Introduction
Persistence for years after antigen exposure is one hallmark of memory plasma cells (PCs) mediating long-term protection against pathogens. A crucial factor for this is the retention in survival niches, providing extrinsic factors regulating PC maturation and survival. Under homeostatic conditions, the bone marrow (BM) and intestinal lamina propria represent typical locations for memory PCs (1–7). However, PC niches can additionally arise in inflamed non-lymphoid tissues. This is reported for diverse sites in chronic inflammatory autoimmune diseases, such as the central nervous system (CNS) in multiple sclerosis (8), the kidney in systemic lupus erythematosus (SLE) (9), the inflamed synovia in rheumatoid arthritis (RA) (10) or the salivary glands in Sjögren’s syndrome (11). By conferring survival advantages, such microenvironments can protect pathogenic PCs against immunosuppressive therapies and contribute to therapy resistance. Consequently, PC accumulation can support local antibody production, promoting inflammation (12–14), which in turn may modulate PC pathogenicity, e.g. through changes in the glycosylation profile of secreted Ig (15–17). In spite of these findings, our understanding of the biology of pathogenic PCs and their crosstalk with soluble and cellular hematopoietic and non-hematopoietic factors in inflammatory niches remains underexplored. Here, we will discuss the current knowledge of how different aspects of inflammation may change tissue microenvironments to promote PC differentiation, retention, survival and function. We will elucidate commonalities and differences between conventional and pathogenic niches and discuss how communicating niche components may reciprocally shape each other.
Pathogenic PCs - marked by unique immune-phenotypic markers?
Despite their well-documented presence, PCs residing in inflamed tissues are poorly characterized. For instance, a gain or loss of PC marker expression is found in myeloma PCs (18–20). Such knowledge could be valuable for selective targeting approaches in chronic inflammatory diseases. Even in a healthy context, universal approaches to identify PCs are limited (21–24), with CD138 and CD38 being the most salient, however not entirely specific, immune-phenotypic markers. Although additional markers, such as TACI, Sca-1, Ly6C, SLAMF7 or CD98, have been defined in mice, their function and regulation in inflammatory conditions remains unclear (21, 23–27). Considering, for example, that type-I interferon or TNF can modulate Sca-1 expression (21, 28, 29), reveals an important knowledge gap. Differential CD43 and B220 expression in renal PCs, compared to BM and spleen, in lupus-prone mice further suggests that localization may affect PC phenotype (9). Furthermore, there is a need for markers to selectively identify pathogenic PCs. Recently, exclusive Gp49B expression was found in PCs of lupus-prone mice (30). While their role in disease pathology needs to be determined, high co-expression of CD39 and CD326 in murine BM-resident PCs was linked to possibly protective anti-dsDNA IgM production (26). High PC heterogeneity constitutes another obstacle hampering selective targeting. Although this could reflect various PC differentiation stages (31), there is a need to define pathogenic or regulatory PCs in an inflamed context.
PC development and compartmentalization in chronic inflammation
Various factors, such as cellular source, developmental path and final destination, may shape PC heterogeneity. In autoimmune disease, extra-follicular, GC-dependent and T-independent pathways can feed into the pool of short- and long-lived (LL) PCs (32–38). Allelic risk factors (34), chronic antigen exposure and local nutrients and cytokines (39) may influence the choice. PC differentiation in chronically inflamed non-lymphoid organs, adds another level of complexity. Here, inflammation can drive the formation of a) tertiary lymphoid structures (40, 41) found in influenza-infected lungs (42) or organ rejection post-transplantation (43), b) of lymphoid infiltrates without GC-like structure, e.g. in synovium of RA patients or salivary glands of Sjögren’s syndrome (44, 45) or, c) lympho-myeloid infiltrates with or without follicular structure, found in lupus nephritis (38, 46, 47). It is still unclear whether these sites arise in response to inflammation or harbor specific (auto)immune responses to local tissues (38), whether emerging PCs feed the same pool as PCs from lymphoid tissues (48) and, whether preferential homing to the BM versus nearby niches in inflamed organs occurs. In murine lupus, studies indicate a dispersion of autoreactive PC, showing highest frequencies in the kidney compared to the spleen and BM (9, 13). In accordance with data from mucosal immunity, this argues against strict compartmentalization. Here, a fraction of murine IgA+LL-PCs does not recirculate after formation, but persists in the lamina propria, while some join the LL-PC pool in the BM (3). This may ensure stable, long-term protective humoral immunity. However, in autoimmunity and considering that inflammatory niches may newly arise, but also vanish with dissolving inflammation, this may favor the persistence of pathogenic PCs and refractory disease. Conversely, immunization of lupus-prone mice shows that PC-specificity in inflammatory niches is not restricted to self-antigens that may compete with conventional PCs immigrating from lymphoid organs (49, 50). Hence, factors driving dynamics, compartmentalization and competition of PCs for limited numbers of inflamed and non-inflamed niches, should be addressed in further studies.
Concerted actions of inflammation, metabolic status and hypoxia in PC niches
Inflammation may alter microenvironmental nutrient supply/demand ratios and shares an interdependent relationship with hypoxia (51, 52), that may impact the biology of PCs and their niches. For instance, hypoxia increases plasmablast generation from human memory B cells (53) and could affect myeloma PC pathophysiology by altering metabolic pathways (54, 55). Also in non-malignant PC, it may be speculated, that PCs metabolically adapt to such microenvironmental changes on a molecular level. For example, LL-PCs were shown to engage autophagy and pyruvate-dependent respiration (56–60) and are typically located in the physiologically hypoxic BM milieu supporting PC longevity (39, 53, 61, 62). Data from multiple myeloma support such scenarios, revealing high HIF1-α/HIF2-α expression (63), driving critical interactions with BM cells (64). The link between hypoxia and inflammation may even have a wider significance, as HIF-1 pathways and NF-κB signaling are linked, with the latter supporting PC survival (51, 65–68). Hence, inhibition of these pathways, as well as targeting metabolic vulnerabilities of PCs, may be attractive therapy approaches in multiple myeloma and chronic inflammatory diseases.
Infiltrating immune cells may shape inflammatory niches
In homeostasis, the CXCL12-CXCR4-axis controls the access of PCs to “exit points” such as the BM, and their spatial organization within designated domains located there (7, 69), which are enriched in survival factor-producing cells. These include various immune cells, such as megakaryocytes, eosinophils, dendritic cells (DCs), monocytes, myeloid progenitors or regulatory T cells that may redundantly foster the survival of co-localizing PCs through soluble and membrane-bound factors (70–75). For instance, DCs are in frequent contact with PCs and may promote survival via CD80/86, binding CD28 on the PC surface (76–78). Meanwhile, secretion of soluble factors, such as APRIL and IL-6 represents another means of promoting PC survival. They are particularly secreted by myeloid precursors, as well as eosinophils, the role of which in BM niches still needs clarification (70, 73, 79–82). Similarly, immune cells may shape inflammatory niches, PC longevity and functionality. Here prevailing signals may possibly induce quantitative and qualitative changes in accessory immune cell infiltration and differentiation, providing putative therapeutic targets. In murine lupus nephritis, PCs populate the tubulointerstitium (9), an area where DCs and macrophages reside in both a homeostatic and inflamed state (83–85). Kidney-infiltrating macrophages/monocytes in human nephritis have been reported to represent a major source of IL-6, TNF-α and APRIL (86, 87). Furthermore, TNF-α can activate NF-kB signaling (88), which in turn increases the expression of BAFF (89) and CD80 (90, 91). Interestingly, several lupus-prone strains display elevated CXCL12 in inflamed kidneys, and hyper-expression of CXCR4 on PCs (92). This may augment PC homing to inflamed kidneys and co-localization with accessory immune cells. Likewise, in both mice and humans, LL-PC were found in the inflamed CNS within survival niche-like tissue areas, characterized by an up-regulation of APRIL and CXCL12 and the adhesion molecule VCAM-1 (8, 93–95). Moreover, PCs were found in RA synovial tissues, where recruitment of APRIL-producing neutrophils and macrophages was reported (96). Also, both epithelial and infiltrating mononuclear cells in the salivary glands of Sjögren’s patients can be potent producers of CXCL12 and IL-6 (11). In chronic inflammation, further molecules may become relevant for PC homing, such as CXCR3, sensing pro-inflammatory CXCL9, 10 and 11. Due to the interferon-induced up-regulation of this axis, it may gain additional importance in RA, SLE and other inflammatory diseases (49, 97–100). However, incomplete effects in blocking this axis in mice with established lupus nephritis, suggest redundant roles of further, not yet identified pathways (101). Also, whether these guide PCs towards niches with a unique composition is not yet clear. Moreover, it needs to be better understood how recruited PC themselves adapt to their new environments and shape their organization. As discussed below, studies suggest bi-directional communication and mutual influences between PCs and other niche components.
Stromal cell impact on humoral immunity in chronic inflammation
Stromal cell function goes beyond a merely architectural role for tissue integrity and homeostasis. Instead, stromal cells orchestrate tissue microenvironments and immunity and may importantly shape PCs and their niches (102, 103). In the murine BM, about 80% of PCs are in direct contact with stromal cells (104), however, these stromal populations can be highly heterogeneous (105–107). On a molecular level, PC survival is mediated by direct crosstalk between PCs expressing adhesion molecules VLA-4 and LFA-1, interacting with VCAM-1 and ICAM-1 in stroma (62, 108–111). Additionally, soluble factors released by stromal cells, including CXCL12, IL-6, BAFF, and APRIL, are important players in this interaction (62, 104, 112–114). Extracellular matrix components, such as laminin-ß1, could particularly participate in the maintenance of mouse BM IgG-secreting PCs (59). Immunomodulatory stromal cell characteristics and their ability to incite, chronify and uncouple tissue inflammation to distinct anatomical sites (115–121), suggests a role in shaping inflammatory PC niches. On the other hand, inflammation may cause epigenetic modifications and induce ‘inflammatory memory’ at the level of tissue stroma (122), which would fit the concept that persistently activated stromal cells provide a ‘fertile soil’ for the incitement and spread of chronic inflammatory diseases (122–131). Similar to homeostatic niches, stromal and epithelial cells in lupus nephritis (132, 133) and salivary glands in Sjögren’s syndrome (11) were identified as CXCL12 producers, some even produced IL-6 in response to anti-dsDNA antibodies (134). Moreover, chronic inflammation changed immunoregulatory properties of mesenchymal stromal cells (MSCs) which adopt common characteristics of a senescent phenotype able to exacerbate inflammation (135–141). In murine lupus nephritis, MSCs contributed to formation of tertiary lymphoid structures by acting as lymphoid tissue organizer cells (142). Under homeostatic conditions, MSCs could inhibit immunoglobulin production in mouse PCs through CCL2 secretion (143) and suppress excessive B cell maturation by inhibiting BAFF secretion (144). Also, human MSCs could impair B cell differentiation and subsequent Ig secretion and impair their chemotaxis by down-modulation of CXCR4 and CXCR5 (145). This indicates that stroma may exert a determinant role for PC function. Regardless of the niche and in concert with other cellular and soluble participants, they may fulfil the needs for PC longevity in a redundant fashion. Stroma remodeling in PC niches by inflammatory stimuli needs to be investigated further as it may open up new options for treatment of chronic inflammatory diseases.
Communication in inflamed niches may be bi-directional
The viewpoint that PCs only secrete copious amounts of antibodies is increasingly challenged. Their ability to produce cytokines, miRNAs and express co-stimulatory molecules (69) suggests they may communicate in a bidirectional, possibly tripartite way, with other cells. Interestingly, in SLE, even autocrine APRIL production by PCs was reported, which may drive their survival in an autocrine loop (146). Modulating and paracrine effects are best documented for regulatory and IL-10-expressing PC (147–149). While in infectious and cancerous microenvironments IL10+PCs dampened anti-microbial (147, 150) and anti-tumor immunity (150–152), they exert protective effects in autoimmunity (148, 153, 154). Gut-homing PCs can secrete further cytokines such as TNF-α, TGF-β or IL-17 that may drive disease pathology also in inflamed niches (155–157). Moreover, PCs may indirectly increase cytokine levels, supporting their own survival through interaction with other immune cells: as specified above, they could induce IL-6 in DCs via CD28/CD80/CD86 (76). Aged PCs may even modulate myelopoiesis, reportedly in an IL-10- and TLR-dependent manner (158, 159). This is relevant, since myeloid cells and progenitors are important producers of PC survival factors (71, 73, 74, 87) and may provide a positive-feedback loop. Thus, mutual influences between inflammation, immune aging and TLR-signaling may not only be relevant in inflamed PC niches, but also influence the survival of pathogenic PCs in homeostatic niches, which warrants further study.
Conclusion
In conclusion, data suggest that the reciprocal relationship between communicating components in inflamed PC niches may propagate inflammation and disease progression, creating a vicious cycle. More data are required to substantiate these assumptions, identify key players and understand the dynamics in these functional units. Moreover, it is important to define differences and commonalities between conventional and pathogenic PCs and their niches and to clarify whether molecular structures at different sites are shared, although the cells providing these structures are tissue-specific. The identification of defined signatures would offer new perspectives for the design of specific targeting approaches, especially in patients resistant to conventional therapies, thereby saving protective PCs.
Statements
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Funding
This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (TRR 130, project 12), the IMMediate Advanced Clinician Scientist-Program, Department of Medicine II, Medical Center – University of Freiburg and Faculty of Medicine, University of Freiburg, funded by the Bundesministerium für Bildung und Forschung (BMBF, Federal Ministry of Education and Research) - 01EO2103, the Erika Bürgy Fundation (Stiftung für die Region – Sparkasse Pforzheim Calw Treuhandstiftung Erika Bürgy Stiftung) and the EURIdoc programme (cofunded through the Marie Sklodowska-Curie Actions COFUND under the European Union Horizon 2020 Research and Innovation Programme (Grant Agreement Nr. 10103417).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1
Slifka MK Antia R Whitmire JK Ahmed R . Humoral immunity due to long-lived plasma cells. Immunity (1998) 8:363–72. doi: 10.1016/S1074-7613(00)80541-5
2
Manz RA Thiel A Radbruch A . Lifetime of plasma cells in the bone marrow. Nature (1997) 388:133–4. doi: 10.1038/40540
3
Lemke A Kraft M Roth K Riedel R Lammerding D Hauser AE . Long-lived plasma cells are generated in mucosal immune responses and contribute to the bone marrow plasma cell pool in mice. Mucosal Immunol (2016) 9:83–97. doi: 10.1038/mi.2015.38
4
Landsverk OJB Snir O Casado RB Richter L Mold JE Réu P et al . Antibody-secreting plasma cells persist for decades in human intestine. J Exp Med (2017) 214:309–17. doi: 10.1084/jem.20161590
5
Ellyard JI Avery DT Phan TG Hare NJ Hodgkin PD Tangye SG . Antigen-selected, immunoglobulin-secreting cells persist in human spleen and bone marrow. Blood (2004) 103:3805–12. doi: 10.1182/blood-2003-09-3109
6
Chang H-D Tokoyoda K Hoyer B Alexander T Khodadadi L Mei H et al . Pathogenic memory plasma cells in autoimmunity. Curr Opin Immunol (2019) 61:86–91. doi: 10.1016/j.coi.2019.09.005
7
Lindquist RL Niesner RA Hauser AE . In the right place, at the right time: Spatiotemporal conditions determining plasma cell survival and function. Front Immunol (2019) 10:788. doi: 10.3389/fimmu.2019.00788
8
Pachner AR Li L Lagunoff D . Plasma cells in the central nervous system in the theiler’s virus model of multiple sclerosis. J Neuroimmunol (2011) 232:35–40. doi: 10.1016/j.jneuroim.2010.09.026
9
Espeli M Bökers S Giannico G Dickinson HA Bardsley V Fogo AB et al . Local renal autoantibody production in lupus nephritis. J Am Soc Nephrol (2011) 22:296 LP – 305. doi: 10.1681/ASN.2010050515
10
Doorenspleet ME Klarenbeek PL de Hair MJH van Schaik BDC Esveldt REE van Kampen AHC et al . Rheumatoid arthritis synovial tissue harbours dominant b-cell and plasma-cell clones associated with autoreactivity. Ann Rheum Dis (2014) 73:756 LP – 762. doi: 10.1136/annrheumdis-2012-202861
11
Szyszko EA Brokstad KA Øijordsbakken G Jonsson MV Jonsson R Skarstein K . Salivary glands of primary sjögren’s syndrome patients express factors vital for plasma cell survival. Arthritis Res Ther (2011) 13:R2. doi: 10.1186/ar3220
12
Sekine H Watanabe H Gilkeson GS . Enrichment of anti-glomerular antigen antibody-producing cells in the kidneys of MRL/MpJ-faslpr Mice1. J Immunol (2004) 172:3913–21. doi: 10.4049/jimmunol.172.6.3913
13
Starke C Frey S Wellmann U Urbonaviciute V Herrmann M Amann K et al . High frequency of autoantibody-secreting cells and long-lived plasma cells within inflamed kidneys of NZB/W F1 lupus mice. Eur J Immunol (2011) 41:2107–12. doi: 10.1002/eji.201041315
14
Tengnér P Halse A-K Haga H-J Jonsson R Wahren-Herlenius M . Detection of anti-Ro/SSA and anti-La/SSB autoantibody-producing cells in salivary glands from patients with sjögren’s syndrome. Arthritis Rheum (1998) 41:2238–48. doi: 10.1002/1529-0131(199812)41:12<2238::AID-ART20>3.0.CO;2-V
15
Anthony RM Nimmerjahn F . The role of differential IgG glycosylation in the interaction of antibodies with FcγRs in vivo. Curr Opin Organ Transplant (2011) 16:7–14. doi: 10.1097/MOT.0b013e328342538f
16
Kaneko Y Nimmerjahn F Ravetch JV . Anti-inflammatory activity of immunoglobulin G resulting from fc sialylation. Sci (80- ) (2006) 313:670–3. doi: 10.1126/science.1129594
17
Zhou X Motta F Selmi C Ridgway WM Gershwin ME Zhang W . Antibody glycosylation in autoimmune diseases. Autoimmun Rev (2021) 20:102804. doi: 10.1016/j.autrev.2021.102804
18
Robillard N Wuillème S Moreau P Béné MC . Immunophenotype of normal and myelomatous plasma-cell subsets. Front Immunol (2014) 5:137. doi: 10.3389/fimmu.2014.00137
19
Paiva B Almeida J Pérez-Andrés M Mateo G López A Rasillo A et al . Utility of flow cytometry immunophenotyping in multiple myeloma and other clonal plasma cell-related disorders. Cytom Part B Clin Cytom (2010) 78:239–52. doi: 10.1002/cyto.b.20512
20
Kumar S Kimlinger T Morice W . Immunophenotyping in multiple myeloma and related plasma cell disorders. Best Pract Res Clin Haematol (2010) 23:433–51. doi: 10.1016/j.beha.2010.09.002
21
Tellier J Nutt SL . Standing out from the crowd: How to identify plasma cells. Eur J Immunol (2017) 47:1276–9. doi: 10.1002/eji.201747168
22
Sanz I Wei C Jenks SA Cashman KS Tipton C Woodruff MC et al . Challenges and opportunities for consistent classification of human b cell and plasma cell populations. Front Immunol (2019) 10:2458. doi: 10.3389/fimmu.2019.02458
23
Pracht K Meinzinger J Daum P Schulz SR Reimer D Hauke M et al . A new staining protocol for detection of murine antibody-secreting plasma cell subsets by flow cytometry. Eur J Immunol (2017) 47:1389–92. doi: 10.1002/eji.201747019
24
Wilmore JR Jones DD Allman D . Protocol for improved resolution of plasma cell subpopulations by flow cytometry. Eur J Immunol (2017) 47:1386–8. doi: 10.1002/eji.201746944
25
Tellier J Shi W Minnich M Liao Y Crawford S Smyth GK et al . Blimp-1 controls plasma cell function through the regulation of immunoglobulin secretion and the unfolded protein response. Nat Immunol (2016) 17:323–30. doi: 10.1038/ni.3348
26
Dang VD Mohr E Szelinski F Le TA Ritter J Hinnenthal T et al . CD39 and CD326 are bona fide markers of murine and human plasma cells and identify a bone marrow specific plasma cell subpopulation in lupus. Front Immunol (2022) 13:873217. doi: 10.3389/fimmu.2022.873217
27
Shi W Liao Y Willis SN Taubenheim N Inouye M Tarlinton DM et al . Transcriptional profiling of mouse b cell terminal differentiation defines a signature for antibody-secreting plasma cells. Nat Immunol (2015) 16:663–73. doi: 10.1038/ni.3154
28
Malek TR Danis KM Codias EK . Tumor necrosis factor synergistically acts with IFN-gamma to regulate ly-6A/E expression in T lymphocytes, thymocytes and bone marrow cells. J Immunol (1989) 142:1929–36.
29
Khan KD Lindwall G Maher SE Bothwell AL . Characterization of promoter elements of an interferon-inducible ly-6E/A differentiation antigen, which is expressed on activated T cells and hematopoietic stem cells. Mol Cell Biol (1990) 10:5150–9. doi: 10.1128/mcb.10.10.5150-5159.1990
30
Wong YL Su M-T Sugahara-Tobinai A Itoi S Kezuka D Endo S et al . Gp49B is a pathogenic marker for auto-antibody-producing plasma cells in lupus-prone BXSB/Yaa mice. Int Immunol (2019) 31:397–406. doi: 10.1093/intimm/dxz017
31
Medina F Segundo C Campos-Caro A Gonzaílez-Garcıía I Brieva JA . The heterogeneity shown by human plasma cells from tonsil, blood, and bone marrow reveals graded stages of increasing maturity, but local profiles of adhesion molecule expression. Blood (2002) 99:2154–61. doi: 10.1182/blood.V99.6.2154
32
William J Euler C Christensen S Shlomchik MJ . Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Sci (80- ) (2002) 297:2066–70. doi: 10.1126/science.1073924
33
Sang A Niu H Cullen J Choi SC Zheng YY Wang H et al . Activation of rheumatoid factor–specific b cells is antigen dependent and occurs preferentially outside of germinal centers in the lupus-prone NZM2410 mouse model. J Immunol (2014) 193:1609–21. doi: 10.4049/jimmunol.1303000
34
Malkiel S Barlev AN Atisha-Fregoso Y Suurmond J Diamond B . Plasma cell differentiation pathways in systemic lupus erythematosus. Front Immunol (2018) 9:427. doi: 10.3389/fimmu.2018.00427
35
Wellmann U Letz M Herrmann M Angermüller S Kalden JR Winkler TH . The evolution of human anti-double-stranded DNA autoantibodies. Proc Natl Acad Sci (2005) 102:9258–63. doi: 10.1073/pnas.0500132102
36
Foote JB Mahmoud TI Vale AM Kearney JF . Long-term maintenance of polysaccharide-specific antibodies by IgM-secreting cells. J Immunol (2012) 188:57–67. doi: 10.4049/jimmunol.1100783
37
Allman D Wilmore JR Gaudette BT . The continuing story of T-cell independent antibodies. Immunol Rev (2019) 288:128–35. doi: 10.1111/imr.12754
38
Elsner RA Shlomchik MJ . Germinal center and extrafollicular b cell responses in vaccination, immunity, and autoimmunity. Immunity (2020) 53:1136–50. doi: 10.1016/j.immuni.2020.11.006
39
Nguyen DC Duan M Ali M Ley A Sanz I Lee FE-H . Plasma cell survival: The intrinsic drivers, migratory signals, and extrinsic regulators. Immunol Rev (2021) 303:138–53. doi: 10.1111/imr.13013
40
Dieu-Nosjean M-C Goc J Giraldo NA Sautès-Fridman C Fridman WH . Tertiary lymphoid structures in cancer and beyond. Trends Immunol (2014) 35:571–80. doi: 10.1016/j.it.2014.09.006
41
Silva-Cayetano A Linterman MA . Stromal cell control of conventional and ectopic germinal centre reactions. Curr Opin Immunol (2020) 64:26–33. doi: 10.1016/j.coi.2020.03.007
42
Moyron-Quiroz JE Rangel-Moreno J Kusser K Hartson L Sprague F Goodrich S et al . Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med (2004) 10:927–34. doi: 10.1007/82_2019_191
43
Koenig A Thaunat O . Lymphoid neogenesis and tertiary lymphoid organs in transplanted organs. Front Immunol (2016) 7:646. doi: 10.3389/fimmu.2016.00646
44
Schröder AE Greiner A Seyfert C Berek C . Differentiation of b cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis. Proc Natl Acad Sci (1996) 93:221–5. doi: 10.1073/pnas.93.1.221
45
Stott DI Hiepe F Hummel M Steinhauser G Berek C . Antigen-driven clonal proliferation of b cells within the target tissue of an autoimmune disease. the salivary glands of patients with sjögren’s syndrome. J Clin Invest (1998) 102:938–46. doi: 10.1172/JCI3234
46
Clark MR Trotter K Chang A . The pathogenesis and therapeutic implications of tubulointerstitial inflammation in human lupus nephritis. In: Seminars in nephrology. Elsevier (2015). p. 455–64. doi: 10.1016/j.semnephrol.2015.08.007
47
Liarski VM Kaverina N Chang A Brandt D Yanez D Talasnik L et al . Cell distance mapping identifies functional T follicular helper cells in inflamed human renal tissue. Sci Transl Med (2014) 6:230ra46–230ra46. doi: 10.1126/scitranslmed.3008146
48
Liu X Yao J Zhao Y Wang J Qi H . Heterogeneous plasma cells and long-lived subsets in response to immunization, autoantigen and microbiota. Nat Immunol (2022) 23:1564–76. doi: 10.1038/s41590-022-01345-5
49
Hauser AE Debes GF Arce S Cassese G Hamann A Radbruch A et al . Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune Response1. J Immunol (2002) 169:1277–82. doi: 10.4049/jimmunol.169.3.1277
50
Cassese G Lindenau S de Boer B Arce S Hauser A Riemekasten G et al . Inflamed kidneys of NZB / W mice are a major site for the homeostasis of plasma cells. Eur J Immunol (2001) 31:2726–32. doi: 10.1002/1521-4141(200109)31:9<2726::aid-immu2726>3.0.co;2-h
51
Bartels K Grenz A Eltzschig HK . Hypoxia and inflammation are two sides of the same coin. Proc Natl Acad Sci U S A (2013) 110:18351–2. doi: 10.1073/pnas.1318345110
52
Taylor CT . Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation. J Physiol (2008) 586:4055–9. doi: 10.1113/jphysiol.2008.157669
53
Schoenhals M Jourdan M Bruyer A Kassambara A Klein B Moreaux J . Hypoxia favors the generation of human plasma cells. Cell Cycle (2017) 16:1104–17. doi: 10.1080/15384101.2017.1317408
54
Ikeda S Tagawa H . Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma. Cancer Sci (2021) 112:3995–4004. doi: 10.1111/cas.15087
55
Gastelum G Veena M Lyons K Lamb C Jacobs N Yamada A et al . Can targeting hypoxia-mediated acidification of the bone marrow microenvironment kill myeloma tumor cells? Front Oncol (2021) 11:703878. doi: 10.3389/fonc.2021.703878
56
Lam WY Becker AM Kennerly KM Wong R Curtis JD Llufrio EM et al . Mitochondrial pyruvate import promotes long-term survival of antibody-secreting plasma cells. Immunity (2016) 45:60–73. doi: 10.1016/j.immuni.2016.06.011
57
Lam WY Bhattacharya D . Metabolic links between plasma cell survival, secretion, and stress. Trends Immunol (2018) 39:19–27. doi: 10.1016/j.it.2017.08.007
58
D’Souza L Bhattacharya D . Plasma cells: You are what you eat. Immunol Rev (2019) 288:161–77. doi: 10.1111/imr.12732
59
Männe C Takaya A Yamasaki Y Mursell M Hojyo S Wu T-Y et al . Salmonella SiiE prevents an efficient humoral immune memory by interfering with IgG(+) plasma cell persistence in the bone marrow. Proc Natl Acad Sci U S A (2019) 116:7425–30. doi: 10.1073/pnas.1818242116
60
Lam WY Jash A Yao C-H D’Souza L Wong R Nunley RM et al . Metabolic and transcriptional modules independently diversify plasma cell lifespan and function. Cell Rep (2018) 24:2479–92.e6. doi: 10.1016/j.celrep.2018.07.084
61
Nguyen DC Garimalla S Xiao H Kyu S Albizua I Galipeau J et al . Factors of the bone marrow microniche that support human plasma cell survival and immunoglobulin secretion. Nat Commun (2018) 9:3698. doi: 10.1038/s41467-018-05853-7
62
Nguyen DC Joyner CJ Sanz I Lee FE-H . Factors affecting early antibody secreting cell maturation into long-lived plasma cells. Front Immunol (2019) 10:2138. doi: 10.3389/fimmu.2019.02138
63
Giatromanolaki A Bai M Margaritis D Bourantas KL Koukourakis MI Sivridis E et al . Hypoxia and activated VEGF/receptor pathway in multiple myeloma. Anticancer Res (2010) 30:2831–6.
64
Borsi E Perrone G Terragna C Martello M Zamagni E Tacchetti P et al . HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment. Exp Cell Res (2014) 328:444–55. doi: 10.1016/j.yexcr.2014.09.018
65
Rius J Guma M Schachtrup C Akassoglou K Zinkernagel AS Nizet V et al . NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature (2008) 453:807–11. doi: 10.1038/nature06905
66
Cornelis R Hahne S Taddeo A Petkau G Malko D Durek P et al . Stromal cell-contact dependent PI3K and APRIL induced NF-κB signaling prevent mitochondrial- and ER stress induced death of memory plasma cells. Cell Rep (2020) 32:107982. doi: 10.1016/j.celrep.2020.107982
67
Hatzoglou A Roussel J Bourgeade MF Rogier E Madry C Inoue J et al . TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kappa b, elk-1, c-jun n-terminal kinase, and p38 mitogen-activated protein kinase. J Immunol (2000) 165:1322–30. doi: 10.4049/jimmunol.165.3.1322
68
O’Connor BP Raman VS Erickson LD Cook WJ Weaver LK Ahonen C et al . BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med (2004) 199:91–8. doi: 10.1084/jem.20031330
69
Tiburzy B Kulkarni U Hauser AE Abram M Manz RA . Plasma cells in immunopathology: concepts and therapeutic strategies. Semin Immunopathol (2014) 36:277–88. doi: 10.1007/s00281-014-0426-8
70
Chu VT Fröhlich A Steinhauser G Scheel T Roch T Fillatreau S et al . Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat Immunol (2011) 12:151–9. doi: 10.1038/ni.1981
71
Mohr E Serre K Manz RA Cunningham AF Khan M Hardie DL et al . Dendritic cells and monocyte/macrophages that create the IL-6/APRIL-rich lymph node microenvironments where plasmablasts mature. J Immunol (2009) 182:2113–23. doi: 10.4049/jimmunol.0802771
72
Winter O Moser K Mohr E Zotos D Kaminski H Szyska M et al . Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood (2010) 116:1867–75. doi: 10.1182/blood-2009-12-259457
73
Matthes T Dunand-Sauthier I Santiago-Raber M-L Krause K-H Donze O Passweg J et al . Production of the plasma-cell survival factor a proliferation-inducing ligand (APRIL) peaks in myeloid precursor cells from human bone marrow. Blood (2011) 118:1838–44. doi: 10.1182/blood-2011-01-332940
74
Belnoue E Tougne C Rochat A-F Lambert P-H Pinschewer DD Siegrist C-A . Homing and adhesion patterns determine the cellular composition of the bone marrow plasma cell niche. J Immunol (2012) 188:1283–91. doi: 10.4049/jimmunol.1103169
75
Glatman Zaretsky A Konradt C Dépis F Wing JB Goenka R Atria DG et al . T Regulatory cells support plasma cell populations in the bone marrow. Cell Rep (2017) 18:1906–16. doi: 10.1016/j.celrep.2017.01.067
76
Rozanski CH Arens R Carlson LM Nair J Boise LH Chanan-Khan AA et al . Sustained antibody responses depend on CD28 function in bone marrow-resident plasma cells. J Exp Med (2011) 208:1435–46. doi: 10.1084/jem.20110040
77
Rozanski CH Utley A Carlson LM Farren MR Murray M Russell LM et al . CD28 promotes plasma cell survival, sustained antibody responses, and BLIMP-1 upregulation through its distal PYAP proline motif. J Immunol (2015) 194:4717–28. doi: 10.4049/jimmunol.1402260
78
Nair JR Carlson LM Koorella C Rozanski CH Byrne GE Bergsagel PL et al . CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment. J Immunol (2011) 187:1243–53. doi: 10.4049/jimmunol.1100016
79
Chu VT Beller A Rausch S Strandmark J Zänker M Arbach O et al . Eosinophils promote generation and maintenance of immunoglobulin-a-expressing plasma cells and contribute to gut immune homeostasis. Immunity (2014) 40:582–93. doi: 10.1016/j.immuni.2014.02.014
80
Bortnick A Chernova I Spencer SP Allman D . No strict requirement for eosinophils for bone marrow plasma cell survival. Eur J Immunol (2018) 48:815–21. doi: 10.1002/eji.201747229
81
Haberland K Ackermann JA Ipseiz N Culemann S Pracht K Englbrecht M et al . Eosinophils are not essential for maintenance of murine plasma cells in the bone marrow. Eur J Immunol (2018) 48:822–8. doi: 10.1002/eji.201747227
82
Wong TW Kita H Hanson CA Walters DK Arendt BK Jelinek DF . Induction of malignant plasma cell proliferation by eosinophils. PLoS One (2013) 8:e70554. doi: 10.1371/journal.pone.0070554
83
Soos TJ Sims TN Barisoni L Lin K Littman DR Dustin ML et al . CX3CR1+ interstitial dendritic cells form a contiguous network throughout the entire kidney. Kidney Int (2006) 70:591–6. doi: 10.1038/sj.ki.5001567
84
Krüger T Benke D Eitner F Lang A Wirtz M Hamilton-Williams EE et al . Identification and functional characterization of dendritic cells in the healthy murine kidney and in experimental glomerulonephritis. J Am Soc Nephrol (2004) 15:613–21. doi: 10.1097/01.asn.0000114553.36258.91
85
Sean Eardley K Cockwell P . Macrophages and progressive tubulointerstitial disease. Kidney Int (2005) 68:437–55. doi: 10.1111/j.1523-1755.2005.00422.x
86
Takemura T Yoshioka K Murakami K Akano N Okada M Aya N et al . Cellular localization of inflammatory cytokines in human glomerulonephritis. Virchows Arch (1994) 424:459–64. doi: 10.1007/BF00191429
87
Kawakami T Mizushima I Yamada K Fujii H Ito K Yasuno T et al . Abundant a proliferation-inducing ligand (APRIL)-producing macrophages contribute to plasma cell accumulation in immunoglobulin G4-related disease. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc (2019) 34:960–9. doi: 10.1093/ndt/gfy296
88
Tang D Tao D Fang Y Deng C Xu Q Zhou J . TNF-alpha promotes invasion and metastasis via NF-kappa b pathway in oral squamous cell carcinoma. Med Sci Monit Basic Res (2017) 23:141–9. doi: 10.12659/msmbr.903910
89
Moon E-Y Park H . B cell activating factor (BAFF) gene promoter activity depends upon co-activator, p300. Immunobiology (2007) 212:637–45. doi: 10.1016/j.imbio.2007.06.002
90
Zhao J Freeman GJ Gray GS Nadler LM Glimcher LH . A cell type-specific enhancer in the human B7.1 gene regulated by NF-kappaB. J Exp Med (1996) 183:777–89. doi: 10.1084/jem.183.3.777
91
Fong TC Wu Y Kipps TJ . Identification of a promoter element that regulates tissue-specific expression of the human CD80 (B7.1) gene. J Immunol (1996) 157:4442–50. doi: 10.4049/jimmunol.157.10.4442
92
Wang A Fairhurst A-M Tus K Subramanian S Liu Y Lin F et al . CXCR4/CXCL12 hyperexpression plays a pivotal role in the pathogenesis of lupus. J Immunol (2009) 182:4448–58. doi: 10.4049/jimmunol.0801920
93
Pollok K Mothes R Ulbricht C Liebheit A Gerken JD Uhlmann S et al . The chronically inflamed central nervous system provides niches for long-lived plasma cells. Acta Neuropathol Commun (2017) 5:88. doi: 10.1186/s40478-017-0487-8
94
Winter O Dame C Jundt F Hiepe F . Pathogenic long-lived plasma cells and their survival niches in autoimmunity, malignancy, and allergy. J Immunol (2012) 189:5105 LP – 5111. doi: 10.4049/jimmunol.1202317
95
Zilkha-Falb R Kaushansky N Kawakami N Ben-Nun A . Post-CNS-inflammation expression of CXCL12 promotes the endogenous myelin/neuronal repair capacity following spontaneous recovery from multiple sclerosis-like disease. J Neuroinflamm (2016) 13:7. doi: 10.1186/s12974-015-0468-4
96
Gabay C Krenn V Bosshard C Seemayer CA Chizzolini C Huard B . Synovial tissues concentrate secreted APRIL. Arthritis Res Ther (2009) 11:R144. doi: 10.1186/ar2817
97
Tokunaga R Zhang W Naseem M Puccini A Berger MD Soni S et al . CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - a target for novel cancer therapy. Cancer Treat Rev (2018) 63:40–7. doi: 10.1016/j.ctrv.2017.11.007
98
Muehlinghaus G Cigliano L Huehn S Peddinghaus A Leyendeckers H Hauser AE et al . Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory b cells into plasma cells. Blood (2005) 105:3965–71. doi: 10.1182/blood-2004-08-2992
99
Lacotte S Brun S Muller S Dumortier H . CXCR3, inflammation, and autoimmune diseases. Ann N Y Acad Sci (2009) 1173:310–7. doi: 10.1111/j.1749-6632.2009.04813.x
100
Akiyama Y Morikawa T Maeda D Shintani Y Niimi A Nomiya A et al . Increased CXCR3 expression of infiltrating plasma cells in hunner type interstitial cystitis. Sci Rep (2016) 6:28652. doi: 10.1038/srep28652
101
Moser K Kalies K Szyska M Humrich JY Amann K Manz RA . CXCR3 promotes the production of IgG1 autoantibodies but is not essential for the development of lupus nephritis in NZB/NZW mice. Arthritis Rheum (2012) 64:1237–46. doi: 10.1002/art.33424
102
Minges Wols HA Underhill GH Kansas GS Witte PL . The role of bone marrow-derived stromal cells in the maintenance of plasma cell longevity. J Immunol (2002) 169:4213–21. doi: 10.4049/jimmunol.169.8.4213
103
Khodadadi L Cheng Q Radbruch A Hiepe F . The maintenance of memory plasma cells. Front Immunol (2019) 10:721. doi: 10.3389/fimmu.2019.00721
104
Zehentmeier S Roth K Cseresnyes Z Sercan Ö Horn K Niesner RA et al . Static and dynamic components synergize to form a stable survival niche for bone marrow plasma cells. Eur J Immunol (2014) 44:2306–17. doi: 10.1002/eji.201344313
105
Addo RK Heinrich F Heinz GA Schulz D Sercan-Alp Ö Lehmann K et al . Single-cell transcriptomes of murine bone marrow stromal cells reveal niche-associated heterogeneity. Eur J Immunol (2019) 49:1372–9. doi: 10.1002/eji.201848053
106
Green AC Tjin G Lee SC Chalk AM Straszkowski L Kwang D et al . The characterization of distinct populations of murine skeletal cells that have different roles in b lymphopoiesis. Blood (2021) 138:304–17. doi: 10.1182/blood.2020005865
107
Mabuchi Y Okawara C Méndez-Ferrer S Akazawa C . Cellular heterogeneity of mesenchymal Stem/Stromal cells in the bone marrow. Front Cell Dev Biol (2021) 9:689366. doi: 10.3389/fcell.2021.689366
108
DiLillo DJ Hamaguchi Y Ueda Y Yang K Uchida J Haas KM et al . Maintenance of long-lived plasma cells and serological memory despite mature and memory b cell depletion during CD20 immunotherapy in mice. J Immunol (2008) 180:361–71. doi: 10.4049/jimmunol.180.1.361
109
Underhill GH Minges Wols HA Fornek JL Witte PL Kansas GS . IgG plasma cells display a unique spectrum of leukocyte adhesion and homing molecules. Blood (2002) 99:2905–12. doi: 10.1182/blood.v99.8.2905
110
Roldán E García-Pardo A Brieva JA . VLA-4-fibronectin interaction is required for the terminal differentiation of human bone marrow cells capable of spontaneous and high rate immunoglobulin secretion. J Exp Med (1992) 175:1739–47. doi: 10.1084/jem.175.6.1739
111
Benet Z Jing Z Fooksman DR . Plasma cell dynamics in the bone marrow niche. Cell Rep (2021) 34:108733. doi: 10.1016/j.celrep.2021.108733
112
Tokoyoda K Egawa T Sugiyama T Choi B-I Nagasawa T . Cellular niches controlling b lymphocyte behavior within bone marrow during development. Immunity (2004) 20:707–18. doi: 10.1016/j.immuni.2004.05.001
113
Roth K Oehme L Zehentmeier S Zhang Y Niesner R Hauser AE . Tracking plasma cell differentiation and survival. Cytom Part A J Int Soc Anal Cytol (2014) 85:15–24. doi: 10.1002/cyto.a.22355
114
Huang H-Y Rivas-Caicedo A Renevey F Cannelle H Peranzoni E Scarpellino L et al . Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis. Proc Natl Acad Sci (2018) 115:E6826–35. doi: 10.1073/pnas.1712628115
115
Morrison SJ Scadden DT . The bone marrow niche for haematopoietic stem cells. Nature (2014) 505:327–34. doi: 10.1038/nature12984
116
Nowarski R Jackson R Flavell RA . The stromal intervention: Regulation of immunity and inflammation at the epithelial-mesenchymal barrier. Cell (2017) 168:362–75. doi: 10.1016/j.cell.2016.11.040
117
Buckley CD Barone F Nayar S Bénézech C Caamaño J . Stromal cells in chronic inflammation and tertiary lymphoid organ formation. Annu Rev Immunol (2015) 33:715–45. doi: 10.1146/annurev-immunol-032713-120252
118
Kolonin MG Evans KW Mani SA Gomer RH . Alternative origins of stroma in normal organs and disease. Stem Cell Res (2012) 8:312–23. doi: 10.1016/j.scr.2011.11.005
119
Ren G Zhang L Zhao X Xu G Zhang Y Roberts AI et al . Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell (2008) 2:141–50. doi: 10.1016/j.stem.2007.11.014
120
Prockop DJ Oh JY . Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol Ther (2012) 20:14–20. doi: 10.1038/mt.2011.211
121
Waterman RS Tomchuck SL Henkle SL Betancourt AM . A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PloS One (2010) 5:e10088. doi: 10.1371/journal.pone.0010088
122
Owens BMJ . Inflammation, innate immunity, and the intestinal stromal cell niche: Opportunities and challenges. Front Immunol (2015) 6:319. doi: 10.3389/fimmu.2015.00319
123
Patel R Filer A Barone F Buckley CD . Stroma: fertile soil for inflammation. Best Pract Res Clin Rheumatol (2014) 28:565–76. doi: 10.1016/j.berh.2014.10.022
124
Jasso GJ Jaiswal A Varma M Laszewski T Grauel A Omar A et al . Colon stroma mediates an inflammation-driven fibroblastic response controlling matrix remodeling and healing. PLoS Biol (2022) 20:e3001532. doi: 10.1371/journal.pbio.3001532
125
Naylor AJ Filer A Buckley CD . The role of stromal cells in the persistence of chronic inflammation. Clin Exp Immunol (2013) 171:30–5. doi: 10.1111/j.1365-2249.2012.04634.x
126
Fries KM Blieden T Looney RJ Sempowski GD Silvera MR Willis RA et al . Evidence of fibroblast heterogeneity and the role of fibroblast subpopulations in fibrosis. Clin Immunol Immunopathol (1994) 72:283–92. doi: 10.1006/clin.1994.1144
127
Burman A Haworth O Hardie DL Amft EN Siewert C Jackson DG et al . A chemokine-dependent stromal induction mechanism for aberrant lymphocyte accumulation and compromised lymphatic return in rheumatoid arthritis. J Immunol (2005) 174:1693–700. doi: 10.4049/jimmunol.174.3.1693
128
Buechler MB Turley SJ . A short field guide to fibroblast function in immunity. Semin Immunol (2018) 35:48–58. doi: 10.1016/j.smim.2017.11.001
129
Luther SA Bidgol A Hargreaves DC Schmidt A Xu Y Paniyadi J et al . Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J Immunol (2002) 169:424–33. doi: 10.4049/jimmunol.169.1.424
130
West NR Hegazy AN Owens BMJ Bullers SJ Linggi B Buonocore S et al . Oncostatin m drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med (2017) 23:579–89. doi: 10.1038/nm.4307
131
Chang HY Chi J-T Dudoit S Bondre C van de Rijn M Botstein D et al . Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci (2002) 99:12877–82. doi: 10.1073/pnas.162488599
132
Wang W Rangel-Moreno J Owen T Barnard J Nevarez S Ichikawa HT et al . Long-term b cell depletion in murine lupus eliminates autoantibody-secreting cells and is associated with alterations in the kidney plasma cell niche. J Immunol (2014) 192:3011–20. doi: 10.4049/jimmunol.1302003
133
Song A Jiang A Xiong W Zhang C . The role of CXCL12 in kidney diseases: A friend or foe? Kidney Dis (Basel Switzerland) (2021) 7:176–85. doi: 10.1159/000514913
134
Yung S Tsang RCW Sun Y Leung JKH Chan TM . Effect of human anti-DNA antibodies on proximal renal tubular epithelial cell cytokine expression: implications on tubulointerstitial inflammation in lupus nephritis. J Am Soc Nephrol (2005) 16:3281–94. doi: 10.1681/ASN.2004110917
135
Fathollahi A Gabalou NB Aslani S . Mesenchymal stem cell transplantation in systemic lupus erythematous, a mesenchymal stem cell disorder. Lupus (2018) 27:1053–64. doi: 10.1177/0961203318768889
136
Li J Luo M Li B Lou Y Zhu Y Bai X et al . Immunomodulatory activity of mesenchymal stem cells in lupus nephritis: Advances and applications. Front Immunol (2022) 13:843192. doi: 10.3389/fimmu.2022.843192
137
Nie Y Lau C Lie A Chan G Mok M . Defective phenotype of mesenchymal stem cells in patients with systemic lupus erythematosus. Lupus (2010) 19:850–9. doi: 10.1177/0961203309361482
138
Gao L Bird AK Meednu N Dauenhauer K Liesveld J Anolik J et al . Bone marrow-derived mesenchymal stem cells from patients with systemic lupus erythematosus have a senescence-associated secretory phenotype mediated by a mitochondrial antiviral signaling protein-interferon-β feedback loop. Arthritis Rheumatol (Hoboken NJ) (2017) 69:1623–35. doi: 10.1002/art.40142
139
Lasry A Ben-Neriah Y . Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol (2015) 36:217–28. doi: 10.1016/j.it.2015.02.009
140
Lee B-C Yu K-R . Impact of mesenchymal stem cell senescence on inflammaging. BMB Rep (2020) 53:65–73. doi: 10.5483/BMBRep.2020.53.2.291
141
Vernot JP . Senescence-associated pro-inflammatory cytokines and tumor cell plasticity. Front Mol Biosci (2020) 7:63. doi: 10.3389/fmolb.2020.00063
142
Dorraji SE Hovd A-MK Kanapathippillai P Bakland G Eilertsen GØ Figenschau SL et al . Mesenchymal stem cells and T cells in the formation of tertiary lymphoid structures in lupus nephritis. Sci Rep (2018) 8:7861. doi: 10.1038/s41598-018-26265-z
143
Rafei M Hsieh J Fortier S Li M Yuan S Birman E et al . Mesenchymal stromal cell-derived CCL2 suppresses plasma cell immunoglobulin production via STAT3 inactivation and PAX5 induction. Blood (2008) 112:4991–8. doi: 10.1182/blood-2008-07-166892
144
Ma X Che N Gu Z Huang J Wang D Liang J et al . Allogenic mesenchymal stem cell transplantation ameliorates nephritis in lupus mice via inhibition of b-cell activation. Cell Transplant (2013) 22:2279–90. doi: 10.3727/096368912X658692
145
Corcione A Benvenuto F Ferretti E Giunti D Cappiello V Cazzanti F et al . Human mesenchymal stem cells modulate b-cell functions. Blood (2006) 107:367–72. doi: 10.1182/blood-2005-07-2657
146
Chu VT Enghard P Schürer S Steinhauser G Rudolph B Riemekasten G et al . Systemic activation of the immune system induces aberrant BAFF and APRIL expression in b cells in patients with systemic lupus erythematosus. Arthritis Rheum (2009) 60:2083–93. doi: 10.1002/art.24628
147
Lino AC Dang VD Lampropoulou V Welle A Joedicke J Pohar J et al . LAG-3 inhibitory receptor expression identifies immunosuppressive natural regulatory plasma cells. Immunity (2018) 49:120–33.e9. doi: 10.1016/j.immuni.2018.06.007
148
Matsumoto M Baba A Yokota T Nishikawa H Ohkawa Y Kayama H et al . Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity (2014) 41:1040–51. doi: 10.1016/j.immuni.2014.10.016
149
Shen P Roch T Lampropoulou V O’Connor RA Stervbo U Hilgenberg E et al . IL-35-producing b cells are critical regulators of immunity during autoimmune and infectious diseases. Nature (2014) 507:366–70. doi: 10.1038/nature12979
150
Kulkarni U Karsten CM Kohler T Hammerschmidt S Bommert K Tiburzy B et al . IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration. J Allergy Clin Immunol (2016) 137:1487–97.e6. doi: 10.1016/j.jaci.2015.10.018
151
Shalapour S Lin X-J Bastian IN Brain J Burt AD Aksenov AA et al . Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature (2017) 551:340–5. doi: 10.1038/nature24302
152
Shalapour S Font-Burgada J Di Caro G Zhong Z Sanchez-Lopez E Dhar D et al . Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature (2015) 521:94–8. doi: 10.1038/nature14395
153
Teichmann LL Kashgarian M Weaver CT Roers A Müller W Shlomchik MJ . B cell-derived IL-10 does not regulate spontaneous systemic autoimmunity in MRL.Fas(lpr) mice. J Immunol (2012) 188:678–85. doi: 10.4049/jimmunol.1102456
154
Suzuki-Yamazaki N Yanobu-Takanashi R Okamura T Takaki S . IL-10 production in murine IgM(+) CD138(hi) cells is driven by blimp-1 and downregulated in class-switched cells. Eur J Immunol (2017) 47:493–503. doi: 10.1002/eji.201646549
155
Fritz JH Rojas OL Simard N McCarthy DD Hapfelmeier S Rubino S et al . Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut. Nature (2012) 481:199–203. doi: 10.1038/nature10698
156
Kim MS Kim TS . IgA+ plasma cells in murine intestinal lamina propria as a positive regulator of treg differentiation. J Leukoc Biol (2014) 95:461–9. doi: 10.1189/jlb.0613310
157
Bermejo DA Jackson SW Gorosito-Serran M Acosta-Rodriguez EV Amezcua-Vesely MC Sather BD et al . Trypanosoma cruzi trans-sialidase initiates a program independent of the transcription factors RORγt and ahr that leads to IL-17 production by activated b cells. Nat Immunol (2013) 14:514–22. doi: 10.1038/ni.2569
158
Pioli PD Casero D Montecino-Rodriguez E Morrison SL Dorshkind K . Plasma cells are obligate effectors of enhanced myelopoiesis in aging bone marrow. Immunity (2019) 51:351–66.e6. doi: 10.1016/j.immuni.2019.06.006
159
Meng L Almeida LN Clauder A-K Lindemann T Luther J Link C et al . Bone marrow plasma cells modulate local myeloid-lineage differentiation via IL-10. Front Immunol (2019) 10:1183. doi: 10.3389/fimmu.2019.01183
Summary
Keywords
plasma cell, inflammation, plasma cell niche, autoimmunity, microenvironment
Citation
Schäfer A-L, Ruiz-Aparicio PF, Kraemer AN and Chevalier N (2023) Crosstalk in the diseased plasma cell niche – the force of inflammation. Front. Immunol. 14:1120398. doi: 10.3389/fimmu.2023.1120398
Received
09 December 2022
Accepted
07 February 2023
Published
21 February 2023
Volume
14 - 2023
Edited by
Peter Dion Pioli, University of Saskatchewan, Canada
Reviewed by
Marta Ferreira-Gomes, German Rheumatism Research Center (DRFZ), Germany
Updates
Copyright
© 2023 Schäfer, Ruiz-Aparicio, Kraemer and Chevalier.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Nina Chevalier, nina.chevalier@uniklinik-freiburg.de
This article was submitted to B Cell Biology, a section of the journal Frontiers in Immunology
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