Plasma Cells


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.


Benhamron S , Pattanayak SP , Berger M and Tirosh B (2015) mTOR activation promotes plasma cell differentiation and bypasses XBP‐1 for immunoglobulin secretion. Molecular and cellular biology 35 (1): 153–166.

Benson MJ , Dillon SR , Castigli E , et al. (2008) Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. Journal of immunology (Baltimore, Md.: 1950) 180 (6): 3655–3659.

Bortnick A , Chernova I , Quinn WJ 3rd et al. (2012) Long‐lived bone marrow plasma cells are induced early in response to T cell‐independent or T cell‐dependent antigens. Journal of immunology (Baltimore, Md.: 1950) 188 (11): 5389–5396.

Brewer JW and Hendershot LM (2005) Building an antibody factory: a job for the unfolded protein response. Nature immunology 6 (1): 23–29.

Brieva JA , Roldan E , Rodriguez C and Navas G (1994) Human tonsil, blood and bone marrow in vivo‐induced B cells capable of spontaneous and high‐rate immunoglobulin secretion in vitro: differences in the requirements for factors and for adherent and bone marrow stromal cells, as well as distinctive adhesion molecule expression. European journal of immunology 24 (2): 362–366.

Calame KL , Lin KI and Tunyaplin C (2003) Regulatory mechanisms that determine the development and function of plasma cells. Annual Review of Immunology 21: 205–230.

Calfon M , Zeng H , Urano F , et al. (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP‐1 mRNA. Nature 415 (6867): 92–96.

Cascio P , Oliva L , Cerruti F , et al. (2008) Dampening Ab responses using proteasome inhibitors following in vivo B cell activation. European journal of immunology 38 (3): 658–667.

Cassese G , Arce S , Hauser AE , et al. (2003) Plasma cell survival is mediated by synergistic effects of cytokines and adhesion‐dependent signals. Journal of immunology (Baltimore, Md.: 1950) 171 (4): 1684–1690.

Chernova I , Jones DD , Wilmore JR , et al. (2014) Lasting antibody responses are mediated by a combination of newly formed and established bone marrow plasma cells drawn from clonally distinct precursors. Journal of immunology (Baltimore, Md.: 1950) 193 (10): 4971–4979.

Chu VT , Frohlich A , Steinhauser G , et al. (2011) Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nature immunology 12 (2): 151–159.

Conway KL , Kuballa P , Khor B , et al. (2013) ATG5 regulates plasma cell differentiation. Autophagy 9 (4): 528–537.

Cyster JG (2003) Homing of antibody secreting cells. Immunological reviews 194: 48–60.

Delogu A , Schebesta A , Sun Q , et al. (2006) Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells. Immunity 24 (3): 269–281.

Dilillo DJ , Hamaguchi Y , Ueda Y , et al. (2008) Maintenance of long‐lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. Journal of immunology (Baltimore, Md.: 1950) 180 (1): 361–371.

Foote JB , Mahmoud TI , Vale AM and Kearney JF (2012) Long‐term maintenance of polysaccharide‐specific antibodies by IgM‐secreting cells. Journal of immunology (Baltimore, Md.: 1950) 188 (1): 57–67.

Gabler J , Wittmann J , Porstner M , et al. (2013) Contribution of microRNA 24‐3p and Erk1/2 to interleukin‐6‐mediated plasma cell survival. European journal of immunology 43 (11): 3028–3037.

Kopf M , Baumann H , Freer G , et al. (1994) Impaired immune and acute‐phase responses in interleukin‐6‐deficient mice. Nature 368 (6469): 339–342.

Ma Y , Shimizu Y , Mann MJ , Jin Y and Hendershot LM (2010) Plasma cell differentiation initiates a limited ER stress response by specifically suppressing the PERK‐dependent branch of the unfolded protein response. Cell stress & chaperones 15 (3): 281–293.

Manz RA , Lohning M , Cassese G , Thiel A and Radbruch A (1998) Survival of long‐lived plasma cells is independent of antigen. International immunology 10 (11): 1703–1711.

Manz RA , Thiel A and Radbruch A (1997) Lifetime of plasma cells in the bone marrow. Nature 388 (6638): 133–134.

Matus S , Nassif M , Glimcher LH and Hetz C (2009) XBP‐1 deficiency in the nervous system reveals a homeostatic switch to activate autophagy. Autophagy 5 (8): 1226–1228.

McHeyzer‐Williams MG (1997) Immune response decisions at the single cell level. Seminars in immunology 9 (4): 219–227.

Medina F , Segundo C , Campos‐Caro A , Gonzalez‐Garcia I and Brieva JA (2002) The heterogeneity shown by human plasma cells from tonsil, blood, and bone marrow reveals graded stages of increasing maturity, but local profiles of adhesion molecule expression. Blood 99 (6): 2154–2161.

Merville P , Dechanet J , Grouard G , Durand I and Banchereau J (1995) T cell‐induced B cell blasts differentiate into plasma cells when cultured on bone marrow stroma with IL‐3 and IL‐10. International immunology 7 (4): 635–643.

Minges Wols HA , Ippolito JA , Yu Z , et al. (2007) The effects of microenvironment and internal programming on plasma cell survival. International immunology 19 (7): 837–846.

Minges Wols HA , Underhill GH , Kansas GS and Witte PL (2002) The role of bone marrow‐derived stromal cells in the maintenance of plasma cell longevity. Journal of immunology (Baltimore, Md.: 1950) 169 (8): 4213–4221.

O'Connor BP , Gleeson MW , Noelle RJ and Erickson LD (2003) The rise and fall of long‐lived humoral immunity: terminal differentiation of plasma cells in health and disease. Immunological reviews 194: 61–76.

O'Connor BP , Raman VS , Erickson LD , et al. (2004) BCMA is essential for the survival of long‐lived bone marrow plasma cells. The Journal of experimental medicine 199 (1): 91–98.

Ou X , Xu S and Lam KP (2012) Deficiency in TNFRSF13B (TACI) expands T‐follicular helper and germinal center B cells via increased ICOS‐ligand expression but impairs plasma cell survival. Proceedings of the National Academy of Sciences of the United States of America 109 (38): 15401–15406.

Ozaki K , Spolski R , Ettinger R , et al. (2004) Regulation of B cell differentiation and plasma cell generation by IL‐21, a novel inducer of Blimp‐1 and Bcl‐6. Journal of immunology (Baltimore, Md.: 1950) 173 (9): 5361–5371.

Pengo N , Scolari M , Oliva L , et al. (2013) Plasma cells require autophagy for sustainable immunoglobulin production. Nature immunology 14 (3): 298–305.

Pritz T , Lair J , Ban M , et al. (2015) Plasma cell numbers decrease in bone marrow of old patients. European journal of immunology 45 (3): 738–746.

Radbruch A , Muehlinghaus G , Luger EO , et al. (2006) Competence and competition: the challenge of becoming a long‐lived plasma cell. Nature reviews . Immunology 6 (10): 741–750.

Reynolds AE , Kuraoka M and Kelsoe G (2015) Natural IgM is produced by CD5‐ plasma cells that occupy a distinct survival niche in bone marrow. Journal of immunology (Baltimore, Md.: 1950) 194 (1): 231–242.

Rodriguez C , Roldan E , Navas G and Brieva JA (1993) Essential role of tumor necrosis factor‐alpha in the differentiation of human tonsil in vivo induced B cells capable of spontaneous and high‐rate immunoglobulin secretion. European journal of immunology 23 (5): 1160–1164.

Rozanski CH , Arens R , Carlson LM , et al. (2011) Sustained antibody responses depend on CD28 function in bone marrow‐resident plasma cells. The Journal of experimental medicine 208 (7): 1435–1446.

Shaffer AL , Shapiro‐Shelef M , Iwakoshi NN , et al. (2004) XBP1, downstream of Blimp‐1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21 (1): 81–93.

Slifka MK , Antia R , Whitmire JK and Ahmed R (1998) Humoral immunity due to long‐lived plasma cells. Immunity 8 (3): 363–372.

Slocombe T , Brown S , Miles K , et al. (2013) Plasma cell homeostasis: the effects of chronic antigen stimulation and inflammation. Journal of immunology (Baltimore, Md.: 1950) 191 (6): 3128–3138.

Tangye SG (2011) Staying alive: regulation of plasma cell survival. Trends in immunology 32 (12): 595–602.

Taubenheim N , Tarlinton DM , Crawford S , et al. (2012) High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP‐1 deficiency. Journal of immunology (Baltimore, Md.: 1950) 189 (7): 3328–3338.

Todd DJ , McHeyzer‐Williams LJ , Kowal C , et al. (2009) XBP1 governs late events in plasma cell differentiation and is not required for antigen‐specific memory B cell development. The Journal of experimental medicine 206 (10): 2151–2159.

Tokoyoda K , Egawa T , Sugiyama T , Choi BI and Nagasawa T (2004) Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 20 (6): 707–718.

Tsuji S , Cortesao C , Bram RJ , Platt JL and Cascalho M (2011) TACI deficiency impairs sustained Blimp‐1 expression in B cells decreasing long‐lived plasma cells in the bone marrow. Blood 118 (22): 5832–5839.

Winter O , Moser K , Mohr E , et al. (2010) Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood 116 (11): 1867–1875.

Yoshida H , Matsui T , Yamamoto A , Okada T and Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107 (7): 881–891.

Zehentmeier S , Roth K , Cseresnyes Z , et al. (2014) Static and dynamic components synergize to form a stable survival niche for bone marrow plasma cells. European journal of immunology 44 (8): 2306–2317.

Further Reading

Belnoue E , Tougne C , Rochat AF , et al. (2012) Homing and adhesion patterns determine the cellular composition of the bone marrow plasma cell niche. Journal of immunology (Baltimore, Md.: 1950) 188 (3): 1283–1291.

Bortnick A and Allman D (2013) What is and what should always have been: long‐lived plasma cells induced by T cell‐independent antigens. Journal of immunology (Baltimore, Md.: 1950) 190 (12): 5913–5918.

Cenci S (2014) Autophagy, a new determinant of plasma cell differentiation and antibody responses. Molecular immunology 62 (2): 289–295.

Cenci S , Van Anken E and Sitia R (2011) Proteostenosis and plasma cell pathophysiology. Current opinion in cell biology 23 (2): 216–222.

Hofer T , Muehlinghaus G , Moser K , et al. (2006) Adaptation of humoral memory. Immunological reviews 211: 295–302.

Iwakoshi NN , Lee AH and Glimcher LH (2003) The X‐box binding protein‐1 transcription factor is required for plasma cell differentiation and the unfolded protein response. Immunological reviews 194: 29–38.

Moens L and Tangye SG (2014) Cytokine‐mediated regulation of plasma cell generation: IL‐21 takes center stage. Frontiers in immunology 5: 65.

Sze DM , Toellner KM , Garcia De Vinuesa C , Taylor DR and MacLennan IC (2000) Intrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival. The Journal of experimental medicine 192 (6): 813–821.

Tarlinton D , Radbruch A , Hiepe F and Dorner T (2008) Plasma cell differentiation and survival. Current opinion in immunology 20 (2): 162–169.

Van Anken E , Romijin EP , Maggioni C , et al. (2003) Sequential waves of functionally related proteins are expressed when B cells prepare for antibody secretion. Immunity 18 (2): 243–253.

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