these secrete lower affinity antibody. Alternatively, plasma cells may be long‐lived, surviving decades or the lifetime of an animal, secreting high‐affinity antibody resulting from somatic hypermutation within a germinal centre reaction.
  • Long‐lived plasma cells are primarily found in the bone marrow, where specialized niches provide contact and growth factors necessary for survival.
  • Multiple cell types in the niches can contribute to the extended lifespan of bone marrow plasma cells. However, plasma cells are not completely eliminated when any one cell type is depleted, suggesting that all of the supporting cells are critical and contributing components.
  • As B cells differentiate into plasma cells, they undergo molecular and morphological changes that better suit a highly secretory cell. They are easily identifiable via microscopy by their voluminous cytoplasm full of immunoglobulin and rough endoplasmic reticulum (RER).
  • Plasma cells can be identified by high surface expression of Syndecan‐1 (CD138) protein, and little to no expression of BCR, B220 or MHC class II.

Keywords: plasma cell; plasmablast; stromal cell; bone marrow; niche; IL‐6; CXCL12 ; APRIL ; Blimp‐1

Figure 1. Comparison of naïve B cell versus plasma cell morphology. Bone marrow B220+ naïve B cells and Syndecan‐1+ (CD138+) plasma cells were stained with Diff‐Quik staining reagent.
Figure 2. Schematic of plasma cell development and resultant phenotype. Naïve B cells stimulated with antigen in peripheral tissue form antibody‐secreting, proliferation‐capable plasmablasts. Provided with the appropriate cues, plasmablasts emigrate from peripheral tissue and migrate to the marrow where they will complete differentiation into plasma cells. Plasma cells express Syndecan‐1 (CD138), CXCR4 and VLA‐4 on their surface (among others); they ultimately downregulate expression of MHC class II, B220 and the B‐cell receptor (BCR) complex. Further, plasma cells express Blimp‐1 and XBP‐1, which results in inhibition of proliferation and expression of Pax‐5, among others (Figure). ± = little to no expression.
Figure 3. A model of the elements necessary for maintaining plasma cell survival. Plasma cells and CAR cells interact in the bone marrow via VLA‐4 on the plasma cell and an unknown ligand on the CXC12‐abundant reticular (CAR) cell. Contact with CAR cells and dendritic cells (via CD28 and CD80/86) induces the expression of IL‐6 mRNA and consequently interleukin‐6 secretion, which is critical to maintain plasma cell longevity. Eosinophils and dendritic cells can also produce IL‐6. In addition, CAR cells secrete CXCL12 which is important for attracting plasmablasts to the marrow, for retention of plasma cells in the marrow via CXCR4, and possibly for maintaining plasma cell survival. Further, APRIL is secreted by eosinophils, dendritic cells and, in small quantities, from megakaryocytes. APRIL can bind plasma cells via the BCMA or TACI receptor.
Figure 4. A simplified model of the regulatory cascades initiated during plasma cell differentiation. Targets activated by a particular factor are indicated by arrows; targets repressed are indicated by bars.
Figure 5. Various pathways converge and coordinate to maintain homeostasis, and perhaps regulate lifespan, in plasma cells. Concomitant with plasma cell differentiation, Blimp‐1 expression increases, which in turn reorganizes the cell's secretory machinery. As the ER expands to accommodate the increasing protein load, the UPR is induced, resulting in the splicing of XBP‐1 and induction of immunoglobulin synthesis. Similarly, as misfolded proteins accumulate, the need for protein degradation via the proteasome increases. However, in plasma cells, the proteasome capacity is reduced as compared to the overall load in the cell. As a result, at least in short‐lived plasma cells, ubiquitinated proteins accumulate leaving less free ubiquitin and apoptosis ultimately ensues. Finally, the autophagy protein ATG5 is necessary to restrict the size of the ER and contain immunoglobulin synthesis to manageable amounts.
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Further Reading

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Minges Wols, Heather A(Aug 2015) Plasma Cells. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0004030.pub2]