Staying alive: regulation of plasma cell survival
2011; Elsevier BV; Volume: 32; Issue: 12 Linguagem: Inglês
10.1016/j.it.2011.09.001
ISSN1471-4981
Autores Tópico(s)Complement system in diseases
ResumoOn describing the catastrophic effect of the plague during the Peloponnesian War, Greek historian Thucydides (c ∼450 BC) made the prescient observation that the “same man was never attacked twice – never at least fatally”. This is probably the first description of the mammalian immune systems’ remarkable ability to elicit a pathogen-specific response that potentially protects the host for its lifetime. This protection is largely mediated by plasma cells (PCs) that produce copious quantities of antibodies for extended periods of time, even after pathogen clearance. Here, I review the requirements for PC longevity in mice and humans, in particular the roles of survival niches in bone marrow and other tissues, and the “dialogue” between PCs and other cells that are crucial for long-lived humoral immunity. On describing the catastrophic effect of the plague during the Peloponnesian War, Greek historian Thucydides (c ∼450 BC) made the prescient observation that the “same man was never attacked twice – never at least fatally”. This is probably the first description of the mammalian immune systems’ remarkable ability to elicit a pathogen-specific response that potentially protects the host for its lifetime. This protection is largely mediated by plasma cells (PCs) that produce copious quantities of antibodies for extended periods of time, even after pathogen clearance. Here, I review the requirements for PC longevity in mice and humans, in particular the roles of survival niches in bone marrow and other tissues, and the “dialogue” between PCs and other cells that are crucial for long-lived humoral immunity. B lymphocytes develop from bone marrow (BM) multipotent stem cells. A series of maturation stages yields naïve B cells expressing a functional B cell receptor [1LeBien T.W. Tedder T.F. B lymphocytes: how they develop and function.Blood. 2008; 112: 1570-1580Crossref PubMed Scopus (815) Google Scholar, 2Cassese G. et al.Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals.J. Immunol. 2003; 171: 1684-1690PubMed Google Scholar] (Figure 1). When naïve B cells traffic through secondary lymphoid tissues and encounter foreign antigen (Ag), they can differentiate into multiple fates depending on the type, strength and timing of signals received within the lymphoid microenvironment. Thus, both T-independent and T-dependent (TD) Ags induce naïve B cells to become short-lived antibody (Ab)-secreting plasmablasts that localize to extrafollicular regions of lymphoid tissues [3Allen C.D. et al.Germinal-center organization and cellular dynamics.Immunity. 2007; 27: 190-202Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar, 4Chan T.D. et al.In vivo control of B-cell survival and antigen-specific B-cell responses.Immunol. Rev. 2010; 237: 90-103Crossref PubMed Scopus (32) Google Scholar, 5Nutt S.L. Tarlinton D.M. Germinal center B and follicular helper T cells: siblings, cousins or just good friends?.Nat. Immunol. 2011; 12: 472-477Crossref PubMed Scopus (171) Google Scholar, 6Elgueta R. et al.The immortality of humoral immunity.Immunol. Rev. 2010; 236: 139-150Crossref PubMed Scopus (80) Google Scholar]. TD Ags also induce naïve B cells to seed germinal centers (GCs) in lymphoid follicles. Within GCs, B cells undergo somatic hypermutation, isotype switching and affinity-based selection, which collectively result in the generation of long-lived memory and PCs [3Allen C.D. et al.Germinal-center organization and cellular dynamics.Immunity. 2007; 27: 190-202Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar, 4Chan T.D. et al.In vivo control of B-cell survival and antigen-specific B-cell responses.Immunol. Rev. 2010; 237: 90-103Crossref PubMed Scopus (32) Google Scholar, 5Nutt S.L. Tarlinton D.M. Germinal center B and follicular helper T cells: siblings, cousins or just good friends?.Nat. Immunol. 2011; 12: 472-477Crossref PubMed Scopus (171) Google Scholar, 7Liu Y.J. Banchereau J. The paths and molecular controls of peripheral B-cell development.Immunologist. 1996; 4: 55-66Google Scholar] (Figure 1). Both of these cells then migrate from the GC to distinct sites, such as the splenic red pulp, medullary cords of lymph nodes (LNs) or mucosal-associated lymphoid tissues (MALT) of the gut for PCs, or splenic marginal zone or tonsillar epithelium for memory B cells [3Allen C.D. et al.Germinal-center organization and cellular dynamics.Immunity. 2007; 27: 190-202Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar, 6Elgueta R. et al.The immortality of humoral immunity.Immunol. Rev. 2010; 236: 139-150Crossref PubMed Scopus (80) Google Scholar, 7Liu Y.J. Banchereau J. The paths and molecular controls of peripheral B-cell development.Immunologist. 1996; 4: 55-66Google Scholar, 8Kunkel E.J. Butcher E.C. Plasma-cell homing.Nat. Rev. Immunol. 2003; 3: 822-829Crossref PubMed Scopus (431) Google Scholar]. Alternatively, the cells can egress from their tissue of origin, enter the circulation and take up residence in distal sites: for PCs, this is predominantly the BM [8Kunkel E.J. Butcher E.C. Plasma-cell homing.Nat. Rev. Immunol. 2003; 3: 822-829Crossref PubMed Scopus (431) Google Scholar, 9Benner R. et al.The bone marrow: the major source of serum immunoglobulins, but still a neglected site of antibody formation.Clin. Exp. Immunol. 1981; 46: 1-8PubMed Google Scholar] (Figure 1, Figure 2). During inflammatory or autoimmune responses, PCs can also home to inflamed tissues [10Cassese G. et al.Inflamed kidneys of NZB/W mice are a major site for the homeostasis of plasma cells.Eur. J. Immunol. 2001; 31: 2726-2732Crossref PubMed Scopus (196) Google Scholar, 11Yoshida T. et al.Memory B and memory plasma cells.Immunol. Rev. 2010; 237: 117-139Crossref PubMed Scopus (216) Google Scholar]. Migration of PCs from GCs is achieved by alterations in expression of chemokine receptors: they downregulate the B- and T-zone homing receptors chemokine CXC receptor (CXCR)5 and chemokine CC receptor (CCR)7, respectively, and increase CXCR4 [12Hargreaves D.C. et al.A coordinated change in chemokine responsiveness guides plasma cell movements.J. Exp. Med. 2001; 194: 45-56Crossref PubMed Scopus (522) Google Scholar, 13Nakayama T. et al.Cutting edge: profile of chemokine receptor expression on human plasma cells accounts for their efficient recruitment to target tissues.J. Immunol. 2003; 170: 1136-1140PubMed Google Scholar, 14Wehrli N. et al.Changing responsiveness to chemokines allows medullary plasmablasts to leave lymph nodes.Eur. J. Immunol. 2001; 31: 609-616Crossref PubMed Scopus (100) Google Scholar, 15Ellyard J.I. et al.Antigen-selected, immunoglobulin-secreting cells persist in human spleen and bone marrow.Blood. 2004; 103: 3805-3812Crossref PubMed Scopus (112) Google Scholar, 16Ellyard J.I. et al.Contribution of stromal cells to the migration, function and retention of plasma cells in human spleen: potential roles of CXCL12, IL-6 and CD54.Eur. J. Immunol. 2005; 35: 699-708Crossref PubMed Scopus (57) Google Scholar], thereby facilitating recruitment to sites of production of its ligand CXC ligand (CXCL)12. Although PCs express receptors for other chemokines (e.g. CXCR3, CXCR6, CCR25, CCR28, the latter two being important for homing to MALT; [8Kunkel E.J. Butcher E.C. Plasma-cell homing.Nat. Rev. Immunol. 2003; 3: 822-829Crossref PubMed Scopus (431) Google Scholar, 13Nakayama T. et al.Cutting edge: profile of chemokine receptor expression on human plasma cells accounts for their efficient recruitment to target tissues.J. Immunol. 2003; 170: 1136-1140PubMed Google Scholar]), whereas the CXCR4−CXCL12 axis is important for their initial migration to the BM [12Hargreaves D.C. et al.A coordinated change in chemokine responsiveness guides plasma cell movements.J. Exp. Med. 2001; 194: 45-56Crossref PubMed Scopus (522) Google Scholar, 17Tokoyoda K. et al.Cellular niches controlling B lymphocyte behavior within bone marrow during development.Immunity. 2004; 20: 707-718Abstract Full Text Full Text PDF PubMed Scopus (622) Google Scholar]. However, production of CXCR3 ligands in inflamed tissue probably underlies the ability of PCs to localize to such sites, including tissues under autoimmune attack [11Yoshida T. et al.Memory B and memory plasma cells.Immunol. Rev. 2010; 237: 117-139Crossref PubMed Scopus (216) Google Scholar]. PCs can also be generated from memory B cells following re-exposure to the initial Ag [18Tangye S.G. Tarlinton D.M. Memory B cells: effectors of long-lived immune responses.Eur. J. Immunol. 2009; 39: 2065-2075Crossref PubMed Scopus (175) Google Scholar] (Figure 1, Figure 2). Thus, PCs can arise from numerous precursors at different stages during an immune response, for example, naïve B cells, which generate short-lived plasmablasts that provide the first line of protection; GC B cells, which yield high-affinity long-lived PCs; and memory B cells, which potentially replenish the pool of long-lived PCs on re-encounter with specific pathogens/Ags.Figure 2Migration and positioning of B cells at distinct stages of activation and differentiation. Human spleen section was stained for CD27 (orange) and IgD (blue) to delineate naïve B cells in the follicle (IgDhiCD27–), memory B cells in the marginal zone (IgDlo/−CD27+), PCs in the red pulp (CD27hi) and T cells in the T-zone (CD27+). The follicle, marginal zone and T cell zone are demarcated by dotted white lines. GC B cells transiently appear within the B-cell follicle (not abundantly present in this tissue section example). PCs migrate away from the GC under the influence of chemokines (i.e. CXCL12; shown in black print) produced by stromal cells in the red pulp. PCs can remain in the red pulp, where their survival is maintained by stromal-cell-derived IL-6 (shown in black print), as well as cell–cell (e.g. adhesion) interactions between the stromal cells and PCs. Alternatively, PCs can exit the tissue of origin and migrate to distant sites, predominantly the BM. This migration is also mediated by the CXCR4–CXCL12 axis. Memory B cells can also remain in the spleen, where they relocate to the marginal zone and are tethered there by interactions with adhesion molecules.View Large Image Figure ViewerDownload (PPT) Although B cells have multiple functions including Ag presentation, CD4+ T cell stimulation and immune regulation via cytokine production [1LeBien T.W. Tedder T.F. B lymphocytes: how they develop and function.Blood. 2008; 112: 1570-1580Crossref PubMed Scopus (815) Google Scholar], their most important function is unquestionably the production of Abs that efficiently neutralize and/or clear invading pathogens from the host. Indeed, the ability of naïve B cells to differentiate into Ab-secreting cells underlies the success of most – if not all – current vaccines [19Rajewsky K. Clonal selection and learning in the antibody system.Nature. 1996; 381: 751-758Crossref PubMed Scopus (1402) Google Scholar]. The continual secretion of neutralizing Ab by PCs, and the rapid differentiation of memory cells into PCs following recurrent exposure to the initial Ag/pathogen, provide mechanisms by which these cells maintain long-term humoral immunity and host protection against recurrent infections [18Tangye S.G. Tarlinton D.M. Memory B cells: effectors of long-lived immune responses.Eur. J. Immunol. 2009; 39: 2065-2075Crossref PubMed Scopus (175) Google Scholar, 19Rajewsky K. Clonal selection and learning in the antibody system.Nature. 1996; 381: 751-758Crossref PubMed Scopus (1402) Google Scholar]. This fundamental function of B cells is evident from the primary immunodeficiences X-linked and autosomal recessive agammaglobulinemia, in which B cell development is blocked in the BM, resulting in a severe reduction (100–1000-fold fewer than healthy donors) in mature recirculating B cells and a lack of serum Ab of all isotypes [20Conley M.E. et al.Primary B cell immunodeficiencies: comparisons and contrasts.Annu. Rev. Immunol. 2009; 27: 199-227Crossref PubMed Scopus (341) Google Scholar]. Affected individuals can be successfully treated by Ig replacement therapy, despite the perpetual absence of B cells [20Conley M.E. et al.Primary B cell immunodeficiencies: comparisons and contrasts.Annu. Rev. Immunol. 2009; 27: 199-227Crossref PubMed Scopus (341) Google Scholar]. Thus, although individuals can survive without B cells, their mortality is greatly compromised by an absence of secreted Ab. Although the importance of Ab to long-lived humoral immunity has been appreciated for several decades, and the existence of immunological memory known for centuries, we are only now starting to understand the requirements and mechanisms responsible for PC longevity. This has largely come about by recognizing the importance of survival niches for PCs not only in BM but also other lymphoid tissues, and the underlying ‘dialog’ between PCs and other cells that occupy the survival niche. A fascinating feature of the mammalian immune response to TD Ags is the ability to detect protective Abs for an entire lifetime following initial immunization or infectious exposure [21Amanna I.J. et al.Duration of humoral immunity to common viral and vaccine antigens.N. Engl. J. Med. 2007; 357: 1903-1915Crossref PubMed Scopus (869) Google Scholar, 22Crotty S. et al.Cutting edge: long-term B cell memory in humans after smallpox vaccination.J. Immunol. 2003; 171: 4969-4973PubMed Google Scholar, 23Hammarlund E. et al.Duration of antiviral immunity after smallpox vaccination.Nat. Med. 2003; 9: 1131-1137Crossref PubMed Scopus (712) Google Scholar]. The half-life of serum Ab against non-replicating protein Ag (e.g. tetanus or diphtheria) is 10–20 years, whereas the half-life of Ab specific for live viruses [e.g. measles, mumps, rubella, vaccinia (smallpox), varicella, Epstein–Barr virus) is 50–200 years [21Amanna I.J. et al.Duration of humoral immunity to common viral and vaccine antigens.N. Engl. J. Med. 2007; 357: 1903-1915Crossref PubMed Scopus (869) Google Scholar]. Although it has been hypothesized that memory B cells maintain humoral immunity by differentiating into PCs polyclonally following exposure to Toll-like receptor (TLR) ligands present in many pathogens [24Bernasconi N.L. et al.Maintenance of serological memory by polyclonal activation of human memory B cells.Science. 2002; 298: 2199-2202Crossref PubMed Scopus (1089) Google Scholar], the data supporting this proposal are limited. For instance, the numbers of Ag-specific memory B cells does not always correlate with concentrations of Ag-specific Ab in serum [21Amanna I.J. et al.Duration of humoral immunity to common viral and vaccine antigens.N. Engl. J. Med. 2007; 357: 1903-1915Crossref PubMed Scopus (869) Google Scholar, 25Leyendeckers H. et al.Correlation analysis between frequencies of circulating antigen-specific IgG-bearing memory B cells and serum titers of antigen-specific IgG.Eur. J. Immunol. 1999; 29: 1406-1417Crossref PubMed Scopus (111) Google Scholar]. Similarly, although anti-CD20 mAb therapies deplete most peripheral B cells, serum titers of Ag-specific Abs are largely unaffected [26Cambridge G. et al.Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis.Arthritis Rheum. 2003; 48: 2146-2154Crossref PubMed Scopus (411) Google Scholar]. Lastly, individual with mutations in MYD88 or IRAK4, which are required for signaling through most TLRs, have intact humoral immune response to TD Ag [27Picard C. et al.Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency.Medicine (Baltimore). 2010; 89: 403-425Crossref PubMed Scopus (325) Google Scholar]. These findings suggest that memory cells and PCs are subject to distinct regulatory mechanisms and contribute to the longevity of humoral immunity by independent processes. Based on these observations, it is clear that PCs are the primary cell type responsible for sustained production of protective Abs in the absence of repeated Ag exposure. Although Abs produced by PCs can be detected for decades, PCs themselves are not intrinsically long-lived. Following isolation from human or mouse spleen, tonsils or BM, PCs undergo rapid apoptosis unless they are co-cultured with stromal-type feeder cells or exogenous cytokines [2Cassese G. et al.Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals.J. Immunol. 2003; 171: 1684-1690PubMed Google Scholar, 15Ellyard J.I. et al.Antigen-selected, immunoglobulin-secreting cells persist in human spleen and bone marrow.Blood. 2004; 103: 3805-3812Crossref PubMed Scopus (112) Google Scholar, 28Minges Wols H.A. et al.The role of bone marrow-derived stromal cells in the maintenance of plasma cell longevity.J. Immunol. 2002; 169: 4213-4221Crossref PubMed Scopus (223) Google Scholar]. These in vitro observations are consistent with in vivo studies that have discovered that, irrespective of the absolute number of PCs generated during an immune response, the spleen can only support survival of a finite number following resolution of infection and/or clearance of the pathogen [29Sze D.M. et al.Intrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival.J. Exp. Med. 2000; 192: 813-821Crossref PubMed Scopus (238) Google Scholar]. Together, these findings have led to the concept that the long-term persistence and function of PCs depends upon specialized niches within lymphoid tissues that facilitate their survival [30Radbruch A. et al.Competence and competition: the challenge of becoming a long-lived plasma cell.Nat. Rev. Immunol. 2006; 6: 741-750Crossref PubMed Scopus (789) Google Scholar]. In the presence of an excessive number of PCs, only those that successfully compete for these niches will survive. Similarly, newly generated plasmablasts are proposed to displace resident, non-migratory PCs generated during previous immune responses from their survival niches [30Radbruch A. et al.Competence and competition: the challenge of becoming a long-lived plasma cell.Nat. Rev. Immunol. 2006; 6: 741-750Crossref PubMed Scopus (789) Google Scholar]. This hypothesis provides an explanation for the simultaneous detection of both Ag-specific and non-specific PCs in the circulation following immunization – with one population representing recently generated niche-seeking PCs, and the other being ‘older’ displaced PCs [24Bernasconi N.L. et al.Maintenance of serological memory by polyclonal activation of human memory B cells.Science. 2002; 298: 2199-2202Crossref PubMed Scopus (1089) Google Scholar, 31Gonzalez-Garcia I. et al.Immunization-induced perturbation of human blood plasma cell pool: progressive maturation, IL-6 responsiveness, and high PRDI-BF1/BLIMP1 expression are critical distinctions between antigen-specific and nonspecific plasma cells.J. Immunol. 2006; 176: 4042-4050Crossref PubMed Scopus (59) Google Scholar, 32Odendahl M. et al.Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response.Blood. 2005; 105: 1614-1621Crossref PubMed Scopus (346) Google Scholar] – as well as the progressive decline in the levels of Ag-specific Ab in serum [21Amanna I.J. et al.Duration of humoral immunity to common viral and vaccine antigens.N. Engl. J. Med. 2007; 357: 1903-1915Crossref PubMed Scopus (869) Google Scholar]. Survival niches for PCs have been best characterized in BM. For PCs to access survival niches, they need to exit lymphoid follicles and traffic to distal sites. CXCR4 is important for PC recruitment to the BM. Indeed, mice whose B cells lack CXCR4 have reduced numbers of BM PCs [12Hargreaves D.C. et al.A coordinated change in chemokine responsiveness guides plasma cell movements.J. Exp. Med. 2001; 194: 45-56Crossref PubMed Scopus (522) Google Scholar, 17Tokoyoda K. et al.Cellular niches controlling B lymphocyte behavior within bone marrow during development.Immunity. 2004; 20: 707-718Abstract Full Text Full Text PDF PubMed Scopus (622) Google Scholar]. However, this is not absolute because some CXCR4– PCs do reach the BM, especially at later times [17Tokoyoda K. et al.Cellular niches controlling B lymphocyte behavior within bone marrow during development.Immunity. 2004; 20: 707-718Abstract Full Text Full Text PDF PubMed Scopus (622) Google Scholar, 33Nie Y. et al.The role of CXCR4 in maintaining peripheral B cell compartments and humoral immunity.J. Exp. Med. 2004; 200: 1145-1156Crossref PubMed Scopus (285) Google Scholar]. Despite this, a role for CXCR4 in attracting PCs to the BM is supported by the positioning of PCs in close proximity to BM stromal cells expressing CXCL12 [34Tarlinton D. et al.Plasma cell differentiation and survival.Curr. Opin. Immunol. 2008; 20: 162-169Crossref PubMed Scopus (163) Google Scholar]. PC survival within BM niches is influenced by direct cell contact with, or exposure to soluble factors released by, stromal cells (Figure 3). Early studies have dissected the contribution of stromal cells by culturing isolated PCs with cytokines or agonistic mAbs to mimic cell/cell interactions, or with normal or gene-deficient stromal cells in the presence or absence of neutralizing mAbs. One of the key cytokines consistently identified as a stromal-cell-derived PC survival factor is interleukin (IL)-6 [2Cassese G. et al.Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals.J. Immunol. 2003; 171: 1684-1690PubMed Google Scholar, 15Ellyard J.I. et al.Antigen-selected, immunoglobulin-secreting cells persist in human spleen and bone marrow.Blood. 2004; 103: 3805-3812Crossref PubMed Scopus (112) Google Scholar, 16Ellyard J.I. et al.Contribution of stromal cells to the migration, function and retention of plasma cells in human spleen: potential roles of CXCL12, IL-6 and CD54.Eur. J. Immunol. 2005; 35: 699-708Crossref PubMed Scopus (57) Google Scholar, 28Minges Wols H.A. et al.The role of bone marrow-derived stromal cells in the maintenance of plasma cell longevity.J. Immunol. 2002; 169: 4213-4221Crossref PubMed Scopus (223) Google Scholar, 35Roldan E. Brieva J.A. Terminal differentiation of human bone marrow cells capable of spontaneous and high-rate immunoglobulin secretion: role of bone marrow stromal cells and interleukin 6.Eur. J. Immunol. 1991; 21: 2671-2677Crossref PubMed Scopus (54) Google Scholar, 36O’Connor B.P. et al.BCMA is essential for the survival of long-lived bone marrow plasma cells.J. Exp. Med. 2004; 199: 91-98Crossref PubMed Scopus (808) Google Scholar] (Figure 3 and Table 1). This is consistent with upregulated expression of IL-6 receptor on PCs [37Good K.L. et al.Resting human memory B cells are intrinsically programmed for enhanced survival and responsiveness to diverse stimuli compared to naive B cells.J. Immunol. 2009; 182: 890-901PubMed Google Scholar], and the well-known association between IL-6 and PC malignancies [38Klein B. et al.Survival and proliferation factors of normal and malignant plasma cells.Int. J. Hematol. 2003; 78: 106-113Crossref PubMed Scopus (180) Google Scholar]. Tumor necrosis factor (TNF)-α has also been implicated in survival of human PCs in vitro, however, it is unclear whether this is produced by B cells or stromal cells [2Cassese G. et al.Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals.J. Immunol. 2003; 171: 1684-1690PubMed Google Scholar, 39Rodriguez C. et al.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.Eur. J. Immunol. 1993; 23: 1160-1164Crossref PubMed Scopus (36) Google Scholar]. Interestingly, CXCL12 also promotes PC survival in vitro [2Cassese G. et al.Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals.J. Immunol. 2003; 171: 1684-1690PubMed Google Scholar]. Thus, the CXCR4−CXCL12 axis plays several important roles in PC biology: first, it attracts PCs to stromal-cell-containing niches in the BM; and second, it functions to maintain their viability and Ab secretion (Figure 3 and Table 1). This bifurcated role of CXCR4 is reflected in the time-dependent reduction in responses of PCs to the chemotactic, but not pro-survival, effects of CXCL12 [2Cassese G. et al.Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals.J. Immunol. 2003; 171: 1684-1690PubMed Google Scholar, 40Hauser A.E. et al.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: 1277-1282PubMed Google Scholar]. IL-6 and CXCL12 probably also contribute to the maintenance of long-lived PCs in non-BM sites because these factors are abundantly produced by stromal cells isolated from spleens and LNs [16Ellyard J.I. et al.Contribution of stromal cells to the migration, function and retention of plasma cells in human spleen: potential roles of CXCL12, IL-6 and CD54.Eur. J. Immunol. 2005; 35: 699-708Crossref PubMed Scopus (57) Google Scholar, 41Minges Wols H.A. et al.The effects of microenvironment and internal programming on plasma cell survival.Int. Immunol. 2007; 19: 837-846Crossref PubMed Scopus (38) Google Scholar]. Intriguingly, BM stromal cells are more efficient at maintaining PCs than splenic and LN stromal cells. This does not reflect greater production of IL-6, but rather is associated with increased expression of CXCL12 [41Minges Wols H.A. et al.The effects of microenvironment and internal programming on plasma cell survival.Int. Immunol. 2007; 19: 837-846Crossref PubMed Scopus (38) Google Scholar]. This observation goes some way to explaining the substantially larger proportion of PCs in the BM relative to spleen and LNs [40Hauser A.E. et al.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: 1277-1282PubMed Google Scholar, 41Minges Wols H.A. et al.The effects of microenvironment and internal programming on plasma cell survival.Int. Immunol. 2007; 19: 837-846Crossref PubMed Scopus (38) Google Scholar], because the chemotactic gradient established by elevated levels of CXCL12 in BM would potentially recruit a greater number of PCs than in the spleen. It is also possible that the increased CXCL12 derived from BM stromal cells contributes to prolonged survival of BM PCs, however, this remains to be formally demonstrated.Table 1Components of PC niches, and mechanisms contributing to PC longevity.Cell typeNiche locationSurvival factorEvidenceReferencesStromal cellsSpleenIL-6• Reduced PC function in co-cultures with anti-IL-6 mAb16Ellyard J.I. et al.Contribution of stromal cells to the migration, function and retention of plasma cells in human spleen: potential roles of CXCL12, IL-6 and CD54.Eur. J. Immunol. 2005; 35: 699-708Crossref PubMed Scopus (57) Google Scholar, 41Minges Wols H.A. et al.The effects of microenvironment and internal programming on plasma cell survival.Int. Immunol. 2007; 19: 837-846Crossref PubMed Scopus (38) Google ScholarStromal cellsBMIL-6, CXCL12• Increased PC survival in vitro with IL-6, CXCL12• reduced survival with IL-6-deficient stromal cells2Cassese G. et al.Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals.J. Immunol. 2003; 171: 1684-1690PubMed Google Scholar, 28Minges Wols H.A. et al.The role of bone marrow-derived stromal cells in the maintenance of plasma cell longevity.J. Immunol. 2002; 169: 4213-4221Crossref PubMed Scopus (223) Google Scholar, 40Hauser A.E. et al.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: 1277-1282PubMed Google Scholar, 41Minges Wols H.A. et al.The effects of microenvironment and internal programming on plasma cell survival.Int. Immunol. 2007; 19: 837-846Crossref PubMed Scopus (38) Google ScholarDCsLNsSpleenBMBAFF, APRIL, IL-6, CD28* (*only in BM)• Colocalization• reduced plasmablasts following treatment with TACI-Ig• impaired Ab responses/PC survival in Cd28–/– mice42Garcia De Vinuesa C. et al.Dendritic cells associated with plasmablast survival.Eur. J. Immunol. 1999; 29: 3712-3721Crossref PubMed Scopus (127) Google Scholar, 43Balazs M. et al.Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses.Immunity. 2002; 17: 341-352Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar, 44Mohr E. et al.Dendritic cells and monocyte/macrophages that create the IL-6/APRIL-rich lymph node microenvironments where plasmablasts mature.J. Immunol. 2009; 182: 2113-2123Crossref PubMed Scopus (154) Google Scholar, 73Rozanski C.H. et al.Sustained antibody responses depend on CD28 function in bone marrow-resident plasma cells.J. Exp. Med. 2011; 208: 1435-1446Crossref PubMed Scopus (137) Google ScholarEosinophilsBMAPRIL, IL-6• Colocalization• reduced PCs in eosinophil-depleted mice• Reduced PC function in co-cultures with anti-APRIL/IL-647Chu V.T. et al.Eosinophils are required for the maintenance of plasma cells in the bone marrow.Nat. Immunol. 2011; 12: 151-159Crossref PubMed Scopus (401) Google ScholarMegakaryocytesBMAPRIL, IL-6• Colocalization• reduced PCs in megakaryocyte-deficient mice49Winter O. et al.Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow.Blood. 2010; 116: 1867-1875Crossref PubMed Scopus (173) Google ScholarBasophilsSpleen (no effect on BM PCs)IL-6,• Colocalization• reduced PCs in basophil-depleted mice46Rodriguez Gomez M. et al.Basophils support the survival of plasma cells in mice.J. Immunol. 2010; 185:
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