Plasma cells are morphologically distinct, terminally differentiated B cells committed to abundant antibody production. They are generated after the activation of B cells through signals from the BCR, CD40, TLRs, and other receptors including cytokine receptors. BLIMP1, a transcriptional repressor, and IRF4, a transcriptional activator, are key transcription factors induced in some of the activated B cells that commit these cells to a plasma cell fate. In addition to suppressing BCL-6, the repressor that maintains the germinal center B-cell reaction, BLIMP1 suppresses a second transcription factor, PAX5, which is required for the maintenance of mature B cells. Thus, BLIMP1 is permissive for plasma cell development. IRF4 contributes to the expression of XBP1, a transcription factor that plays a critical role in the unfolded protein response. XBP1 protects developing plasma cells from the injurious consequences of unfolded proteins, which are produced as a consequence of the massive increase in protein synthesis, and thus contributes to the maturation of plasma cells and the enhanced synthesis of Ig seen in these cells. There are two types of plasma cells:
• Plasmablasts and short-lived plasma cells are generated during T-independent responses and early during T-dependent responses in extrafollicular B-cell foci, described earlier. Circulating antibody-secreting cells that do not express CD20, a marker of mature B cells, but still express CD19 and the BCR are referred to as plasmablasts. These short-lived cells may differentiate further into more differentiated short-lived plasma cells that do not express CD19 or the BCR and are found only in secondary lymphoid organs and peripheral nonlymphoid tissues but not in the blood.
• Long-lived plasma cells are most often generated in T-dependent germinal center responses to protein antigens. A subset of activated germinal center–derived B cells may home to the bone marrow and differentiate into long-lived plasma cells. These plasma cells are maintained by cytokines of the BAFF family that bind to a plasma cell membrane receptor called BCMA, thus allowing the cells to survive for long periods. Typically, 2 to 3 weeks after immunization with a T cell–dependent antigen, the bone marrow becomes a major site of antibody production. Plasma cells in the bone marrow may continue to secrete antibodies for decades after the antigen is no longer present. These antibodies can provide immediate protection if the antigen is encountered later. It is estimated that almost half the antibodies in the blood of a healthy adult are produced by long-lived plasma cells and are specific for antigens that were encountered in the past. Secreted antibodies enter the circulation and mucosal secretions, but mature plasma cells do not recirculate. The durability of plasma cells in the bone marrow depends on their interaction with other cells in that compartment. These supporting cells include activated megakaryocytes that express integrin ligands that interact with integrins on the plasma cells. The supporting cells also secrete APRIL, a ligand for BCMA on the plasma cells and promotes survival of the plasma cells. The generation of long-lived plasma cells is more frequent in responses that involve germinal center reactions, but there is evidence that long-lived plasma cells may also be generated in the course of some extrafollicular B-cell responses.
The differentiation of B cells into antibody-secreting plasma cells involves structural alterations in components of the endoplasmic reticulum and secretory pathway and increased Ig production as well as a change in Ig heavy chains from the membrane to the secreted form. The cell enlarges dramatically and the ratio of the area of the cytoplasm to the nucleus observed under a microscope also undergoes a striking increase. The endoplasmic reticulum and golgi complex become prominent and the cell is transformed into a secretory cell that bears little or no resemblance to a B lymphocyte.
The change in Ig production from the membrane form (characteristic of B cells) to the secreted form (in plasma cells) requires post-transcriptional changes during plasma cell differentiation that lead to an altered carboxy terminal of the Ig heavy-chain protein (Fig. 1). For instance, in membrane µ, Cµ4 is followed by a short spacer, 26 hydrophobic residues, and a cytoplasmic tail of three amino acids (lysine, valine, and lysine). In secreted IgM, on the other hand, the Cµ4 domain is followed by a tail piece containing polar amino acids. This transition from membrane to secreted Ig is caused by alternative RNA processing of the heavy-chain messenger RNA (mRNA). The primary RNA transcript in all IgM-producing B cells contains the rearranged VDJ cassette, the four Cµ exons coding for the constant (C) region domains, and the two exons encoding the transmembrane and cytoplasmic domains. Alternative processing of this transcript, which is regulated by RNA cleavage and the choice of polyadenylation sites, determines whether or not the transmembrane and cytoplasmic exons are included in the mature mRNA. If they are included, the µ chain produced contains the amino acids that make up the transmembrane and cytoplasmic segments and is therefore anchored in the lipid bilayer of the plasma membrane. If, on the other hand, the transmembrane segment is excluded from the µ chain, the carboxy terminus consists of approximately 20 amino acids constituting the tail piece. Because this protein does not have a stretch of hydrophobic amino acids or a positively charged cytoplasmic tail, it cannot remain anchored in the endoplasmic reticulum membrane and is secreted. Thus, each B cell can synthesize both mem brane and secreted Ig. Most of the Ig heavy-chain mRNA in a plasma cell is cleaved at the upstream polyadenylation site, so most of this mRNA is of the secretory form. All CH genes contain similar membrane exons, and all heavy chains can be potentially expressed in membrane-bound and secreted forms.
Fig1. Production of membrane and secreted IgM in B lymphocytes. Alternative processing of a primary RNA transcript results in the formation of mRNA for the membrane or secreted form of the µ heavy chain. B-cell differentiation results in an increasing fraction of the µ protein produced as the secreted form. TP, TM, and CY refer to tail piece, transmembrane, and cytoplasmic segments, respectively, and AAA refers to polyadenylation. Cµ1, Cµ2, Cµ3, and Cµ4 are four exons of the Cµ gene. Ig, Immunoglobulin.
