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Keywords:

  • plasma cells;
  • antibodies;
  • immunological memory;
  • secondary lymphoid organs;
  • bone marrow

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information

Plasma cells play a crucial role for the humoral immune response as they represent the body's factories for antibody production. The differentiation from a B cell into a plasma cell is controlled by a complex transcriptional network and happens within secondary lymphoid organs. Based on their lifetime, two types of antibody secreting cells can be distinguished: Short-lived plasma cells are located in extrafollicular sites of secondary lymphoid organs such as lymph node medullary cords and the splenic red pulp. A fraction of plasmablasts migrate from secondary lymphoid organs to the bone marrow where they can become long-lived plasma cells. Bone marrow plasma cells reside in special microanatomical environments termed survival niches, which provide factors promoting their longevity. Reticular stromal cells producing the chemokine CXCL12, which is known to attract plasmablasts to the bone marrow but also to promote plasma cell survival, play a crucial role in the maintenance of these niches. In addition, hematopoietic cells are contributing to the niches by providing other soluble survival factors. Here, we review the current knowledge on the factors involved in plasma cell differentiation, their localization and migration. We also give an overview on what is known regarding the maintenance of long lived plasma cells in survival niches of the bone marrow. © 2013 International Society for Advancement of Cytometry


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information

In the course of an adaptive immune response, the humoral arm of the immune system generates distinct types of antigen-specific B lymphocytes in secondary lymphoid organs: memory B cells form a persisting population of antigen-specific B cells that can become activated and quickly differentiate into plasma cells upon re-exposure to the same antigen [1]. Terminally differentiated antibody secreting plasma cells constitute effector cells of humoral immunity by functioning as immunoglobulin (Ig) secreting cells [2]. They can become long-lived and persist in specialized survival niches in the bone marrow for extended periods of time (several years in humans), thereby secreting antibodies constantly. Together, these different B cell populations ensure an initial defense as well as long-lasting protection against antigens upon rechallenge, thus marking an important part of immunologic memory against pathogens. However, long-lived plasma cells can also be harmful by secreting autoreactive antibodies.

Molecular Events Governing Plasma Cell Differentiation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information

Memory B cells and plasma cells of high affinity are derived from highly organized histological structures in secondary lymphoid tissue called germinal centers (GCs) [3-6]. Mature GCs can be divided into different zones: the dark zone (DZ) at the base of the GC (proximal to the T cell zone), and the light zone (LZ) at the apical pole of the GC, characterized by the presence of follicular dendritic cells (FDCs) [7]. The border between the GC area and the naïve B cells in the follicular mantle is termed outer zone [8]. The GC constitutes a site where several crucial decisions on B cell fate are made: After extensive proliferation and somatic hypermutation [9], the B cells undergo a selection process based on the affinity of their BCR [10]. This is thought to involve competition for antigen (Ag) captured on the surface of follicular dendritic cells (FDCs) [11]. Only B cell receptors harboring high affinities for a given antigen survive, whereas lower affinity B cells undergo apoptosis, ultimately resulting in affinity maturation of the humoral immune response [12]. After the selection process, a second decision step follows for a B cell: It can either stay in the GC to enter a further round of division [13], or it leaves the GC. Exiting B cells can either become memory B cells, or they terminally differentiate into antibody secreting plasma cells [7].

Over the past few years, a model of the complex transcriptional regulatory network for terminal differentiation of B cells into antibody secreting cells has been developed. The earliest known molecular step involves down regulation of the transcription factor Pax5 [14, 15]. The transcriptional repressor Pax5 is required for maintenance of the identity of mature B cells [16], and is also expressed in memory B cells. Pax5 negatively regulates Ig production by repressing Igh [17] and Igk [18] transcription, expression of J chain [19] and XBP-1 [20]. Loss of Pax5–by an unknown regulator- is sufficient to induce the onset of IgM secretion [14, 21]. On the other hand, Pax-5 promotes expression of BACH2 [22], which support the formation and functions of GCs such as class switching [23, 24].

Bcl-6 is another transcriptional repressor, which is highly expressed in GC B cells [25] as well as in T follicular helper cells [26]. It is required for the formation of GCs [27-29] and promotes GC functions such as proliferation as well as class-switch recombination and somatic hypermutation. Additionally, Bcl-6 inhibits plasma cell differentiation in GCs by suppressing Blimp-1 [30] in association with MTA3 [31, 32].

Another crucial transcription factor controlling not only GC formation but also differentiation into plasma cells is IRF4 [33, 34]. IRF4 seems to act in a dose-dependent way: It promotes GC formation and functions, e.g., class switch recombination when abundant in low concentrations. At higher concentrations it can trigger plasma cell differentiation. IRF4 expression is controlled and kept at low levels in B cells by MITF, hence MITF-deficient B cells spontaneously differentiate into antibody secreting cells [35]. In cooperation with STAT3, IRF4 up-regulates the expression of Prdm1, the gene encoding Blimp-1 in an IL-21-dependent mechanism [36].

Blimp-1, the master regulator of plasma cell differentiation, silences genes expressed in mature B cells, including Pax-5 [37], class II transactivator and CXCR5. Blimp-1 is also able to repress Bcl-6 [14, 21, 38]. On the other hand, Blimp-1 up-regulates the expression of XBP-1, which induces genes involved in the regulation of protein synthesis and secretory pathways that are important for the secretion of large amounts of antibodies [39]. Importantly, Blimp-1 is not necessary for the earliest steps in plasma cell differentiation, including the onset of immunoglobulin secretion [15]. Maturation from the plasmablast stage to long-lived bone marrow ASCs is accompanied by an increase in Blimp-1 expression [40, 41] and it is actually required for the maintenance of long-lived bone marrow plasma cells. Notably, Blimp-1 is not expressed in memory B cells [42, 43].

Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information

Inhibition of Bcl-6 by Blimp-1 [and vice versa [30]] explains why only very few Blimp-1+ plasma cells can be detected inside GCs of mice and humans by histology [42, 44, 45]. However, CD138+ antibody secreting cells have been detected to be located adjacent to GCs, lining the border between GC dark zone and T cell zone [46]. It is this region where, in the course of an immune response, the first cognate interactions between B and T cells happen [47]. After activation, B cells upregulate CCR7 (the receptor for T cell zone chemokines CCL19/21) and are directed to the T-B border [48]. In this region, the initial interactions of B cells with T cells take place, subsequently leading to the formation of GCs. Intravital imaging has revealed dark zone B cells in mature GCs to move in a directed fashion towards the T-B border [49]. The presence of plasmablasts at this location [Fig. 1 and [46]] further underlines the importance of this region, not only during the initiation but also during the maintenance of the GC response.

image

Figure 1. Localization and migration of plasmablasts and plasma cells in lymph nodes. (A) The majority of Blimp-1+ antibody secreting cells in lymph nodes are localized at the medullary cords. Some Blimp-1+ cells are found in the border area between germinal centers and the T cell zone. NP-specific B cells from Blimp-1:GFPxCdt1:K Orange reporter mice were adoptively transferred into C57BL/6 recipients, which were subsequently immunized with NP-CGG. Seven days later the draining popliteal lymph node was harvested, fixed, and snap-frozen. Seven micrometer sections were stained as indicated and analyzed by confocal microscopy. Scale bar 200 μm. Pictures on the right represent enlarged views of the areas within the white boxes. IgD+ B cells (left) and CD4+ T cells (middle and right) are shown in blue, Blimp-1:GFP+ plasma blasts are green, B cells and plasmablasts in the G1 phase of the cell cycle [indicated by expression of Cdt-1:KOrange [50]] are shown in red. (B) Tracking the migration of naïve polyclonal B cells (light blue), NP-specific B cells inside and outside GCs (red) and Blimp-1+ plasma cells (green) in different regions of the popliteal lymph node of live mice over time. Stills are taken from Supplementary Movie 1 at indicated time points. Mice were treated as described in the legend for Supplementary Movie 1 and analysis was performed using Bitplane Imaris software. The collagen capsule of the lymph node appears blue due to second harmonic generation. For clarity, FDCs are not shown here. White letters indicate tissue areas in the lymph node: GC, germinal center; FM, follicular mantle; MC, medullary cords. White arrows point on a Blimp1+ cell that is moving from the GC towards the medullary cords. Scale bar 50 μm. (C) Displacement rate of B cell populations in the lymph node. NP-specific B cells outside of GCs move significantly more directed than naïve B cells and B cells inside GCs, as shown by a higher displacement rate. Blimp1+ plasma cells in medullary cords are sessile. Differences between the displacement rates are all significant by student's t-test, with p < 0.0001 for all tested conditions except for B cells inside vs. outside GCs (p = 0.029) and follicular polyclonal B cells versus Blimp1+ cells in medullary cords (p = 0.014).

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image

Figure 2. Localization of plasma cells in the bone marrow. (A) Overview of a whole murine femoral section. Blimp-1:GFP Mice were immunized twice with NP-CGG and bones were harvested and processed for immunofluorescence analysis. Antibodies against laminin (red) were used to stain the stromal network, DAPI (blue) was used to visualize cell nuclei. (B) Plasma cells (Blimp1:GFP+) in the bone marrow are in close contact with laminin+ stromal cells (white). Some plasma cells are seen in contact with MBP+ eosinophils (red). Higher magnifications reveal a tight interaction between plasma cells and the dendrites of stromal cells expressing laminin (C, D) and fibronectin (E, F).

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The majority of antibody secreting cells within secondary lymphoid organs are located in lymph node medullary cords (Fig. 1), and in extrafollicular foci of the splenic red pulp. In histology, accumulations of plasma cells can be observed reaching from the follicles throughout the T cell zone to the medullary cords (Fig. 1).

Two-photon studies have revealed GC B cells to be highly motile [49]. In contrast, at least a fraction of plasma cells in medullary cords are thought to be rather sessile [50, 51]. Upregulation of the plasma cell-specific transcription factor Blimp-1, which goes along with terminal differentiation, i.e., transition from the plasmablast to the plasma cell stage [40] negatively correlates with their motility [45]. In line with this, the term “plasmablast” is now widely used for a migratory antibody secreting cell, although it historically refers to an antibody secreting cell that still has the capacity to divide.

How is the translocation from plasmablasts generated in the GCs to medullary cords and extracellular foci mediated? Plasmablasts down-regulate CXCR5 [53] and thus lose their capacity to migrate towards high concentrations of the B cell chemokine CXCL13 in vitro [54]. Instead, they migrate towards CXCL12, a chemokine that is highly expressed in medullary cords and the splenic red pulp [55]. However, CXCL12 is also abundant in the dark zone of GCs [56, 57] and it is not completely clear how the migration from the GCs to the CXCL12-rich environment in extrafollicular sites of secondary lymphoid organs is regulated. Expression of EBI2 is up-regulated on plasma cells [58] and this 7-transmembrane receptor has been shown to direct B cells to the outer follicle areas [58, 59] and extrafollicular foci [60]. However, Fooksman et al. have shown that pertussis toxin was not able to block the migration of plasmablasts from B cell follicles to lymph node medullary cords in vivo. This indicates that G protein-coupled receptor signaling is not involved in this translocation, thereby ruling out a critical role for EBI2 as well as for chemokine receptors and the receptors for sphingosine-1-phosphate. When compared to naive B cells and GC B cells, plasma cells display a more directed pattern of migration [Fig. 1 and Ref. [45]]. Fooksman et al. suggested this type of migration pattern provides an efficient way to translocate from follicles to medullary cords even without chemotactic signals. Alternatively, the influence of other, yet undefined chemotactic cues could account for an active migration to the medullary cords.

Extrafollicular plasma cells are thought to be mainly short-lived as a high degree of apoptosis has been shown to occur among them [61]; however, there are also reports about the persistence of long-lived plasma cells in the spleen [62]. Notably, long-lived plasma cells have been shown to occur in secondary lymphoid organs of NZW/B mice, a model for systemic lupus erythematosus [63]. Moreover, chronically inflamed organs have also been shown to harbor long-lived antibody secreting cells [64-66]. However, the physiological site for the maintenance of long-lived plasma cells is the bone marrow.

Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information

A fraction of plasmablasts generated in systemic immune responses leave the secondary lymphoid organs and travel via the blood to the bone marrow. These plasmablasts are generally thought to originate from GC responses. However, recent data challenge this view: Long-lived plasma cells have been shown to be induced in a T-independent response as well as after inhibiting the formation of GCs by blocking CD40L in vivo [67]. The exact routes, which these cells take to exit from spleen and lymph nodes have not yet been defined, but it is known that egress of antibody secreting cells from the spleen and from Peyer's Patches requires signaling through S1P1 [68, 69]. S1P, the ligand for S1P1 is produced by erythrocytes and therefore highly abundant in the blood stream [70], plasmablasts in the blood express higher amounts of S1P1 as compared to their counterparts in secondary lymphoid organs. Treatment of mice with the immunosuppressant S1P antagonist FTY720 inhibits plasmablast egress into the blood in vivo [67]. In addition, beta-2 Integrin has been shown to play a role in plasmablast exit from peripheral lymph nodes [71].

Plasmablast entry pathways into the bone marrow are not yet fully elucidated. Presumably plasma blasts enter via sinusoidal veins in the bone marrow, but the mechanisms that mediate their transmigration have not been investigated in detail. One possible candidate involved into this process may be CD62L, as plasma blasts have been reported to express this homing receptor [72]. Another candidate is the adhesion molecule CD22, which is expressed on plasmablasts and becomes downregulated in terminally differentiated plasma cells. Sialylated ligands for CD22 have been reported to be present on sinusoidal endothelial cells of the bone marrow [73].

Clearly, efficient homing of plasmablasts to the bone marrow depends on CXCR4, the receptor for CXCL12, a chemokine which is produced in high amounts by bone marrow stromal cells, hence its name stromal derived factor 1 (SDF-1) [74]. Plasmablasts lacking CXCR4 fail to reach the bone marrow and instead accumulate in the blood, suggesting a crucial role for this receptor on these cells in entering the bone marrow from the blood [55]. Interestingly, the capacity of splenic plasmablasts to migrate to CXCL12 ex vivo is restricted to a tight time window, during the first week of a systemic immune response [54], since they have been shown to lose their migratory capacity between day 8 and 12 after boost immunization. In line with this, the number of antigen-specific plasmablasts is found to peak in the blood of immunized humans at day 7 after boost [75]. How other chemokines act on bone marrow plasma cells to fine-tune their localization and retention in the parenchyma remains to be investigated. Potential candidates are ligands of CCR2, as antigen-specific antibody titers were significantly reduced in mice with plasma cells deficient for this chemokine receptor [21]. A fraction of plasmablasts has also been shown to migrate to ligands of CXCR3 [54], suggesting a role of this chemokine receptor in the accumulation of antibody secreting cells in inflamed organs. In fact, chronically inflamed kidneys of NZB/W lupus mice have been shown to contain CXCR3+ antibody secreting cells [66] and a role for this chemokine receptor in the entry of plasmablasts into the inflamed CNS has been demonstrated in a mouse model of viral encephalomyelitis [76].

Dynamics of Mucosal Plasma Cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information

The largest fraction of antibody secreting cells in the body is actually located in mucosal associated lymphoid tissue (MALT). Virtually all plasma cells induced in mucosal immune reactions secrete antibodies of the IgA isotype. Class switch of B cells to IgA is induced in isolated lymphoid follicles, Peyer's Patches and mesenteric lymph nodes. These tissues provide an environment rich in factors like transforming growth factor beta (TGFߚβ) and a proliferation inducing ligand (APRIL), which have been shown to promote IgA responses [77]. A polymeric immunoglobulin receptor-dependent mechanism allows dimeric IgA to be transported via the gut epithelium into the lumen, where IgA is present mainly as a part of the mucus layer covering the surface [78]. Mucosal IgA+ plasmablasts first use lymph vessels to migrate to the mesenteric lymph nodes, and then they enter the blood circulation through the thoracic duct and home back to the lamina propria. The chemokine receptors CCR9 and CCR10 on plasma blasts are responsible for homing to the small and large intestine, respectively. Retinoic acid plays a role in imprinting of the gut homing mechanism of IgA+ plasmablasts by inducing CCR9 [79]. The adhesion molecule a4ß7 is also mediating gut tropism in plasmablasts [80]. Besides that, a fraction of IgA+ plasma cells in the diffuse lamina propria has been proposed to be generated locally, without the need for recirculation [81]. The majority of plasma cells in the blood of humans in steady state are derived from mucosal immune responses [82]. By FACS, up to 50% of bone marrow plasma cells in mice have been shown to be IgA+, but these values have to be interpreted with caution since the bone marrow contains large blood-filled sinusoids, therefore one cannot rule out a contribution of blood-derived plasma cells. While IgA+ plasma cells have been shown to express CXCR4 and migrate to the bone marrow [83], it is not known to what extent they can contribute to the resident long lived plasma cell compartment. Antibody secreting cells in the lamina propria have been thought to be short-lived [84] but there is indirect evidence in the recent literature that there might be a long-lived compartment present in this tissue as well [85, 86]. A recent study has described that some lamina propria plasma cells are able to produce tumor necrosis factor alpha (TNFα) and inducible nitric oxide synthase (INOS), revealing an unexpected heterogeneity in the antibody secreting cell compartment in the gut [87].

Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information

The abundance of plasma cells in the bone marrow was already recognized in the 1970s [6]. Twenty years later the group of Radbruch and coworkers first showed that the murine bone marrow contains a fraction of long-lived plasma cells [88]. Slifka et al. made a similar observation using irradiation of mice [89] and showed that the lifespan of plasma cells can reach values that are similar to the lifetime of a mouse. The independence of the long-lived plasma cell compartment from replenishment through memory B cells was later confirmed using different strategies of memory B cell depletion [90, 91].

The bone marrow is thought to sustain the survival of plasma cells in specialized microanatomical niches. Plasma cells have been shown to depend on a combination of extrinsic survival factors to survive [92] and their colocalization with several cell types, which produce these survival factors has been demonstrated by histology: plasma cells in the bone marrow are in close contact with reticular stromal cells (Fig. 2). These stromal cells have been shown to produce the chemokine CXCL12 [93]. CXCL12 seems to act in two different ways on plasmablasts versus plasma cells: as a chemokine, which has been shown to regulate plasma immigration into the bone marrow [54, 55], but also as a potent plasma cell survival factor as it has been demonstrated in vitro [92]. Besides its function in plasma cell migration and survival, it also plays a crucial B cell development and in the formation of the hematopoietic stem cell niches and lymphoid progenitor niches [94, 95]. Whether there is a heterogeneity among the CXCL12-producing stromal cells, i.e., whether the same stromal cell type can form a plasma cell niche or a hematopoietic stem cell niche has not yet been addressed. The isolation of bone marrow stroma cells for flow cytometric characterization is a technical challenge and markers like VCAM-1 or laminin, which are used to label bone marrow stromal cells in histology are also part of the extracellular matrix, making the interpretation of the stainings difficult. The recently reported generation of fluorescent reporter mice for different stromal cell populations in the bone marrow will help to overcome the challenge of visualizing stromal cells in vivo [95].

Accessory Cells of the Plasma Cell Survival Niches

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information

In addition to stromal cells, a number of cell types have been suggested in the literature to play an additional role as accessory cells for plasma cell maintenance. Colocalization of bone marrow plasma cells with megakaryocytes producing interleukin (IL)-6 APRIL has been demonstrated by histology [96]. IL-6 has been shown to support plasma cell survival in vivo [97] and in vitro [92]. The TNF-receptor family member APRIL binds to BCMA and TACI on plasma cells and mediates survival on plasma cells [98, 99]. Its function on plasma cells is mainly mediated via signaling through BCMA [100], which recently has been shown to induce high expression of mcl-1, a member of the bcl-2 family of pro-survival molecules [97]. Induction of mcl-1 crucially depends on BCMA-signaling in plasma cells from the bone marrow but not from the spleen, underlining the role of APRIL in the survival of long lived plasma cells.

Mice deficient for the megakaryocyte growth factor receptor Cmpl have 8-fold reduced numbers of megakaryocytes and plasma cells are reduced to one-third. Another study found 50–70% of bone marrow plasma cells in the vicinity of APRIL+ IL-6+ eosinophils [101]. Mice lacking eosinophils displayed a 70% reduction of long-lived bone marrow plasma cells in vivo, suggesting that the eosinophils had provided survival signals for these plasma cells. Activation of eosinophils has been shown to trigger the expression of plasma cell survival factors and their number in the bone marrow was increased after secondary immunization, suggestive of a previously unrecognized role of this cell type in immunological memory [102]. Of note, the half-life of eosinophils is only a few days under physiological conditions, but it has been shown to be prolonged in the case of infections [103]. It is currently not clear whether this is also the case for eosinophils in the plasma cell niches, allowing for a prolonged supply of APRIL for the plasma cells.

Another group demonstrated that myeloid precursor cells are actually the main producers of APRIL in the bone marrow [104]. Basophils have also been shown to support plasma cell survival in vitro and in vivo, partially through the production of IL-4 and IL-6 [105].

Ly-6Chi monocytes [106], and DCs [107] have also been proposed to play a role in plasma cell survival in mouse models. Bone marrow DCs have been shown to directly contact plasma cells, and they are able to support plasma cell survival via CD80 and CD86, which interact with CD28 on plasma cells [107]. Notably, stimulation with anti-CD28 antibodies in vitro resulted in activation of the prosurvival NF-kB-pathway and prolonged survival in plasma cells from the bone marrow, while it had no effect on splenic plasma cells. Whether this effect can be attributed to different stages of maturation or to the existence of distinct subsets of antibody secreting cells is not clear. Crosslinking of CD80/86 by CD28 on plasma cells in addition induced the production of IL-6 in bone marrow DCs, this in turn enhanced immunoglobulin production in the plasma cells. Notably, plasma cells in the lymph node have also been shown to instruct myeloid cells to produce APRIL and IL-6 [108].

Finally, osteoclasts have been shown to support human plasma cell survival in vitro [109]. Except for stroma cells, all of the aforementioned cell types are of hematopoietic origin, therefore one would expect a high degree of turnover, leading to a replacement of these cell types in the niches. This raises the question how plasma cells are continuously provided with survival factors from the transient cells over extended periods of time. There are several facts, which suggest that long lived plasma cells in the bone marrow are sessile, although this has not yet been demonstrated directly. They express high levels of Blimp-1 [40] and in antibody secreting cells in the lymph nodes Blimp-1 expression levels have been shown to negatively correlate with cellular motility [45]. Furthermore, plasma cells lose their capacity to migrate to chemotactic signals after their arrival in the bone marrow [54]. Together, these findings suggest that the plasma cell niche consists of static parts, which organize the niche and control its composition (e.g., reticular stroma cells) as well as dynamic components (e.g., hematopoietic cells, as most of the accessory cell types that have been described to be a part of the niche have a lifespan that is much shorter than that of a long-lived plasma cell). A stable stromal cell population of defined size, which provides a limited amount of niche space by supplying survival factors and attracting other, transient accessory cells to the niche may function to control the size and homeostasis of the long-lived plasma cell pool. In humans, antigen-specific HLA-DRhi plasmablasts that are on their way to the bone marrow can be detected one week after immunization [75]. However, in parallel also the frequency of mature (HLA-DRlo) plasma cells in the blood increases, leading to the hypothesis that sessile long-lived bone marrow residents can be outcompeted and replaced in their niches by incoming, motile blasts [110]. Assuming a random exchange of plasma cells in the bone marrow by influxing newly generated plasmablasts, computational modeling has implicated that it would take more than 500 years in humans to reduce the number of antigen-specific bone marrow plasma cells generated in one immune response if an individual undergoes on average four infections per year [111]. However, this model does not explain that antigens differ in their capacity to elicit longevity of plasma cells in the bone marrow. Whether this reflects variations between different immunizations in the number of generated plasma cells that reach the bone marrow or whether the plasma cells show an intrinsic difference in their capacity to survive is not clear.

Direct evidence for such a competition model is not yet available. In the future, it will therefore be crucial to investigate the impact of dynamics of the survival niches (i.e., cell motility and turnover of all cellular niche components). Intravital multiphoton imaging in the bone marrow has already been successfully applied to understand the biology of perivascular immune niches [112] as well as stem cell niches [113], and it will help to understand the dynamics of plasma cell niches.

Morphologic data describing the localization of plasma cells in the bone marrow have been derived from static histology. These data have been very helpful in understanding the structure of the bone marrow; however, colocalization analyses, which do not take the variation of frequencies and cell size distributions of different bone marrow cell populations into account, cannot discriminate between random or nonrandom colocalization events. Systems biology approaches, which simulate the distribution of the different bone marrow cell populations, may help to solve this question in the future. First of all, the crucial cell-interactions of the niche components have to be identified. It might be that plasma cells can induce or enhance the secretion of survival factors in the niche cells.

One also has to take into account that many of the plasma cell survival factors are soluble, so a direct contact between the cell providing the factor and the consuming plasma cell might not even be required to deliver the survival signals. In the human lamina propria, heparan sulfate proteoglycans on stromal cells have been shown to bind APRIL produced by neutrophils and therefore create a local microenvironment for plasma cells where this survival factor is enriched [114]. It has been shown for multiple myeloma cells that CD138, a surface molecule, which is also expressed by nonmalignant plasma cells can act as a coreceptor for APRIL [115], providing a mechanism how these cells catch soluble survival factors. A more detailed analysis of the motility of the niche cells as well as the distribution of the soluble survival factors will be needed to solve this question.

On the other hand, adhesion molecules like VLA-4 and LFA-1 are essential for plasma cell survival in the bone marrow. Administering a combination of blocking antibodies against these two molecules in vivo resulted in a 75% reduction of bone marrow plasma cells [91]. Ligands for VLA-4 that are present in the bone marrow include VCAM-1, fibronectin, and osteopontin, LFA-1 binds to ICAM-1,-2,-3. Both VLA-4 and LFA-1 probably act by fixing the plasma cells into their niches. Another molecule that has been suggested to promote survival of plasma cells by functioning as an adhesion molecule is CD93 [116].

Plasma Cells as Therapeutic Targets

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information

Autoantibodies are known to play a crucial role in the pathogenesis of several autoimmune diseases. Consequently, the depletion of long-lived autoreactive plasma cells is a promising therapeutic option, especially under conditions where targeting of B cells via CD20 has proven to be inefficient, e.g., in refractory systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) [117]. One obvious option is to interfere with the signals promoting plasma cell survival, and the development of Atacicept (TACI-Ig), a fusion protein of the human immunoglobulin constant region and TACI, the soluble receptor for the B cell survival factor BAFF and the plasma cell survival factor APRIL, has shown promising results in two independent phase 2 clinical trials for RA [118, 119]. In the future it will be a challenge to translate the increasing knowledge about the bone marrow plasma cell survival niche into new therapeutic strategies to interfere with these niches in order to deplete autoreactive plasma cells.

Another strategy for plasma cell depletion is targeting them intrinsically. The proteasome inhibitor Bortezomib has been shown to efficiently deplete short- and long-lived autoreactive plasma cells in two different mouse models for SLE. Bortezomib acts via activating the terminal unfolded protein response (UPR) [120]. Plasma cells produce enormous amounts of immunoglobulins [up to 10,000 molecules/s and cell [121]], which inevitably results in the accumulation of un- or misfolded proteins, and which renders them especially susceptible for apoptosis after the regular function of the proteasome is inhibited. Importantly, Bortezomib treatment was not only able to prevent the onset of the disease but it also ameliorated disease after the onset of clinical symptoms by reducing autoantibody titers, a finding which is of relevance especially for a future translation into the clinics. However, there are side effects that have to be considered when using Bortezomib, such as peripheral neuropathy [122], therefore the development of proteasome inhibitors, which more specifically target antibody secreting cells is desirable for the future. The recent finding that plasma cells crucially depend on autophagy for their homeostasis and longevity may also open alternative options for targeting these cells in the future [123]. In summary, all the currently available therapeutic options have in common that they do not distinguish between pathogenic, autoreactive plasma cells, and “normal” protective plasma cells, conferring protective antibodies, which are equally depleted. The long-term goal therefore should be the development of therapies, which specifically target autoantibody-producing plasma cells in the individual patient as a step to a more personalized medicine.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information

In summary, a lot of progress has been made in unraveling the complex transcriptional network that governs the differentiation of B cells into plasma cells. Intravital microscopy has helped to understand the migration and interactions of B cells and plasmablasts in secondary lymphoid tissues. Long-lived plasma cells are located in the bone marrow but we are only beginning to understand their lifestyle. In the future it will be necessary to further analyze them in the tissue context in order to fully understand the mechanisms, which keep them alive in their survival niches.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information

This project is funded by the Deutsche Forschungsgemeinschaft (DFG HA5354/4ߚ1 to A.E.H.) and JIMIߚa DFG core facility network grant for intravital microscopy. The authors thank Sabine Gruczek, Patrick Thiemann, and Manuela Ohde for assistance with animal care and Robert Günther for excellent technical assistance. We thank the lab of J.J. Lee (Mayo Clinic, Scottsdale, AZ) for providing the anti-MBP antibody. We are grateful to A. Miyawaki, RIKEN Brain Institute, Japan for the Cdt1-mKO cell cycle reporter mice and to S. Nutt, WEHI Melbourne, Australia for Blimp-1:GFP reporter mice.

Literature Cited

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information
  • 1
    Anderson SM, Tomayko MM, Shlomchik MJ. Intrinsic properties of human and murine memory B cells. Immunol Rev 2006;211:280294.
  • 2
    Manz RA, Hauser AE, Hiepe F, Radbruch A. Maintenance of serum antibody levels. Annu Rev Immunol 2005;23:367386.
  • 3
    Jacob J, Przylepa J, Miller C, Kelsoe G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells. J Exp Med 1993;178:12931307.
  • 4
    Coico RF, Bhogal BS, Thorbecke GJ. Relationship of germinal centers in lymphoid tissue to immunologic memory. VI. Transfer of B cell memory with lymph node cells fractionated according to their receptors for peanut agglutinin. J Immunol 1983;131:22542257.
  • 5
    Tew JG, DiLosa RM, Burton GF, Kosco MH, Kupp LI, Masuda A, Szakal AK. Germinal centers and antibody production in bone marrow. Immunol Rev 1992;126:99112.
  • 6
    Benner R, van Oudenaren A, de Ruiter H. Antibody formation in mouse bone marrow. IX. Peripheral lymphoid organs are involved in the initiation of bone marrow antibody formation. Cell Immunol 1977;34:125137.
  • 7
    MacLennan IC. Germinal centers. Annu Rev Immunol 1994;12:117139.
  • 8
    Hardie DL, Johnson GD, Khan M, MacLennan IC. Quantitative analysis of molecules which distinguish functional compartments within germinal centers. Eur J Immunol 1993;23:9971004.
  • 9
    Zhang J, MacLennan IC, Liu YJ, Lane PJ. Is rapid proliferation in B centroblasts linked to somatic mutation in memory B cell clones? Immunol Lett 1988;18:297299.
  • 10
    Liu YJ, Joshua DE, Williams GT, Smith CA, Gordon J, MacLennan IC. Mechanism of antigen-driven selection in germinal centres. Nature 1989;342:929931.
  • 11
    Haberman AM, Shlomchik MJ. Reassessing the function of immune-complex retention by follicular dendritic cells. Nat Rev Immunol 2003;3:757764.
  • 12
    Berek C, Berger A, Apel M. Maturation of the immune response in germinal centers. Cell 1991;67:11211129.
  • 13
    Hauser AE, Shlomchik MJ, Haberman AM. In vivo imaging studies shed light on germinal-centre development. Nat Rev Immunol 2007;7:499504.
  • 14
    Nera KP, Kohonen P, Narvi E, Peippo A, Mustonen L, Terho P, Koskela K, Buerstedde JM, Lassila O. Loss of Pax5 promotes plasma cell differentiation. Immunity 2006;24:283293.
  • 15
    Kallies A, Hasbold J, Fairfax K, Pridans C, Emslie D, McKenzie BS, Lew AM, Corcoran LM, Hodgkin PD, Tarlinton DM, et al. Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1. Immunity 2007;26:555566.
  • 16
    Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5: The guardian of B cell identity and function. Nat Immunol 2007;8:463470.
  • 17
    Linderson Y, Eberhard D, Malin S, Johansson A, Busslinger M, Pettersson S. Corecruitment of the Grg4 repressor by PU.1 is critical for Pax5-mediated repression of B-cell-specific genes. EMBO Rep 2004;5:291296.
  • 18
    Roque MC, Smith PA, Blasquez VC. A developmentally modulated chromatin structure at the mouse immunoglobulin kappa 3″ enhancer. Mol Cell Biol 1996;16:31383155.
  • 19
    Rinkenberger JL, Wallin JJ, Johnson KW, Koshland ME. An interleukin-2 signal relieves BSAP (Pax5)-mediated repression of the immunoglobulin J chain gene. Immunity 1996;5:377386.
  • 20
    Reimold AM, Ponath PD, Li YS, Hardy RR, David CS, Strominger JL, Glimcher LH. Transcription factor B cell lineage-specific activator protein regulates the gene for human X-box binding protein 1. J Exp Med 1996;183:393401.
  • 21
    Delogu A, Schebesta A, Sun Q, Aschenbrenner K, Perlot T, Busslinger M. Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells. Immunity 2006;24:269281.
  • 22
    Schebesta A, McManus S, Salvagiotto G, Delogu A, Busslinger GA, Busslinger M. Transcription factor Pax5 activates the chromatin of key genes involved in B cell signaling, adhesion, migration, and immune function. Immunity 2007;27:4963.
  • 23
    Muto A, Tashiro S, Nakajima O, Hoshino H, Takahashi S, Sakoda E, Ikebe D, Yamamoto M, Igarashi K. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 2004;429:566571.
  • 24
    Muto A, Ochiai K, Kimura Y, Itoh-Nakadai A, Calame KL, Ikebe D, Tashiro S, Igarashi K. Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch. EMBO J 2010;29:40484061.
  • 25
    Cattoretti G, Shaknovich R, Smith PM, Jack HM, Murty VV, Alobeid B. Stages of germinal center transit are defined by B cell transcription factor coexpression and relative abundance. J Immunol 2006;177:69306939.
  • 26
    Yu D, Rao S, Tsai LM, Lee SK, He Y, Sutcliffe EL, Srivastava M, Linterman M, Zheng L, Simpson N, et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 2009;31:457468.
  • 27
    Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 1997;276:589592.
  • 28
    Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, Leung C, Nouri-Shirazi M, Orazi A, Chaganti RS, et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet 1997;16:161170.
  • 29
    Fukuda T, Yoshida T, Okada S, Hatano M, Miki T, Ishibashi K, Okabe S, Koseki H, Hirosawa S, Taniguchi M, et al. Disruption of the Bcl6 gene results in an impaired germinal center formation. J Exp Med 1997;186:439448.
  • 30
    Tunyaplin C, Shaffer AL, Angelin-Duclos CD, Yu X, Staudt LM, Calame KL. Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J Immunol 2004;173:11581165.
  • 31
    Fujita N, Jaye DL, Geigerman C, Akyildiz A, Mooney MR, Boss JM, Wade PA. MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation. Cell 2004;119:7586.
  • 32
    Parekh S, Polo JM, Shaknovich R, Juszczynski P, Lev P, Ranuncolo SM, Yin Y, Klein U, Cattoretti G, Dalla Favera R, et al. BCL6 programs lymphoma cells for survival and differentiation through distinct biochemical mechanisms. Blood 2007;110:20672074.
  • 33
    Sciammas R, Shaffer AL, Schatz JH, Zhao H, Staudt LM, Singh H. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 2006;25:225236.
  • 34
    Klein U, Casola S, Cattoretti G, Shen Q, Lia M, Mo T, Ludwig T, Rajewsky K, Dalla-Favera R. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat Immunol 2006;7:773782.
  • 35
    Lin L, Gerth AJ, Peng SL. Active inhibition of plasma cell development in resting B cells by microphthalmia-associated transcription factor. J Exp Med 2004;200:115122.
  • 36
    Kwon H, Thierry-Mieg D, Thierry-Mieg J, Kim HP, Oh J, Tunyaplin C, Carotta S, Donovan CE, Goldman ML, Tailor P, et al. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 2009;31:941952.
  • 37
    Lin KI, Angelin-Duclos C, Kuo TC, Calame K. Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol Cell Biol 2002;22:47714780.
  • 38
    Calame KL, Lin KI, Tunyaplin C. Regulatory mechanisms that determine the development and function of plasma cells. Annu Rev Immunol 2003;21:205230.
  • 39
    Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee AH, Qian SB, Zhao H, Yu X, Yang L, Tan BK, Rosenwald A, et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 2004;21:8193.
  • 40
    Kallies A, Hasbold J, Tarlinton DM, Dietrich W, Corcoran LM, Hodgkin PD, Nutt SL. Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J Exp Med 2004;200:967977.
  • 41
    Shapiro-Shelef M, Lin KI, Savitsky D, Liao J, Calame K. Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow. J Exp Med 2005;202:14711476.
  • 42
    Angelin-Duclos C, Cattoretti G, Lin KI, Calame K. Commitment of B lymphocytes to a plasma cell fate is associated with Blimp-1 expression in vivo. J Immunol 2000;165:54625471.
  • 43
    Blink EJ, Light A, Kallies A, Nutt SL, Hodgkin PD, Tarlinton DM. Early appearance of germinal center-derived memory B cells and plasma cells in blood after primary immunization. J Exp Med 2005;201:545554.
  • 44
    Cattoretti G, Angelin-Duclos C, Shaknovich R, Zhou H, Wang D, Alobeid B. PRDM1/Blimp-1 is expressed in human B-lymphocytes committed to the plasma cell lineage. J Pathol 2005;206:7686.
  • 45
    Fooksman DR, Schwickert TA, Victora GD, Dustin ML, Nussenzweig MC, Skokos D. Development and migration of plasma cells in the mouse lymph node. Immunity 2010;33:118127.
  • 46
    Meyer-Hermann M, Mohr E, Pelletier N, Zhang Y, Victora GD, Toellner KM. A theory of germinal center B cell selection, #division, and exit. Cell Rep 2012;2:162174.
  • 47
    Okada T, Miller MJ, Parker I, Krummel MF, Neighbors M, Hartley SB, O'Garra A, Cahalan MD, Cyster JG. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS Biol 2005;3:e150.
  • 48
    Reif K, Ekland EH, Ohl L, Nakano H, Lipp M, Forster R, Cyster JG. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 2002;416:9499.
  • 49
    Hauser AE, Junt T, Mempel TR, Sneddon MW, Kleinstein SH, Henrickson SE, von Andrian UH, Shlomchik MJ, Haberman AM. Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns. Immunity 2007;26:655667.
  • 50
    Aiba Y, Kometani K, Hamadate M, Moriyama S, Sakaue-Sawano A, Tomura M, Luche H, Fehling HJ, Casellas R, Kanagawa O, et al. Preferential localization of IgG memory B cells adjacent to contracted germinal centers. Proceedings of the National Academy of Sciences of the United States of America 2010;107:1219212197.
  • 51
    Allen CD, Okada T, Tang HL, Cyster JG. Imaging of germinal center selection events during affinity maturation. Science 2007;315:528531.
  • 52
    Schwickert TA, Lindquist RL, Shakhar G, Livshits G, Skokos D, Kosco-Vilbois MH, Dustin ML, Nussenzweig MC. In vivo imaging of germinal centres reveals a dynamic open structure. Nature 2007;446:8387.
  • 53
    Wehrli N, Legler DF, Finke D, Toellner KM, Loetscher P, Baggiolini M, MacLennan IC, Acha-Orbea H. Changing responsiveness to chemokines allows medullary plasmablasts to leave lymph nodes. Eur J Immunol 2001;31:609616.
  • 54
    Hauser AE, Debes GF, Arce S, Cassese G, Hamann A, Radbruch A, Manz RA. Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response. J Immunol 2002;169:12771282.
  • 55
    Hargreaves DC, Hyman PL, Lu TT, Ngo VN, Bidgol A, Suzuki G, Zou YR, Littman DR, Cyster JG. A coordinated change in chemokine responsiveness guides plasma cell movements. J Exp Med 2001;194:4556.
  • 56
    Allen CD, Ansel KM, Low C, Lesley R, Tamamura H, Fujii N, Cyster JG. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat Immunol 2004;5:943952.
  • 57
    Victora GD, Schwickert TA, Fooksman DR, Kamphorst AO, Meyer-Hermann M, Dustin ML, Nussenzweig MC. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 2010;143:592605.
  • 58
    Pereira JP, Kelly LM, Xu Y, Cyster JG. EBI2 mediates B cell segregation between the outer and centre follicle. Nature 2009;460:11221126.
  • 59
    Gatto D, Wood K, Brink R. EBI2 operates independently of but in cooperation with CXCR5 and CCR7 to direct B cell migration and organization in follicles and the germinal center. J Immunol 2011;187:46214628.
  • 60
    Gatto D, Paus D, Basten A, Mackay CR, Brink R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity 2009;31:259269.
  • 61
    Smith KG, Hewitson TD, Nossal GJ, Tarlinton DM. The phenotype and fate of the antibody-forming cells of the splenic foci. Eur J Immunol 1996;26:444448.
  • 62
    Sze DM, Toellner KM, Garcia de Vinuesa C, Taylor DR, MacLennan IC. Intrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival. J Exp Med 2000;192:813821.
  • 63
    Hoyer BF, Moser K, Hauser AE, Peddinghaus A, Voigt C, Eilat D, Radbruch A, Hiepe F, Manz RA. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J Exp Med 2004;199:15771584.
  • 64
    Cassese G, Lindenau S, de Boer B, Arce S, Hauser A, Riemekasten G, Berek C, Hiepe F, Krenn V, Radbruch A, et al. Inflamed kidneys of NZB/W mice are a major site for the homeostasis of plasma cells. Eur J Immunol 2001;31:27262732.
  • 65
    Starke C, Frey S, Wellmann U, Urbonaviciute V, Herrmann M, Amann K, Schett G, Winkler T, Voll RE. High frequency of autoantibody-secreting cells and long-lived plasma cells within inflamed kidneys of NZB/W F1 lupus mice. Eur J Immunol 2011;41:21072112.
  • 66
    Lacotte S, Decossas M, Le Coz C, Brun S, Muller S, Dumortier H. Early differentiated CD138(high)MHCII(+)IgG(+) plasma cells express CXCR3 and localize into inflamed kidneys of lupus mice. PLoS One 2013;8:e58140.
  • 67
    Bortnick A, Chernova I, Quinn WJ III, Mugnier M, Cancro MP, Allman D. Long-lived bone marrow plasma cells are induced early in response to T cell-independent or T cell-dependent antigens. J Immunol 2012;188:53895396.
  • 68
    Kabashima K, Haynes NM, Xu Y, Nutt SL, Allende ML, Proia RL, Cyster JG. Plasma cell S1P1 expression determines secondary lymphoid organ retention versus bone marrow tropism. J Exp Med 2006;203:26832690.
  • 69
    Gohda M, Kunisawa J, Miura F, Kagiyama Y, Kurashima Y, Higuchi M, Ishikawa I, Ogahara I, Kiyono H. Sphingosine 1-phosphate regulates the egress of IgA plasmablasts from Peyer's patches for intestinal IgA responses. J Immunol 2008;180:53355343.
  • 70
    Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, Camerer E, Zheng YW, Huang Y, Cyster JG, et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 2007;316:295298.
  • 71
    Pabst O, Peters T, Czeloth N, Bernhardt G, Scharffetter-Kochanek K, Forster R. Cutting edge: egress of newly generated plasma cells from peripheral lymph nodes depends on beta 2 integrin. J Immunol 2005;174:74927495.
  • 72
    Kallies A, Hasbold J, Tarlinton DM, Dietrich W, Corcoran LM, Hodgkin PD, Nutt SL. Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J Exp Med 2004;200:967977.
  • 73
    Nitschke L, Floyd H, Ferguson DJ, Crocker PR. Identification of CD22 ligands on bone marrow sinusoidal endothelium implicated in CD22-dependent homing of recirculating B cells. J Exp Med 1999;189:15131518.
  • 74
    Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, Yoshida N, Kikutani H, Kishimoto T. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996;382:635638.
  • 75
    Odendahl M, Mei H, Hoyer BF, Jacobi AM, Hansen A, Muehlinghaus G, Berek C, Hiepe F, Manz R, Radbruch A, et al. Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood 2005;105:16141621.
  • 76
    Marques CP, Kapil P, Hinton DR, Hindinger C, Nutt SL, Ransohoff RM, Phares TW, Stohlman SA, Bergmann CC. CXCR3-dependent plasma blast migration to the central nervous system during viral encephalomyelitis. J Virol 2011;85:61366147.
  • 77
    Cerutti A, Rescigno M. The biology of intestinal immunoglobulin A responses. Immunity 2008;28:740750.
  • 78
    Brandtzaeg P. Mucosal immunity: Induction, #dissemination, #and effector functions. Scand J Immunol 2009;70:505515.
  • 79
    Hammerschmidt SI, Friedrichsen M, Boelter J, Lyszkiewicz M, Kremmer E, Pabst O, Forster R. Retinoic acid induces homing of protective T and B cells to the gut after subcutaneous immunization in mice. J Clin Invest 2011;121:30513061.
  • 80
    Quiding-Jarbrink M, Nordstrom I, Granstrom G, Kilander A, Jertborn M, Butcher EC, Lazarovits AI, Holmgren J, Czerkinsky C. Differential expression of tissue-specific adhesion molecules on human circulating antibody-forming cells after systemic, #enteric, #and nasal immunizations. A molecular basis for the compartmentalization of effector B cell responses. J Clin Invest 1997;99:12811286.
  • 81
    Fagarasan S, Kinoshita K, Muramatsu M, Ikuta K, Honjo T. In situ class switching and differentiation to IgA-producing cells in the gut lamina propria. Nature 2001;413:639643.
  • 82
    Mei HE, Yoshida T, Sime W, Hiepe F, Thiele K, Manz RA, Radbruch A, Dorner T. Blood-borne human plasma cells in steady-state are derived from mucosal immune responses. Blood 2009;113:24612469.
  • 83
    Youngman KR, Franco MA, Kuklin NA, Rott LS, Butcher EC, Greenberg HB. Correlation of tissue distribution, #developmental phenotype, #and intestinal homing receptor expression of antigen-specific B cells during the murine anti-rotavirus immune response. J Immunol 2002;168:21732181.
  • 84
    Kamata T, Nogaki F, Fagarasan S, Sakiyama T, Kobayashi I, Miyawaki S, Ikuta K, Muso E, Yoshida H, Sasayama S, et al. Increased frequency of surface IgA-positive plasma cells in the intestinal lamina propria and decreased IgA excretion in hyper IgA (HIGA) mice, a murine model of IgA nephropathy with hyperserum IgA. J Immunol 2000;165:13871394.
  • 85
    Hapfelmeier S, Lawson MA, Slack E, Kirundi JK, Stoel M, Heikenwalder M, Cahenzli J, Velykoredko Y, Balmer ML, Endt K, et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 2010;328:17051709.
  • 86
    Mesin L, Di Niro R, Thompson KM, Lundin KE, Sollid LM. Long-lived plasma cells from human small intestine biopsies secrete immunoglobulins for many weeks in vitro. J Immunol 2011;187:28672874.
  • 87
    Fritz JH, Rojas OL, Simard N, McCarthy DD, Hapfelmeier S, Rubino S, Robertson SJ, Larijani M, Gosselin J, Ivanov II, et al. Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut. Nature 2012;481:199203.
  • 88
    Manz RA, Thiel A, Radbruch A. Lifetime of plasma cells in the bone marrow. Nature 1997;388:133134.
  • 89
    Slifka MK, Antia R, Whitmire JK, Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity 1998;8:363372.
  • 90
    Ahuja A, Anderson SM, Khalil A, Shlomchik MJ. Maintenance of the plasma cell pool is independent of memory B cells. Proc Natl Acad Sci U S A 2008;105:48024807.
  • 91
    DiLillo DJ, Hamaguchi Y, Ueda Y, Yang K, Uchida J, Haas KM, Kelsoe G, Tedder TF. Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J Immunol 2008;180:361371.
  • 92
    Cassese G, Arce S, Hauser AE, Lehnert K, Moewes B, Mostarac M, Muehlinghaus G, Szyska M, Radbruch A, Manz RA. Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J Immunol 2003;171:16841690.
  • 93
    Tokoyoda K, Egawa T, Sugiyama T, Choi BI, Nagasawa T. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 2004;20:707718.
  • 94
    Ding L, Morrison SJ. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 2013;495:231235.
  • 95
    Greenbaum A, Hsu YM, Day RB, Schuettpelz LG, Christopher MJ, Borgerding JN, Nagasawa T, Link DC. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 2013;495:227230.
  • 96
    Winter O, Moser K, Mohr E, Zotos D, Kaminski H, Szyska M, Roth K, Wong DM, Dame C, Tarlinton DM, et al. Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood 2010;116:18671875.
  • 97
    Peperzak V, Vikstrom I, Walker J, Glaser SP, LePage M, Coquery CM, Erickson LD, Fairfax K, Mackay F, Strasser A, et al. Mcl-1 is essential for the survival of plasma cells. Nat Immunol 2013;14:290297.
  • 98
    Belnoue E, Pihlgren M, McGaha TL, Tougne C, Rochat AF, Bossen C, Schneider P, Huard B, Lambert PH, Siegrist CA. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early life bone marrow stromal cells. Blood 2008;111:27552764.
  • 99
    Benson MJ, Dillon SR, Castigli E, Geha RS, Xu S, Lam KP, Noelle RJ. Cutting edge: The dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol 2008;180:36553659.
  • 100
    O'Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, Lin LL, Mantchev GT, Bram RJ, Noelle RJ. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med 2004;199:9198.
  • 101
    Chu VT, Frohlich A, Steinhauser G, Scheel T, Roch T, Fillatreau S, Lee JJ, Lohning M, Berek C. Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat Immunol 2011;12:151159.
  • 102
    Chu VT, Berek C. Immunization induces activation of bone marrow eosinophils required for plasma cell survival. Eur J Immunol 2012;42:130137.
  • 103
    Ohnmacht C, Pullner A, van Rooijen N, Voehringer D. Analysis of eosinophil turnover in vivo reveals their active recruitment to and prolonged survival in the peritoneal cavity. J Immunol 2007;179:47664774.
  • 104
    Matthes T, Dunand-Sauthier I, Santiago-Raber ML, Krause KH, Donze O, Passweg J, McKee T, Huard B. Production of the plasma-cell survival factor a proliferation-inducing ligand (APRIL) peaks in myeloid precursor cells from human bone marrow. Blood 2011;118:18381844.
  • 105
    Rodriguez Gomez M, Talke Y, Goebel N, Hermann F, Reich B, Mack M. Basophils support the survival of plasma cells in mice. J Immunol 2010;185:71807185.
  • 106
    Belnoue E, Tougne C, Rochat AF, Lambert PH, Pinschewer DD, Siegrist CA. Homing and adhesion patterns determine the cellular composition of the bone marrow plasma cell niche. J Immunol 2012;188:12831291.
  • 107
    Rozanski CH, Arens R, Carlson LM, Nair J, Boise LH, Chanan-Khan AA, Schoenberger SP, Lee KP. Sustained antibody responses depend on CD28 function in bone marrow-resident plasma cells. J Exp Med 2011;208:14351446.
  • 108
    Mohr E, Serre K, Manz RA, Cunningham AF, Khan M, Hardie DL, Bird R, MacLennan IC. Dendritic cells and monocyte/macrophages that create the IL-6/APRIL-rich lymph node microenvironments where plasmablasts mature. J Immunol 2009;182:21132123.
  • 109
    Geffroy-Luseau A, Jego G, Bataille R, Campion L, Pellat-Deceunynck C. Osteoclasts support the survival of human plasma cells in vitro. Int Immunol 2008;20:775782.
  • 110
    Radbruch A, Muehlinghaus G, Luger EO, Inamine A, Smith KG, Dorner T, Hiepe F. Competence and competition: The challenge of becoming a long-lived plasma cell. Nat Rev Immunol 2006;6:741750.
  • 111
    Hofer T, Muehlinghaus G, Moser K, Yoshida T, H EM, Hebel K, Hauser A, Hoyer B, E OL, Dorner T, et al. Adaptation of humoral memory. Immunol Rev 2006;211:295302.
  • 112
    Sapoznikov A, Pewzner-Jung Y, Kalchenko V, Krauthgamer R, Shachar I, Jung S. Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches. Nat Immunol 2008;9:388395.
  • 113
    Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J, Cote D, Rowe DW, Lin CP, Scadden DT. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 2009;457:9296.
  • 114
    Huard B, McKee T, Bosshard C, Durual S, Matthes T, Myit S, Donze O, Frossard C, Chizzolini C, Favre C, et al. APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa. J Clin Invest 2008;118:28872895.
  • 115
    Moreaux J, Sprynski AC, Dillon SR, Mahtouk K, Jourdan M, Ythier A, Moine P, Robert N, Jourdan E, Rossi JF, et al. APRIL and TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop. Eur J Haematol 2009;83:119129.
  • 116
    Chevrier S, Genton C, Kallies A, Karnowski A, Otten LA, Malissen B, Malissen M, Botto M, Corcoran LM, Nutt SL, et al. CD93 is required for maintenance of antibody secretion and persistence of plasma cells in the bone marrow niche. Proc Natl Acad Sci U S A 2009;106:38953900.
  • 117
    Hiepe F, Dorner T, Hauser AE, Hoyer BF, Mei H, Radbruch A. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat Rev Rheumatol 2011;7:170178.
  • 118
    van Vollenhoven RF, Kinnman N, Vincent E, Wax S, Bathon J. Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a phase II, randomized, placebo-controlled trial. Arthritis Rheum 2011;63:17821792.
  • 119
    Genovese MC, Kinnman N, de La Bourdonnaye G, Pena RC, Tak PP. Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: results of a phase |II, #randomized, placebo-controlled, dose-finding trial. Arthritis Rheum 2011;63:17931803.
  • 120
    Meister S, Schubert U, Neubert K, Herrmann K, Burger R, Gramatzki M, Hahn S, Schreiber S, Wilhelm S, Herrmann M, et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res 2007;67:17831792.
  • 121
    Hibi T, Dosch HM. Limiting dilution analysis of the B cell compartment in human bone marrow. Eur J Immunol 1986;16:139145.
  • 122
    Zeng Z, Lin J, Chen J. Bortezomib for patients with previously untreated multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Ann Hematol 2013;92:935943.
  • 123
    Pengo N, Cenci S. The role of autophagy in plasma cell ontogenesis. Autophagy 2013;9:942944.

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular Events Governing Plasma Cell Differentiation
  5. Location and Migration of Antibody Secreting Cells Within SecondaryLymphoid Organs
  6. Plasmablast Migration from Secondary Lymphoid Organs to the Bone Marrow
  7. Dynamics of Mucosal Plasma Cells
  8. Bone Marrow Survival Niches: A Specialized Stromal Microenvironment Fostering Long-Lived Plasma Cells
  9. Accessory Cells of the Plasma Cell Survival Niches
  10. Plasma Cells as Therapeutic Targets
  11. Conclusion
  12. Acknowledgments
  13. Literature Cited
  14. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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cytoa22355-sup-0001-suppInfo.docx15KSupporting Information
cytoa22355-sup-0002-suppMov1.mov4642KSupporting Information Movie 1

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