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1
Doyon-Laliberté, Kim, Josiane Chagnon-Choquet, Michelle Byrns, Matheus Aranguren, Meriam Memmi, Pavel Chrobak, John Stagg, Johanne Poudrier, and Michel Roger. "NR4A Expression by Human Marginal Zone B-Cells." Antibodies 8, no. 4 (October 11, 2019): 50. http://dx.doi.org/10.3390/antib8040050.
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We have previously characterized a human blood CD19+CD1c+IgM+CD27+CD21loCD10+ innate-like B-cell population, which presents features shared by both transitional immature and marginal zone (MZ) B-cells, named herein “precursor-like” MZ B-cells. B-cells with similar attributes have been associated with regulatory potential (Breg). In order to clarify this issue and better characterize this population, we have proceeded to RNA-Seq transcriptome profiling of mature MZ and precursor-like MZ B-cells taken from the blood of healthy donors. We report that ex vivo mature MZ and precursor-like MZ B-cells express transcripts for the immunoregulatory marker CD83 and nuclear receptors NR4A1, 2, and 3, known to be associated with T-cell regulatory (Treg) maintenance and function. Breg associated markers such as CD39 and CD73 were also expressed by both populations. We also show that human blood and tonsillar precursor-like MZ B-cells were the main B-cell population to express elevated levels of CD83 and NR4A1-3 proteins ex vivo and without stimulation. Sorted tonsillar precursor-like MZ B-cells exerted regulatory activity on autologous activated CD4+ T-cells, and this was affected by a CD83 blocking reagent. We believe these observations shed light on the Breg potential of MZ populations, and identify NR4A1-3 as potential Breg markers, which as for Tregs, may be involved in stabilization of a regulatory status. Since expression and activity of these molecules can be modulated therapeutically, our findings may be useful in strategies aiming at modulation of Breg responses.
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Muppidi, Jagan R., Tal I. Arnon, Yelena Bronevetsky, Natacha Veerapen, Masato Tanaka, Gurdyal S. Besra, and Jason G. Cyster. "Cannabinoid receptor 2 positions and retains marginal zone B cells within the splenic marginal zone." Journal of Experimental Medicine 208, no. 10 (August 29, 2011): 1941–48. http://dx.doi.org/10.1084/jem.20111083.
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Specialized B cells residing in the splenic marginal zone (MZ) continuously survey the blood for antigens and are important for immunity to systemic infections. However, the cues that uniquely attract cells to the MZ have not been defined. Previous work demonstrated that mice deficient in cannabinoid receptor 2 (CB2) have decreased numbers of MZ B cells but it has been unclear whether CB2 regulates MZ B cell development or positioning. We show that MZ B cells are highly responsive to the CB2 ligand 2-arachidonylglycerol (2-AG) and that CB2 antagonism rapidly displaces small numbers of MZ B cells to the blood. Antagonism for longer durations depletes MZ B cells from the spleen. In mice deficient in sphingosine-1-phosphate receptor function, CB2 antagonism causes MZ B cell displacement into follicles. Moreover, CB2 overexpression is sufficient to position B cells to the splenic MZ. These findings establish a role for CB2 in guiding B cells to the MZ and in preventing their loss to the blood. As a consequence of their MZ B cell deficiency, CB2-deficient mice have reduced numbers of CD1d-high B cells. We show that CB2 deficiency results in diminished humoral responses to a CD1d-restricted systemic antigen.
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Westerberg, Lisa S., Miguel A. de la Fuente, Fredrik Wermeling, Hans D. Ochs, Mikael C. I. Karlsson, Scott B. Snapper, and Luigi D. Notarangelo. "WASP confers selective advantage for specific hematopoietic cell populations and serves a unique role in marginal zone B-cell homeostasis and function." Blood 112, no. 10 (November 15, 2008): 4139–47. http://dx.doi.org/10.1182/blood-2008-02-140715.
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Abstract Development of hematopoietic cells depends on a dynamic actin cytoskeleton. Here we demonstrate that expression of the cytoskeletal regulator WASP, mutated in the Wiskott-Aldrich syndrome, provides selective advantage for the development of naturally occurring regulatory T cells, natural killer T cells, CD4+ and CD8+ T lymphocytes, marginal zone (MZ) B cells, MZ macrophages, and platelets. To define the relative contribution of MZ B cells and MZ macrophages for MZ development, we generated wild-type and WASP-deficient bone marrow chimeric mice, with full restoration of the MZ. However, even in the presence of MZ macrophages, only 10% of MZ B cells were of WASP-deficient origin. We show that WASP-deficient MZ B cells hyperproliferate in vivo and fail to respond to sphingosine-1-phosphate, a crucial chemoattractant for MZ B-cell positioning. Abnormalities of the MZ compartment in WASP−/− mice lead to aberrant uptake of Staphylococcus aureus and to a reduced immune response to TNP-Ficoll. Moreover, WASP-deficient mice have increased levels of “natural” IgM antibodies. Our findings reveal that WASP regulates both development and function of hematopoietic cells. We demonstrate that WASP deficiency leads to an aberrant MZ that may affect responses to blood-borne pathogens and peripheral B-cell tolerance.
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Brunner, Cornelia, Dragan Marinkovic, Jörg Klein, Tatjana Samardzic, Lars Nitschke, and Thomas Wirth. "B Cell–specific Transgenic Expression of Bcl2 Rescues Early B Lymphopoiesis but Not B Cell Responses in BOB.1/OBF.1-deficient Mice." Journal of Experimental Medicine 197, no. 9 (May 5, 2003): 1205–11. http://dx.doi.org/10.1084/jem.20022014.
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Mice deficient for the transcriptional coactivator BOB.1/OBF.1 show several defects in B cell differentiation. Numbers of immature transitional B cells in the bone marrow are reduced and fewer B cells reach the periphery. Furthermore, germinal center B cells are absent and marginal zone (MZ) B lymphocytes are markedly reduced. Increased levels of B cell apoptosis in these mice prompted us to analyze expression and function of antiapoptotic proteins. Bcl2 expression is strongly reduced in BOB.1/OBF.1-deficient pre–B cells. When BOB.1/OBF.1-deficient mice were crossed with Bcl2-transgenic mice, B cell development in the bone marrow and numbers of B cells in peripheral lymphoid organs were normalized. However, neither germinal center B cells nor MZ B cells were rescued. Additionally, Bcl2 did not rescue the defects in signaling and affinity maturation found in BOB.1/OBF.1-deficient mice. Interestingly, Bcl2-transgenic mice by themselves show an MZ B cell defect. Virtually no functional MZ B cells were detected in these mice. In contrast, mice deficient for Bcl2 show a relative increase in MZ B cell numbers, indicating a previously undetected function of Bcl2 for this B cell compartment.
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Song, Haifeng, and Jan Cerny. "Functional Heterogeneity of Marginal Zone B Cells Revealed by Their Ability to Generate Both Early Antibody-forming Cells and Germinal Centers with Hypermutation and Memory in Response to a T-dependent Antigen." Journal of Experimental Medicine 198, no. 12 (December 8, 2003): 1923–35. http://dx.doi.org/10.1084/jem.20031498.
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Marginal zone (MZ) B cells play a major role in the first-line responses against blood-born T-independent bacterial antigens (TI), but the full scope of their immune functions is not known. Here we compare the responses of MZ and follicular (FO) B cells to a T-dependent antigen (TD), hapten–(4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken γ-globulin, in a cell transfer system. Consistent with the conventional paradigm, MZ B cells but not FO B cells rapidly generated the early burst of NP-specific antibody-forming cells (AFC), high levels of IgM Ab, and early IgG with relatively high affinity to NP. However, MZ B cells were also capable of forming germinal centers (GCs) albeit with a delay, compared with FO B cells. The early AFCs and the GCs originated from different MZ precursors, but the MZ- and FO-derived GCs were similar in VH gene repertoire, somatic mutation, and production of late AFC and IgG Ab. Surprisingly, the MZ but not the FO memory response included IgM Ab. We conclude that MZ B cells are heterogeneous, comprising cells for both early AFC response and GC/memory pathway against TD antigens.
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Carey, John B., Chantelle S. Moffatt-Blue, Lisa C. Watson, Amanda L. Gavin, and Ann J. Feeney. "Repertoire-based selection into the marginal zone compartment during B cell development." Journal of Experimental Medicine 205, no. 9 (August 18, 2008): 2043–52. http://dx.doi.org/10.1084/jem.20080559.
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Marginal zone (MZ) B cells resemble fetally derived B1 B cells in their innate-like rapid responses to bacterial pathogens, but the basis for this is unknown. We report that the MZ is enriched in “fetal-type” B cell receptors lacking N regions (N−). Mixed bone marrow (BM) chimeras, made with adult terminal deoxynucleotidyl transferase (TdT)+/+ and TdT−/− donor cells, demonstrate preferential repertoire-based selection of N− B cells into the MZ. Reconstitution of irradiated mice with adult TdT+/+ BM reveals that the MZ can replenish N− B cells in adult life via repertoire-based selection and suggest the possibility of a TdT-deficient precursor population in the adult BM. The mixed chimera data also suggest repertoire-based bifurcations into distinct BM and splenic maturation pathways, with mature “recirculating” BM B cells showing a very strong preference for N+ complementarity-determining region (CDR) 3 compared with follicular B cells. Because the T1 and MZ compartments are both the most enriched for N− H-CDR3, we propose a novel direct T1→MZ pathway and identify a potential T1–MZ precursor intermediate. We demonstrate progressive but discontinuous repertoire-based selection throughout B cell development supporting multiple branchpoints and pathways in B cell development. Multiple differentiation routes leading to MZ development may contribute to the reported functional heterogeneity of the MZ compartment.
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Liechti, Thomas, Claus Kadelka, Dominique L. Braun, Herbert Kuster, Jürg Böni, Melissa Robbiani, Huldrych F. Günthard, and Alexandra Trkola. "Widespread B cell perturbations in HIV-1 infection afflict naive and marginal zone B cells." Journal of Experimental Medicine 216, no. 9 (June 20, 2019): 2071–90. http://dx.doi.org/10.1084/jem.20181124.
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Perturbations in B cells are a hallmark of HIV-1 infection. This is signified by increased numbers of exhausted CD21neg memory B cells, driven by continuous antigen-specific and bystander activation. Using high-dimensional flow cytometry, we demonstrate that this exhausted phenotype is also prevalent among peripheral antigen-inexperienced naive and marginal zone (MZ) B cells in acute and chronic HIV-1 infection. A substantial fraction of naive and MZ B cells exhibit down-regulated CD21 levels and diminished response to B cell receptor (BCR)–dependent stimulation. Compared with CD21pos subsets, the CD21neg naive and MZ B cells differ in the expression of chemokine receptors and activation markers. Effective antiretroviral treatment normalizes peripheral naive and MZ B cell populations. Our results emphasize a more widely spread impairment of B cells in HIV-1 infection than previously appreciated, including antigen-inexperienced cells. This highlights the importance of monitoring functional capacities of naive B cells in HIV-1 infection, as exhausted CD21neg naive B cells may severely impair induction of novel B cell responses.
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Dammers, Peter M., Monique E. Lodewijk, André Zandvoort, and Frans G. M. Kroese. "Marginal Zone B Cells in Neonatal Rats Express Intermediate Levels of CD90 (Thy-1)." Developmental Immunology 9, no. 4 (2002): 187–95. http://dx.doi.org/10.1080/10446670310001593488.
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Here we show that marginal zone (MZ)-B cells in rats can already be detected in neonatal spleen from two days after birth. At this time point, morphologically distinct MZs are not present yet and the vast majority of B cells in spleen are located in a concentric area surrounding the T cell zones (PALS). Before MZs are obviously detectable in spleen (14 days after birth), MZ-B cells seem to be enriched at the outer zones of the concentric B cell areas. Similar to adult rats, neonatal MZ-B cells are intermediate-sized cells that express high levels of surface (s)IgM and HIS57 antigen, and low levels of sIgD and CD45R (HIS24). We show here, however, that in contrast to adult MZ-B cells, MZ-B cells (and also recirculating follicular (RF)-B cells) in neonatal rats express higher levels of CD90 (Thy-1). In adult rats, expression of CD90 on the B cell lineage is confined to immature B cells. We speculate that the expression of CD90 on neonatal MZ-B cells may have implications for their responsiveness to polysaccharide (T cell-independent type 2) antigens.
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Wang, Hongsheng, Natalie Beaty, Sophia Chen, Chen-Feng Qi, Marek Masiuk, Dong-Mi Shin, and Herbert C. Morse. "The CXCR7 chemokine receptor promotes B-cell retention in the splenic marginal zone and serves as a sink for CXCL12." Blood 119, no. 2 (January 12, 2012): 465–68. http://dx.doi.org/10.1182/blood-2011-03-343608.
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The splenic marginal zone (MZ) is comprised of specialized populations of B cells, dendritic cells, and macrophages that are uniquely arrayed outside the white pulp follicles to screen the blood for bacterial and other particulate Ags. Mechanisms responsible for MZ B-cell formation, localization, retention, and function are understood to include antigenic specificity, transcription factors, integrins, and surface receptors for soluble ligands such as S1P. Here, we add to this repertoire by demonstrating that the receptor for CXCL12, CXCR7, is expressed on MZ but not on follicular B cells. Treatment of mice with CXCR7 inhibitors led to disruption of MZ architecture, reduced numbers of MZ B cells, and altered granulocyte homeostasis associated with increasing serum levels of CXCL12. CXCR7 thus appears to function as a scavenger receptor for CXCL12 on MZ B cells.
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Girkontaite, Irute, Vadim Sakk, Martin Wagner, Tilman Borggrefe, Kerry Tedford, Jerold Chun, and Klaus-Dieter Fischer. "The Sphingosine-1-Phosphate (S1P) Lysophospholipid Receptor S1P3 Regulates MAdCAM-1+ Endothelial Cells in Splenic Marginal Sinus Organization." Journal of Experimental Medicine 200, no. 11 (December 6, 2004): 1491–501. http://dx.doi.org/10.1084/jem.20041483.
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Marginal zones (MZs) are microdomains in the spleen that contain various types of immune cells, including MZ B cells, MOMA1+ metallophilic macrophages, and mucosal addressin cell adhesion molecule 1 (MAdCAM-1)+ endothelial cells. MAdCAM-1+ and MOMA1+ cells line the sinus, that separates MZs from splenic follicles. Here we show that a receptor for the lysophospholipid sphingosine-1-phosphate (S1P), S1P3, is required for normal numbers of splenic immature and MZ B cells, and for S1P-induced chemotaxis of MZ B cells. S1P3 is also essential for proper alignment of MOMA1+ macrophages and MAdCAM-1+ endothelial cells along the marginal sinus. The lack of cohesion of the marginal sinus in S1P3−/− mice affects MZ B cell functions, as wild-type (WT) MZ B cells migrate more into S1P3−/− follicles than into WT follicles after treatment with lipopolysaccharide. Additionally, short-term homing experiments demonstrate that WT MZ B cells home to the S1P3−/− spleen in increased numbers, suggesting a role for the marginal sinus in regulating MZ B cells numbers. Moreover, S1P3−/− mice are defective in mounting immune responses to thymus-independent antigen type 2 due to defects in radiation-resistant cells in the spleen. These data identify lysophospholipids and the S1P3 receptor as essential regulators of the MZ sinus and its role as a barrier to the follicle.
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Chen, Ting-Ting, Ming-Hsun Tsai, John T. Kung, Kuo-I. Lin, Thomas Decker, and Chien-Kuo Lee. "STAT1 regulates marginal zone B cell differentiation in response to inflammation and infection with blood-borne bacteria." Journal of Experimental Medicine 213, no. 13 (November 14, 2016): 3025–39. http://dx.doi.org/10.1084/jem.20151620.
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Marginal zone B (MZ B) cells can rapidly produce antibody in response to infection with blood-borne encapsulated pathogens. Although TLR-mediated activation of MZ B is known to trigger humoral immune response, the signal cascade directing this response remains undefined. Here, we demonstrate that STAT1 plays an essential role in TLR-mediated antibody response of MZ B cells. Further, the TLR-induced IgM response is impaired in a type I and type II IFN-independent manner. Although activation, proliferation, and apoptosis are not affected, both differentiation into plasma cells and IgM production are impaired in Stat1−/− MZ B cells. Interestingly, STAT1 directly regulates the expression of Prdm1 (encodes BLIMP-1) by binding to its promoter, and Prdm1 expression is reduced in Stat1−/− MZ B cells. Restoration of BLIMP-1 to cells rescues TLR-induced IgM response. Moreover, Stat1−/− mice are more susceptible to S. pneumoniae infection, which can be rescued by the serum of bacteria-primed WT mice. The increased susceptibility to S. pneumoniae infection in Stat1−/− mice is also intrinsic to STAT1 requirement in MZ B cells. Collectively, these results define a differential regulation of TLR-mediated activation and differentiation of MZ B cells by STAT1 and reveal a STAT1-dependent, but IFN-independent, antibody response during infection and inflammation.
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Hampel, Franziska, Stefanie Ehrenberg, Caroline Hojer, Anne Draeseke, Gabriele Marschall-Schröter, Ralf Kühn, Brigitte Mack, et al. "CD19-independent instruction of murine marginal zone B-cell development by constitutive Notch2 signaling." Blood 118, no. 24 (December 8, 2011): 6321–31. http://dx.doi.org/10.1182/blood-2010-12-325944.
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Abstract B cell–specific gene ablation of Notch2 results in the loss of the marginal zone (MZ) B-cell lineage. To analyze the effects of constitutive Notch2 signaling in B cells, we have generated a transgenic mouse strain that allows the conditional expression of a constitutively active, intracellular form of Notch2 (Notch2IC). Expression of Notch2IC at the earliest developmental stages of the B-cell lineage completely abolished B-cell generation and led to the development of ectopic T cells in the bone marrow (BM), showing that Notch2IC is acting redundantly with Notch1IC in driving ectopic T-cell differentiation. In B cells clearly committed to the B-cell lineage induction of Notch2IC drove all cells toward the MZ B-cell compartment at the expense of follicular B cells. Notch2IC-expressing B cells reflected the phenotype of wild-type MZ B cells for their localization in the MZ, the expression of characteristic surface markers, their enhanced proliferation after stimulation, and increased basal activity of Akt, Erk, and Jnk. Notch2IC-driven MZ B-cell generation in the spleen was achieved even in the absence of CD19. Our results implicate that a constitutive Notch2 signal in transitional type 1 B cells is sufficient to drive MZ B-cell differentiation.
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Turchinovich, Gleb, Thi Thanh Vu, Friederike Frommer, Jan Kranich, Sonja Schmid, Melanie Alles, Jean-Baptiste Loubert, et al. "Programming of marginal zone B-cell fate by basic Krüppel-like factor (BKLF/KLF3)." Blood 117, no. 14 (April 7, 2011): 3780–92. http://dx.doi.org/10.1182/blood-2010-09-308742.
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Abstract Splenic marginal zone (MZ) B cells are a lineage distinct from follicular and peritoneal B1 B cells. They are located next to the marginal sinus where blood is released. Here they pick up antigens and shuttle the load onto follicular dendritic cells inside the follicle. On activation, MZ B cells rapidly differentiate into plasmablasts secreting antibodies, thereby mediating humoral immune responses against blood-borne type 2 T-independent antigens. As Krüppel-like factors are implicated in cell differentiation/function in various tissues, we studied the function of basic Krüppel-like factor (BKLF/KLF3) in B cells. Whereas B-cell development in the bone marrow of KLF3-transgenic mice was unaffected, MZ B-cell numbers in spleen were increased considerably. As revealed in chimeric mice, this occurred cell autonomously, increasing both MZ and peritoneal B1 B-cell subsets. Comparing KLF3-transgenic and nontransgenic follicular B cells by RNA-microarray revealed that KLF3 regulates a subset of genes that was similarly up-regulated/down-regulated on normal MZ B-cell differentiation. Indeed, KLF3 expression overcame the lack of MZ B cells caused by different genetic alterations, such as CD19-deficiency or blockade of B-cell activating factor-receptor signaling, indicating that KLF3 may complement alternative nuclear factor-κB signaling. Thus, KLF3 is a driving force toward MZ B-cell maturation.
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Simonetti, Giorgia, Amanda Carette, Kathryn Silva, Haowei Wang, Nilushi S. De Silva, Nicole Heise, Christian W. Siebel, Mark J. Shlomchik, and Ulf Klein. "IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity." Journal of Experimental Medicine 210, no. 13 (December 9, 2013): 2887–902. http://dx.doi.org/10.1084/jem.20131026.
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The transcription factor interferon regulatory factor-4 (IRF4) is expressed in B cells at most developmental stages. In antigen-activated B cells, IRF4 controls germinal center formation, class-switch recombination, and the generation of plasma cells. Here we describe a novel function for IRF4 in the homeostasis of mature B cells. Inducible deletion of irf4 specifically in B cells in vivo led to the aberrant accumulation of irf4-deleted follicular B cells in the marginal zone (MZ) area. IRF4-deficient B cells showed elevated protein expression and activation of NOTCH2, a transmembrane receptor and transcriptional regulator known to be required for MZ B cell development. Administration of a NOTCH2-inhibitory antibody abolished nuclear translocation of NOTCH2 in B cells within 12 h and caused a rapid and progressive disintegration of the MZ that was virtually complete 48 h after injection. The disappearance of the MZ was accompanied by a transient increase of MZ-like B cells in the blood rather than increased B cell apoptosis, demonstrating that continued NOTCH2 activation is critical for the retention of B cells in the MZ. Our results suggest that IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression. These findings may have implications for the understanding of B cell malignancies with dysregulated IRF4 and NOTCH2 activity.
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Srivastava, Bhaskar, William J. Quinn, Kristin Hazard, Jan Erikson, and David Allman. "Characterization of marginal zone B cell precursors." Journal of Experimental Medicine 202, no. 9 (October 31, 2005): 1225–34. http://dx.doi.org/10.1084/jem.20051038.
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Selection of recently formed B cells into the follicular or marginal zone (MZ) compartments is proposed to occur by way of proliferative intermediates expressing high levels of CD21/35 and CD23. However, we show that CD21/35high CD23+ splenocytes are not enriched for proliferative cells, and do not contribute substantially to the generation of follicular B cells. Instead, ontogenic relationships, steady-state labeling kinetics, and adoptive transfer experiments suggest that CD21/35high CD23+ splenocytes serve primarily as precursors for MZ B cells, although their developmental potential seems to be broader and is influenced by environmental cues that are associated with lymphopenia. Furthermore, CD21/35high CD23+ splenocytes share several key functional characteristics with MZ B cells, including their capacity to trap T-independent antigen and a heightened proliferative response to LPS. These observations challenge previous models of peripheral B cell maturation, and suggest that MZ B cells develop by way of CD21/35high CD23+ intermediates.
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Zerra, Patricia E., Seema R. Patel, Connie M. Arthur, Kathryn R. Girard-Pierce, Ashley Bennett, and Sean R. Stowell. "Marginal Zone B Cells Regulate RBC Alloimmunization Toward Distinct RBC Alloantigens." Blood 128, no. 22 (December 2, 2016): 3847. http://dx.doi.org/10.1182/blood.v128.22.3847.3847.
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Abstract Background: While red blood cell (RBC) transfusion can be beneficial, exposure to allogeneic RBCs can result in the development of RBC alloantibodies that can make it difficult to obtain compatible RBCs for future transfusions. Aside from phenotype matching protocols, no strategy currently exists that is capable of preventing RBC alloimmunization following therapeutic transfusion. As RBC alloantigens represent diverse determinants capable of driving distinct immune pathways, common immunological nodes must be identified in order to successfully prevent RBC alloimmunization against a variety of different alloantigens. Recent results demonstrate that marginal zone (MZ) B cells mediate anti-KEL antibody formation in the complete absence of CD4 T cells. However, whether MZ B cells similarly regulate RBC alloantibody formation against other RBC alloantigens remains unknown. As a result, we examined the role of MZ B cells and CD4 T cells in the development of RBC alloantibodies following exposure to the HOD (hen egg lysozyme, ovalbumin and duffy) antigen. Methods: Each recipient was transfused with HOD or KEL RBCs following either MZ B cell or CD4 T cell depletion using a cocktail of MZ B cell (anti-CD11a and anti-CD49d) or anti-CD4 depleting antibody, 4 and 2 days prior to transfusion. Control groups received isotype control injections in parallel. MZ B cell deficient (CD19cre/+ X Notch2flx/flx) and CD4 T cell deficient (MHC class II knockout) recipients were also used to examine the role of MZ B cells and CD4 T cells, respectively. Serum collected on days 5 and 14 post-transfusion was evaluated for anti-HOD or anti-KEL antibodies by incubating HOD or KEL RBCs with serum, followed by detection of bound antibodies using anti-IgM and anti-IgG and subsequent flow cytometric analysis. Evaluation of antibody engagement and overall survival of HOD or KEL RBCs was accomplished by labeling RBCs with the lipophilic dye, DiI, prior to transfusion, followed by examination for bound antibody and RBC clearance on days 5 and 14 post-transfusion by flow cytometry. Results: Similar to the ability of MZ B cell depletion to reduce anti-KEL antibody formation following KEL RBC exposure, depletion of MZ B cells significantly reduced anti-HOD IgM and IgG antibodies following HOD RBC transfusion. In contrast, injection of recipients with isotype control antibodies in parallel failed to prevent alloantibody formation following HOD or KEL RBC transfusion. Similar results were obtained following HOD or KEL RBC transfusion into recipients genetically deficient in MZ B cells. In contrast, although MZ B cells were required for HOD and KEL RBC-alloantibody formation, manipulation of CD4 T cells differentially impacted the ability of each antigen to induce alloantibodies. While transfusion of HOD or KEL RBCs resulted in robust IgM alloantibodies in the absence of CD4 T cells, depletion or genetic elimination of CD4 T cells significantly inhibited anti-HOD IgG antibody formation, while failing to impact IgG anti-KEL antibody formation. Consistent with this, while manipulation of CD4 T cells protected HOD RBCs from antibody deposition and subsequent RBC clearance, this same approach failed to similarly protect KEL RBCs following transfusion. In contrast, depletion of MZ B cells not only prevented detectable alloantibody production, but also completely protected HOD or KEL RBCs from antibody deposition and subsequent RBC clearance. Conclusion: These results suggest that while MZ B cells mediate a robust IgM antibody response following either KEL or HOD antigen exposure, MZ B cells appear to possess the capacity to orchestrate unique downstream IgG responses through CD4 T cell dependent and independent pathways contingent on target alloantigen. As a result, while manipulation of CD4 T cells may prevent alloantibody formation against some antigens, targeting this immune population inadequately prevents RBC alloantibody formation against all RBC antigens. As chronic transfusion therapy exposes recipients to a wide variety of alloantigens, these results suggest that MZ B cells may represent a central initiating node that governs RBC alloimmunization against a variety of RBC alloantigens, and may therefore serve as a useful target in preventing alloantibody formation in chronically transfused individuals. Disclosures No relevant conflicts of interest to declare.
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Carvalho, Thiago L., Tomaz Mota-Santos, Ana Cumano, Jocelyne Demengeot, and Paulo Vieira. "Arrested B Lymphopoiesis and Persistence of Activated B Cells in Adult Interleukin 7−/− Mice." Journal of Experimental Medicine 194, no. 8 (October 15, 2001): 1141–50. http://dx.doi.org/10.1084/jem.194.8.1141.
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Interleukin 7 is a crucial factor for the development of murine T and B lymphocytes. We now report that, in the absence of interleukin 7, B lymphocyte production takes place exclusively during fetal and perinatal life, ceasing after 7 wk of age. In peripheral organs, however, the pool of B lymphocytes is stable throughout adult life and consists only of cells that belong to the B1 and marginal zone (MZ) compartments. This is accompanied by a 50-fold increase in the frequency of immunoglobulin (Ig)M- and IgG-secreting cells, and the concentration of serum immunoglobulins is increased three- to fivefold. Both the MZ phenotype and the increase in serum IgM are T cell independent. These findings reveal a previously undescribed pathway of B lymphopoiesis that is active in early life and is interleukin 7 independent. This pathway generates B1 cells and a normal sized MZ B lymphocyte compartment.
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Zerra, Patricia E., Courtney Cox, W. Hunter Baldwin, Seema R. Patel, Connie M. Arthur, Pete Lollar, Shannon L. Meeks, and Sean R. Stowell. "Marginal zone B cells are critical to factor VIII inhibitor formation in mice with hemophilia A." Blood 130, no. 23 (December 7, 2017): 2559–68. http://dx.doi.org/10.1182/blood-2017-05-782912.
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de Vera Mudry, Maria Cristina, Franziska Regenass-Lechner, Laurence Ozmen, Bernd Altmann, Matthias Festag, Thomas Singer, Lutz Müller, Helmut Jacobsen, and Alexander Flohr. "Morphologic and Functional Effects of Gamma Secretase Inhibition on Splenic Marginal Zone B Cells." International Journal of Alzheimer's Disease 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/289412.
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Theγ-secretase complex is a promising target in Alzheimer’s disease because of its role in the amyloidogenic processing ofβ-amyloid precursor protein. This enzyme also catalyzes the cleavage of Notch receptor, resulting in the nuclear translocation of intracellular Notch where it modulates gene transcription. Notch signaling is essential in cell fate decisions during embryogenesis, neuronal differentiation, hematopoiesis, and development of T and B cells, including splenic marginal zone (MZ) B cells. This B cell compartment participates in the early phases of the immune response to blood-borne bacteria and viruses. Chronic treatment with the oralγ-secretase inhibitor RO4929097 resulted in dose-dependent decreased cellularity (atrophy) of the MZ of rats and mice. Significant decreases in relative MZ B-cell numbers of RO4929097-treated animals were confirmed by flow cytometry. Numbers of MZ B cells reverted to normal after a sufficient RO4929097-free recovery period. Functional characterization of the immune response in relation to RO4929097-related MZ B cell decrease was assessed in mice vaccinated with inactivated vesicular stomatitis virus (VSV). Compared with the immunosuppressant cyclosporin A, RO4929097 caused only mild and reversible delayed early neutralizing IgM and IgG responses to VSV. Thus, the functional consequence of MZ B cell decrease on host defense is comparatively mild.
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Li, Zhaoyang, Hongsheng Wang, Liquan Xue, Dong-Mi Shin, Derry Roopenian, Wu Xu, Chen-Feng Qi, et al. "Eμ-BCL10 mice exhibit constitutive activation of both canonical and noncanonical NF-κB pathways generating marginal zone (MZ) B-cell expansion as a precursor to splenic MZ lymphoma." Blood 114, no. 19 (November 5, 2009): 4158–68. http://dx.doi.org/10.1182/blood-2008-12-192583.
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Abstract BCL10, required for nuclear factor κB (NF-κB) activation during antigen-driven lymphocyte responses, is aberrantly expressed in mucosa-associated lymphoid tissue-type marginal zone (MZ) lymphomas because of chromosomal translocations. Eμ-driven human BCL10 transgenic (Tg) mice, which we created and characterize here, had expanded populations of MZ B cells and reduced follicular and B1a cells. Splenic B cells from Tg mice exhibited constitutive activation of both canonical and noncanonical NF-κB signaling pathways is associated with increased expression of NF-κB target genes. These genes included Tnfsf13b, which encodes the B-cell activating factor (BAFF). In addition, levels of BAFF were significantly increased in sera from Tg mice. MZ B cells of Tg mice exhibited reduced turnover in vivo and enhanced survival in vitro, indicative of lymphoaccumulation rather than lymphoproliferation as the cause of MZ expansion. In vivo antibody responses to both T-independent, and especially T-dependent, antigens were significantly reduced in Tg mice. Mortality was accelerated in Tg animals, and some mice older than 8 months had histologic and molecular findings indicative of clonal splenic MZ lymphoma. These results suggest that, in addition to constitutive activation of BCL10 in MZ B cells, other genetic factors or environmental influences are required for short latency oncogenic transformation.
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Samardzic, Tatjana, Dragan Marinkovic, Peter J. Nielsen, Lars Nitschke, and Thomas Wirth. "BOB.1/OBF.1 Deficiency Affects Marginal-Zone B-Cell Compartment." Molecular and Cellular Biology 22, no. 23 (December 1, 2002): 8320–31. http://dx.doi.org/10.1128/mcb.22.23.8320-8331.2002.
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ABSTRACT Marginal-zone (MZ) B cells represent a first line of defense against particulate blood-borne antigens. Together with the B1 cells, they are responsible for the early response against type II T-independent antigens. The molecular pathways controlling the development of MZ B cells are only poorly understood. We found that these cells are virtually absent in mice deficient in the BOB.1/OBF.1 coactivator. Loss of these B cells was demonstrated by the lack of cells showing the appropriate cell surface phenotype but also by histological analyses and tri-nitro-phenol-Ficoll capturing. The lack of these cells is a B-cell-intrinsic defect, as shown by bone marrow complementation experiments. We also show that the expression of BOB.1/OBF.1 in peripheral B cells is required for the development of MZ B lymphocytes. Our analysis of BOB.1/OBF.1-deficient splenic B cells reveals alterations in cell motility, tumor necrosis factor receptor expression, and B-cell receptor (BCR) signaling. These changes could contribute to the loss of MZ B lymphocytes by altering the maturation of the cells. Interestingly, development of and BCR signaling in B1 B cells are completely normal in BOB.1/OBF.1 mutant mice.
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Toda, Munetoyo, Risa Hisano, Hajime Yurugi, Kaoru Akita, Kouji Maruyama, Mizue Inoue, Takahiro Adachi, Takeshi Tsubata, and Hiroshi Nakada. "Ligation of tumour-produced mucins to CD22 dramatically impairs splenic marginal zone B-cells." Biochemical Journal 417, no. 3 (January 16, 2009): 673–83. http://dx.doi.org/10.1042/bj20081241.
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CD22 [Siglec-2 (sialic acid-binding, immunoglobulin-like lectin-2)], a negative regulator of B-cell signalling, binds to α2,6- sialic acid-linked glycoconjugates, including a sialyl-Tn antigen that is one of the typical tumour-associated carbohydrate antigens expressed on various mucins. Many epithelial tumours secrete mucins into tissues and/or the bloodstream. Mouse mammary adenocarcinoma cells, TA3-Ha, produce a mucin named epiglycanin, but a subline of them, TA3-St, does not. Epiglycanin binds to CD22 and inhibits B-cell signalling in vitro. The in vivo effect of mucins in the tumour-bearing state was investigated using these cell lines. It should be noted that splenic MZ (marginal zone) B-cells were dramatically reduced in the mice bearing TA3-Ha cells but not in those bearing TA3-St cells, this being consistent with the finding that the thymus-independent response was reduced in these mice. When the mucins were administered to normal mice, a portion of them was detected in the splenic MZ associated with the MZ B-cells. Furthermore, administration of mucins to normal mice clearly reduced the splenic MZ B-cells, similar to tumour-bearing mice. These results indicate that mucins in the bloodstream interacted with CD22, which led to impairment of the splenic MZ B-cells in the tumour-bearing state.
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Mandik-Nayak, Laura, Jennifer Racz, Barry P. Sleckman, and Paul M. Allen. "Autoreactive marginal zone B cells are spontaneously activated but lymph node B cells require T cell help." Journal of Experimental Medicine 203, no. 8 (July 31, 2006): 1985–98. http://dx.doi.org/10.1084/jem.20060701.
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In K/BxN mice, arthritis is induced by autoantibodies against glucose-6-phosphate-isomerase (GPI). To investigate B cell tolerance to GPI in nonautoimmune mice, we increased the GPI-reactive B cell frequency using a low affinity anti-GPI H chain transgene. Surprisingly, anti-GPI B cells were not tolerant to this ubiquitously expressed and circulating autoantigen. Instead, they were found in two functionally distinct compartments: an activated population in the splenic marginal zone (MZ) and an antigenically ignorant one in the recirculating follicular/lymph node (LN) pool. This difference in activation was due to increased autoantigen availability in the MZ. Importantly, the LN anti-GPI B cells remained functionally competent and could be induced to secrete autoantibodies in response to cognate T cell help in vitro and in vivo. Therefore, our study of low affinity autoreactive B cells reveals two distinct but potentially concurrent mechanisms for their activation, of which one is T cell dependent and the other is T cell independent.
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Zheng, Yongwei, Mei Yu, Andrew Podd, Debra K. Newman, Renren Wen, Gowthami M. Arepally, and Demin Wang. "Critical Role for Mouse Marginal Zone B Cells in PF4/Heparin Antibody Production." Blood 120, no. 21 (November 16, 2012): 1175. http://dx.doi.org/10.1182/blood.v120.21.1175.1175.
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Abstract Abstract 1175 Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder that can cause fatal arterial or venous thrombosis/thromboembolism. Immune complexes consisting of platelet factor 4 (PF4), heparin and PF4/heparin-reactive antibodies are central to the pathogenesis of HIT. However, the B-cell origin of HIT antibody production is not known. Here we show that upon challenge with PF4/heparin complexes, anti-PF4/heparin antibody production is severely impaired in B cell-specific Notch2-deficient mice (CD19CreNotch2fl/fl) that specifically lack marginal zone (MZ) B cells, and that antibody production is readily generated in wild-type mice (CD19CreNotch2+/+). As expected, Notch2-deficient mice responded normally to challenge with T cell-dependent antigen NP-CGG but not T cell-independent antigen TNP-Ficoll, in agreement with the lack of MZ B cells in the mutant mice. PF4/heparin-specific antibodies produced by wild-type mice on a C57BL/6 background were IgG2b and IgG3 isotypes. An in vitro class-switching assay showed that MZ B cells from wild-type C57BL/6 mice were capable of producing antibodies of IgG2b and IgG3 isotypes. Lastly, MZ, but not follicular (FO), B cells adoptively transferred into B cell-deficient muMT mice responded to PF4/heparin complex challenge by producing PF4/heparin-specific antibodies of IgG2b and IgG3 isotypes. Taken together, these data demonstrate that MZ B cells play a critical role in production of PF4/heparin-specific antibodies. Disclosures: Arepally: Teva Pharmaceuticals: Research Funding.
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Bagnara, Davide, Margherita Squillario, David Kipling, Thierry Mora, Aleksandra Walczak, Deborah K. Dunn-Walters, Jean-Claude Weill, and Claude-Agnès Reynaud. "High-Throughput Ig Sequencing of Paired Blood and Spleen Samples Allows a Redefinition of Memory IgM Subsets in Humans." Blood 124, no. 21 (December 6, 2014): 565. http://dx.doi.org/10.1182/blood.v124.21.565.565.
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Abstract In humans, whether B cells with the IgM+IgD+CD27+ phenotype represent an independent lineage involved in T-independent responses, similar to mouse marginal zone B cells, or whether they are part of the germinal center-derived memory B-cell pool generated during responses to T-dependent antigens, is still a debated issue. To address this question, we performed high-throughput Ig sequencing of B-cell subsets from paired blood and spleen samples and analyzed the clonal relationships between them. We isolated and analyzed 3 different B cell subsets based on CD27 and IgD staining from both blood and spleen: IgD+CD27+ (MZ) - amplified with Cmu primers IgD-CD27+ (switched and IgM-only) with Cmu, Cgamma and Calpha primers IgD-CD27- (CD27- memory or double-negative DN) with the same three primers We obtained 95729 unique sequences that clustered in 49199 different clones: 1125 clones were shared between blood and spleen of the same B-cell subset, and 1681 clones were shared between different subsets, allowing us to trace their relationships. We analyzed these clones that share sequences from different subsets/tissues for their mutation frequency distribution, CDR3-length, and VH/JH family usage, and compared these different characteristics with the bulk of sequences from their respective subset of origin. The analysis of clones shared between blood and spleen for switched IgG/IgA and for MZ subsets suggests different recirculation dynamics. For switched cells, the blood appears to be a mixture of splenic and other lymphoid tissues B cells. For MZ B cells in contrast, the blood appear to be only composed of a subgroup of the splenic repertoire, in agreement with the observation that marginal zone B cells recirculate and are mainly generated in the spleen. Clonal relationships between the IgM clones (originating from the MZ, IgM-only and double negative compartments) show that the clones involved display the characteristics of IgM-only B cells whatever their subset of origin, even in the case of the paired MZ/double-negative sequences that were not supposed to include IgM-only sequences. We therefore conclude that the clones shared between the various IgM subsets do not represent b between them, but rather correspond to a heterogeneous phenotype of the IgM-only population that concerns both IgD and CD27 expression, leading to a partial overlap with the MZ and double-negative gates. Clones shared between the MZ and the switched IgG and IgA compartment also show, for their IgM part, the mutation and repertoire characteristics of IgM-only cells and not of MZ B cells, reinforcing the conclusion that IgM-only are true memory B cells, and constitute the only subset showing clonal relationships with switched memory B cells. In summary, we report that MZ B cells have different recirculation characteristics and do not show real clonal relationships with IgM-only and switched memory B cells, in agreement with the notion that they represent a distinct differentiation pathway. In contrast, the only precursor-product relationship between IgM memory and switched B cells appear to concern a B cell subset that has been described as "IgM-only", but appears to have a more heterogeneous expression of IgD than previously reported and therefore contribute to 3-15% of the MZ compartment. Searching for markers that would permit to discriminate between marginal zone and germinal center-derived IgM memory B cells is obviously required to further delineate their respective function. Disclosures No relevant conflicts of interest to declare.
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Tortola, Luigi, Koshika Yadava, Martin F. Bachmann, Christoph Müller, Jan Kisielow, and Manfred Kopf. "IL-21 induces death of marginal zone B cells during chronic inflammation." Blood 116, no. 24 (December 9, 2010): 5200–5207. http://dx.doi.org/10.1182/blood-2010-05-284547.
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Abstract Interleukin-2 (IL-2) and IL-21 share activities in the control of T- and B-cell maturation, proliferation, function, and survival. However, opposing roles for IL-2 and IL-21 have been reported in the development of regulatory T cells. To dissect unique, redundant, and opposing activities of IL-2 and IL-21, we compared T- and B-cell development and function in mice lacking both IL-2 receptor α (IL-2Rα) and IL-21R (double knockouts [DKO]) with single knockout and wild-type (WT) mice. Similarly to il2ra−/− mice, DKO showed reduced numbers of regulatory T cells and, consequently, hyper-activation and proliferation of T cells associated with inflammatory disease (ie, colitis), weight loss, and reduced survival. The absence of IL-2Rα resulted in overproduction of IL-21 by IFN-γ–producing CD4+ T cells, which induced apoptosis of marginal zone (MZ) B cells. Hence, MZ B cells and MZ B-cell immunoglobulin M antibody responses to Streptococcus pneumoniae phosophorylcholine were absent in il2ra−/− mice but were completely restored in DKO mice. Our results highlight key roles of IL-2 in inhibiting IL-21 production by CD4+ T cells and of IL-21 in negatively regulating MZ B-cell survival and antibody production.
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Guo, Feng, Debra Weih, Elke Meier, and Falk Weih. "Constitutive alternative NF-κB signaling promotes marginal zone B-cell development but disrupts the marginal sinus and induces HEV-like structures in the spleen." Blood 110, no. 7 (October 1, 2007): 2381–89. http://dx.doi.org/10.1182/blood-2007-02-075143.
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Nuclear factor-κB (NF-κB) plays a crucial role in B-cell and lymphoid organ development. Here, we studied the consequences of constitutive, signal-independent activation of the alternative NF-κB pathway for the splenic marginal zone (MZ). In contrast to nfkb2−/− mice, which lack both p100 and p52, mice that lack only the inhibitory p100 precursor but still express the p52 subunit of NF-κB2 (p100−/−) had markedly elevated MZ B-cell numbers. Both cell-intrinsic mechanisms and increased stromal expression of vascular cell adhesion molecule-1 (VCAM-1) contributed to the accumulation of MZ B cells in p100−/− spleens. While migration of p100−/− MZ B cells toward the lysophospholipid sphingosine-1 phosphate (S1P) was not affected, CXCL13-stimulated chemotaxis was impaired, correlating with reduced migration of MZ B cells into follicles in response to lipopolysaccharide (LPS). Strikingly, p100 deficiency resulted in the absence of a normal marginal sinus, strongly induced expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and glycosylated cell adhesion molecule-1 (GlyCAM-1), and the formation of nonfunctional ectopic high endothelial venule (HEV)–like structures in the red pulp. Thus, constitutive activation of the alternative NF-κB pathway favors MZ B-cell development and accumulation but leads to a disorganized spleen microarchitecture.
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Cox, Courtney, Patricia Zerra, Connie Authur, Seema Patel, Shannon Meeks, and Sean R. Stowell. "Marginal Zone B Cell Depletion Prevents Factor VIII Inhibitor Development in Model of Hemophilia." Blood 126, no. 23 (December 3, 2015): 1068. http://dx.doi.org/10.1182/blood.v126.23.1068.1068.
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Abstract Background While Factor VIII (fVIII) therapy can provide a life saving intervention in patients with hemophilia A, patients receiving fVIII can develop anti-fVIII antibodies. These antibodies, otherwise known as fVIII inhibitors, often prevent the therapeutic impact of fVIII. As a result, hemophilia A patients with fVIII inhibitors often experience increased morbidity and mortality. Given the unique role of the splenic marginal sinus in the immune response to blood borne antigens, we hypothesized that key immunological constituents within the marginal zone (MZ) likely play a critical role in the initiation and development of anti-fVIII antibodies in hemophilia A recipients. Methods: To deplete MZ B-cells, complete F8 gene knockout mice (TKO mice) received two initial 100 µg intraperitoneal injections of MZ B-cell depleting antibodies (anti-CD11a and anti-CD49d) or isotype controls on days -4, -2, 10 and 20. Additional mice that received MZ B cell depleting antibodies were examined for MZ B cell depletion efficacy and specificity on days 0, 7, 14, 21 and 28 by staining splenocytes with CD3, CD4, CD8, CD11b, CD11c, NK1.1, B220, CD21 and CD23. Starting on day 0, mice received 4 weekly retro-orbital injections of 2 µg of B-domain deleted human fVIII (BDD hfVIII). At 6 weeks, mice received a 4 µg "boost" dose of BDD hfVIII. At eight weeks, mice were then re-challenged with 4 weekly doses of 2 µg of BDD hfVIII. At each interval (pre-boost, post-boost, and after re-challenge) mice were bled and ELISA and inhibitor titers were determined. Results: As the development of detectable anti-fVIII antibodies often requires repeat fVIII exposure, we examined whether repeat injection of MZ B cell depleting antibodies could sustain MZ B cell depletion. Injection of MZ B cell depleting antibodies on days -4, -2, 10 and 20 completely prevented MZ B cell localization within the spleen for 28 days, while failing to alter follicular B cell, NK cell, CD4 T cell, dendritic cell and macrophage numbers. Injection of isotype controls failed to alter MZ B cell numbers when evaluated in parallel. Weekly injection of BDD hfVIII during the first four weeks completely failed to induce an anti-fVIII antibody response in MZ B cell depleted recipients (p<0.0015, Mann Whitney), while isotype control treated recipients developed inhibitors at the same rate as non-treated controls. However, following MZ B cell reconstitution at day 35, recipients previously treated with the MZ B cell depletion regiment developed an immune response that closely resembles naive hemophilia A recipients. Conclusion: These results demonstrate that marginal zone constituents, in particular MZ B cells, play a critical role in the initiation and development of fVIII inhibitors. While MZ B cell depleted recipients failed to generate anti-fVIII antibodies following fVIII exposure, MZ B cell reconstitution after fVIII exposure readily induced anti-fVIII antibodies, suggesting that transient removal of MZ B cell may provide a unique mechanism to prevent fVIII antibody formation without permanently altering host immunity. As a result, MZ B cells and additional unique targets within the marginal sinus may be used to develop specific strategies to prevent anti-fVIII antibody formation in patients with hemophilia A. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Li, Zhaoyang, Liquan Xue, Dong-Mi Shin, Chen-Feng Qi, Quangeng Zhang, Wu Xu, Stephan W. Morris, Herbert Morse, and Hongsheng Wang. "Constitutive Activation of the Canonical NF-κB Signaling Pathway and Expanded Populations of Splenic Marginal Zone B Cells Characterize Em-BCL10 Transgenic Mice." Blood 110, no. 11 (November 16, 2007): 1341. http://dx.doi.org/10.1182/blood.v110.11.1341.1341.
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Abstract The BCL10 gene was isolated from the breakpoint region of the t(1;14)(p22;q32) chromosomal translocation, a recurrent chromosomal abnormality in mucosa-associated lymphoid tissue (MALT)-type lymphomas. The translocation results in constitutive over-expression and nuclear location of the BCL10 protein. To understand the physiological and pathogenic roles played by BCL10 in B-cell biology, a transgenic (TG) mouse model was developed with a human BCL10 gene driven by Em. The TG was expressed in thymic but not peripheral T cells and in the spleen; lymph nodes were negative. Although the lymphoid compartments of the TG mice were grossly normal, histologic studies showed the splenic marginal zone (MZ) to be significantly expanded and, in older mice, to compress the white pulp. In addition, about 10% of animals developed B-cell neoplasms by 18 months of age. By FACS analyses, the number of MZ B cells was increased nearly 2-fold, and both MZ and follicular (FOL) B cells exhibited a marked down-regulation of CD23 expression. In the peritoneum of TG mice, the B1a B-cell population was markedly reduced while the B1b subset was increased over 2-fold. Studies of purified MZ and FOL B cells from normal and TG mice showed that MZ B cells from TG mice had a survival advantage in culture. Studies of the canonical NF-κB signaling pathway that lies downstream from BCL10 showed that it was constitutively activated with high levels of nuclear p50 and p65 protein identified by Western blotting. Quantitative real-time RT-PCR analyses of purified splenic B cells from normal and TG mice for expression of 384 genes identified 44 with significant differences in expression. Almost half of these genes were known NF-κB targets and included genes known to influence B-cell survival (BAFF, IL-10) or associated with MZ lymphomas (S100A9). These results indicate that constitutive expression of BCL10 in B cells is not sufficient to induce transformation alone and that as-yet-unknown secondary mutations are required. Nonetheless, expression of BCL10 clearly resulted in constitutive activation of the canonical NF-κB signaling pathway and a prominent expansion of the MZ B-cell population, thereby setting the stage for later development of lymphomas.
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Qian, Ye, Kara L. Conway, Xiangdong Lu, Heather M. Seitz, Glenn K. Matsushima, and Stephen H. Clarke. "Autoreactive MZ and B-1 B-cell activation by Faslpr is coincident with an increased frequency of apoptotic lymphocytes and a defect in macrophage clearance." Blood 108, no. 3 (August 1, 2006): 974–82. http://dx.doi.org/10.1182/blood-2005-12-006858.
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Abstract Murine autoreactive anti-Smith (Sm) B cells are negatively regulated by anergy and developmental arrest, but are also positively selected into the marginal zone (MZ) and B-1 B-cell populations. Despite positive selection, anti-Sm production occurs only in autoimmune-prone mice. To investigate autoreactive B-cell activation, an anti-Sm transgene was combined with the lpr mutation, a mutation of the proapoptotic gene Fas (Faslpr), on both autoimmune (MRL) and nonautoimmune backgrounds. Faslpr induces a progressive and autoantigen-specific loss of anti-Sm MZ and B-1 B cells in young adult Faslpr and MRL/Faslpr mice that does not require that Faslpr be B-cell intrinsic. This loss is accompanied by a bypass of the early pre–plasma cell (PC) tolerance checkpoint. Although the MRL bkg does not lead to a progressive loss of anti-Sm MZ or B-1 B cells, it induces a robust bypass of the early pre-PC tolerance checkpoint. Faslpr mice have a high frequency of apoptotic lymphocytes in secondary lymphoid tissues and a macrophage defect in apoptotic cell phagocytosis. Since Sm is exposed on the surface of apoptotic cells, we propose that anti-Sm MZ and B-1 B-cell activation is the result of a Faslpr-induced defect in apoptotic cell clearance.
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King, Jennifer K., Nolan Ung, May Paing, Jorge R. Contreras, Michael O. Alberti, Thilini Fernando, Kelvin Zhang, Matteo Pellegrini, and Dinesh S. Rao. "Regulation of Marginal Zone B Cell Differentiation By microRNA-146a Via the Numb-Notch Pathway." Blood 128, no. 22 (December 2, 2016): 3701. http://dx.doi.org/10.1182/blood.v128.22.3701.3701.
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Abstract B cell development in bone marrow is followed by specification into spleen subsets, including marginal zone (MZ) cells. MZ require elaboration of distinct gene expression programs for development. Given their role in gene regulation, its not surprising that microRNAs (miRNAs) influence cell development. Recent work demonstrated that deficiency of NF-κB feedback regulator, Mir146 (miR-146a), led to a range of hematopoietic phenotypes, but B cells have not been extensively characterized. Here, we found miR-146a deficient mice demonstrate a reduction in MZ B cells, likely from a T cell independent developmental block. Utilizing comparative analysis of developmental stage-specific transcriptomes, we show MZ cell differentiation was impaired due to decreases in Notch2 signaling. Further, we discovered that the cell-fate regulatory protein, Numb, is a direct target of miR-146a, and its derepression in miR-146a deficient B cells underlies the decreases in Notch2. Our studies reveal miR-146a-dependent B cell phenotypes regulated by the Numb-Notch2 pathway. Disclosures No relevant conflicts of interest to declare.
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Zerra, Patricia E., Seema R. Patel, Ryan Philip Jajosky, Connie M. Arthur, James W. McCoy, Jerry William Lynn Allen, Satheesh Chonat, et al. "Marginal zone B cells mediate a CD4 T-cell–dependent extrafollicular antibody response following RBC transfusion in mice." Blood 138, no. 8 (April 19, 2021): 706–21. http://dx.doi.org/10.1182/blood.2020009376.
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Abstract Red blood cell (RBC) transfusions can result in alloimmunization toward RBC alloantigens that can increase the probability of complications following subsequent transfusion. An improved understanding of the immune mechanisms that underlie RBC alloimmunization is critical if future strategies capable of preventing or even reducing this process are to be realized. Using the HOD (hen egg lysozyme [HEL] and ovalbumin [OVA] fused with the human RBC antigen Duffy) model system, we aimed to identify initiating immune factors that may govern early anti-HOD alloantibody formation. Our findings demonstrate that HOD RBCs continuously localize to the marginal sinus following transfusion, where they colocalize with marginal zone (MZ) B cells. Depletion of MZ B cells inhibited immunoglobulin M (IgM) and IgG anti-HOD antibody formation, whereas CD4 T-cell depletion only prevented IgG anti-HOD antibody development. HOD-specific CD4 T cells displayed similar proliferation and activation following transfusion of HOD RBCs into wild-type or MZ B-cell–deficient recipients, suggesting that IgG formation is not dependent on MZ B-cell–mediated CD4 T-cell activation. Moreover, depletion of follicular B cells failed to substantially impact the anti-HOD antibody response, and no increase in antigen-specific germinal center B cells was detected following HOD RBC transfusion, suggesting that antibody formation is not dependent on the splenic follicle. Despite this, anti-HOD antibodies persisted for several months following HOD RBC transfusion. Overall, these data suggest that MZ B cells can initiate and then contribute to RBC alloantibody formation, highlighting a unique immune pathway that can be engaged following RBC transfusion.
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Aslam, Mohammad, Yusuke Kishi, and Takeshi Tsubata. "Excess CD40L does not rescue anti-DNA B cells from clonal anergy." F1000Research 2 (October 17, 2013): 218. http://dx.doi.org/10.12688/f1000research.2-218.v1.
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CD40L, a member of the tumor necrosis factor (TNF) ligand family, is overexpressed in patients with systemic lupus erythematosus and in lupus mouse models. Previously, we demonstrated that B cells producing pathogenic anti-Sm/RNP antibodies are deleted in the splenic marginal zone (MZ), and that MZ deletion of these self-reactive B cells is reversed by excess CD40L, leading to autoantibody production. To address whether excess CD40L also perturbs clonal anergy, another self-tolerance mechanism of B cells whereby B cells are functionally inactivated and excluded from follicles in the peripheral lymphoid tissue, we crossed CD40L-transgenic mice with the anti-DNA H chain transgenic mouse line 3H9, in which Ig λ1+ anti-DNA B cells are anergized. However, the percentage and localization of Ig λ1+ B cells in CD40L/3H9 double transgenic mice were no different from those in 3H9 mice. This result indicates that excess CD40L does not perturb clonal anergy, including follicular exclusion. Thus, MZ deletion is distinct from clonal anergy, and is more liable to tolerance break.
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Aslam, Mohammad, Yusuke Kishi, and Takeshi Tsubata. "Excess CD40L does not rescue anti-DNA B cells from clonal anergy." F1000Research 2 (January 15, 2014): 218. http://dx.doi.org/10.12688/f1000research.2-218.v2.
Full textAbstract:
CD40L, a member of the tumor necrosis factor (TNF) ligand family, is overexpressed in patients with systemic lupus erythematosus and in lupus mouse models. Previously, we demonstrated that B cells producing pathogenic anti-Sm/RNP antibodies are deleted in the splenic marginal zone (MZ), and that MZ deletion of these self-reactive B cells is reversed by excess CD40L, leading to autoantibody production. To address whether excess CD40L also perturbs clonal anergy, another self-tolerance mechanism of B cells whereby B cells are functionally inactivated and excluded from follicles in the peripheral lymphoid tissue, we crossed CD40L-transgenic mice with the anti-DNA H chain transgenic mouse line 3H9, in which Ig λ1+ anti-DNA B cells are anergized. However, the percentage and localization of Ig λ1+ B cells in CD40L/3H9 double transgenic mice were no different from those in 3H9 mice. This result indicates that excess CD40L does not perturb clonal anergy, including follicular exclusion. Thus, MZ deletion is distinct from clonal anergy, and is more liable to tolerance break.
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Chaganti, Sridhar, Noelia Begue Pastor, Gouri Baldwin, Claire Shannon-Lowe, Regina Feederle, Debbie Croom-Carter, Juliana Stylianou, Andrew I. Bell, Alan B. Rickinson, and Henri-Jacques Delecluse. "EBV Can Induce Somatic Hypermutation in Naïve B Cells In Vitro but Ig Class Switching Requires T Cell Help." Blood 108, no. 11 (November 1, 2006): 2370. http://dx.doi.org/10.1182/blood.v108.11.2370.2370.
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Abstract Following primary infection, Epstein-Barr virus (EBV) establishes life long persistence in the host IgD− CD27+ memory B cell compartment rather than the IgD+ CD27+ marginal zone (MZ)-like or the IgD+ CD27− naïve B cell compartments. One possible explanation for such exclusive persistence in memory B cells is that EBV preferentially infects memory B cells. Alternatively, the virus may infect all B cell subsets but then drive MZ and naïve B cells to acquire the Ig isotype-switched phenotype and hypermutated Ig genotype of memory cells. Here we ask whether there is any evidence for one or other hypothesis from in vitro experiments. B cells from healthy donor blood samples were FACS sorted on the basis of IgD/CD27 expression into naïve, MZ, and memory B cell subsets with purities of >99%, >97% and >98% respectively. Analysis of the IgVH sequence further confirmed purity of the FACS sorted B cell subsets. Accordingly, 102 of 105 IgVH sequences amplified from purified naïve B cells were germ-line where as the vast majority of sequences amplified from MZ and memory B cells were mutated. All three B cell subsets expressed equal amounts of CD21 (EBV receptor on B cells), bound similar amounts of virus, and transformed with equal efficiency to establish B lymphoblastoid cell lines (LCLs) in vitro. Naïve B cell transformants upregulated CD27 expression but retained the IgM+, IgD+ phenotype as determined by FACS analysis and RT-PCR; MZ-B derived LCLs likewise were IgM+, IgD+, CD27+; and memory-B derived LCLs were consistently CD27+, IgD− and expressed either IgG, IgA or in some cases IgM. Therefore, EBV infection per se did not induce class switching. However, both naïve and MZ-B derived LCLs could still be induced to switch to IgG in the presence of CD40 ligand and IL-4; signals that are normally provided by T cells in vivo. To assess if EBV infection might drive Ig hypermutation, we carried out IgVH sequence analysis on the naïve-B derived LCL clones. Interestingly, 42 of 114 clonal IgVH sequences amplified from naïve-B derived LCLs had 3 or more mutations and the patterns of mutation seen were consistent with that produced by somatic hypermutation (SHM). Furthermore, within some naïve-B cell derived LCL clones, there were both germ-line and mutated sequences all sharing the same VDJ rearrangement (CDR3 sequence), again implying sequence diversification following EBV transformation of a single naïve B cell. Some intraclonal variation of the already hypermutated IgVH sequence was also noted in memory and MZ-B derived LCLs further suggesting ongoing mutational activity. Consistent with this, activation-induced cytidine deaminase (AID) expression was upregulated in transformants as assessed by real time RT-PCR. Our in vitro data is therefore compatible with a model of EBV persistence where the virus infects all mature B cell subsets but then drives infected naïve B cells to acquire a memory genotype by inducing SHM. In addition, EBV infected naïve and MZ-B cells may undergo Ig class switching to acquire the IgD− CD27+ memory phenotype in the presence of T cell help in vivo. EBV’s ability to induce SHM may also contribute to the lymphomagenic potential of the virus in addition to its B cell transforming and growth promoting properties.
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Simonetti, Giorgia, Amanda Carette, Haowei Wang, Mark Shlomchik, and Ulf Klein. "The Irf4 Gene, a Susceptibility Locus for Chronic Lymphocytic Leukemia (CLL), Controls Establishment of Follicular and Marginal Zone B Cell Compartments in Mice." Blood 118, no. 21 (November 18, 2011): 285. http://dx.doi.org/10.1182/blood.v118.21.285.285.
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Abstract Abstract 285 Chronic lymphocytic leukemia (CLL) originates from the malignant transformation of mature B cells. Recently, single nucleotide polymorphisms (SNPs) in the 3'UTR region of the Irf4 gene have been associated with an increased risk of developing CLL in independent patient cohorts. IRF4 is a member of the interferon regulatory factor (IRF) family of transcription factors, and in the B lineage is essential for plasma cell differentiation in T-dependent immune responses. Irf4 has been demonstrated to act as an oncogene in multiple myeloma. Conversely, evidence suggests that the corresponding SNPs in the Irf4 gene lead to a reduction of IRF4 mRNA expression, and it was reported that tumor cells in half of CLL cases show reduced IRF4 protein expression compared to normal B cells. Together, these observations suggest that aberrant downregulation of IRF4 expression in mature B cells may contribute to CLL development. However, the normal function of IRF4 in mature B cells is incompletely understood. In order to investigate how IRF4 deficiency affects the biology of mature B cells, we investigated the consequences of deleting Irf4 specifically in B cells in vivo using a conditional Irf4 knockout mouse line. We and others had previously observed that Irf4−/− mice develop an expansion of B cells with a marginal zone (MZ) phenotype (IgMhiIgDloCD23–CD21+). By demarcating the MZ with the MOMA-1 marker, we here show that B cells in Irf4−/− mice localized preferentially in the MZ area, causing MZ hyperplasia. In contrast, the area where follicular B cells normally home contained few B cells. B cell autonomy of the observed phenotype was ascertained by crossing a “floxed” Irf4 allele with CD19-Cre mice to achieve B cell conditional deletion. We then crossed the floxed Irf4 allele with a transgenic mouse that allows inducible deletion of Irf4 specifically in B cells. Whereas flow-cytometric analysis revealed an unchanged ratio between cells with a follicular (IgMloIgDhiCD23+CD21int) vs. a MZ B cell surface phenotype upon Irf4 deletion, immunohistochemical (IHC) stainings of spleen sections for a marker protein (eGFP) that signals gene deletion demonstrated that the Irf4-deleted cells localized preferentially in the MZ, leading to MZ hyperplasia. Together, these results suggest that deletion of Irf4 in B cells alters chemokine responsiveness and migratory capacity. In agreement, global gene expression profile analysis of B cells purified from Irf4−/− and Irf4+/+ mice identified a set of differentially expressed genes with known functions in cell migration and homing. Notably, PLXND1 and the chemokine receptor CXCR7 showed 4.5 and 6.5-fold upregulation, respectively, while the G protein coupled receptor RGS13 and the adhesion molecule ALCAM (CD166) showed 3.5 and 5-fold downregulation in Irf4−/− vs. Irf4+/+ B cells. Unexpectedly, we observed in the profiling analysis that expression of the known NOTCH target genes Deltex1 and Hes5 was significantly upregulated (3 and 5-fold) in Irf4−/− vs. Irf4+/+ B cells. Despite unchanged NOTCH1 and NOTCH2 mRNA levels, Western blot and immunofluorescence analysis showed that Notch2, a gene known to be indispensible for MZ B cell development, was strongly upregulated in Irf4−/− B cells, suggesting that IRF4 is indirectly involved in NOTCH2 repression at a post-transcriptional level. Together with the altered migratory properties of Irf4−/− vs. Irf4+/+ B cells, these findings indicate that a balanced expression of IRF4 and NOTCH2 in B cells is required for establishing the follicular and MZ B cell compartments in mice, and suggest that IRF4 maintains the cellular identity of follicular B cells. The results may have implications for understanding CLL pathogenesis, as both NOTCH1 and NOTCH2 transmembrane receptors were reported to be expressed and activated in CLL B cells, and since NOTCH1 was recently found to be aberrantly activated in a fraction of CLL cases due to genetic mutations. Alterations in the balance of the transcriptional network established by NOTCH and IRF4 either through mutations, polymorphisms, or microenvironmental factors may disrupt normal B cell physiology and thereby contribute to tumorigenesis by an as yet unknown mechanism. Recently, a small fraction of CLL patients were identified that have a recurrent heterozygous somatic mutation in exon 2 of Irf4, providing additional rationale for determining how alterations in IRF4 function may promote CLL pathogenesis. Disclosures: No relevant conflicts of interest to declare.
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Xochelli, Aliki, Vasilis Bikos, Eleftheria Polychronidou, Andreas Agathangelidis, Frederic Charlotte, Panagiotis Moschonas, Zadie Davis, et al. "Unique Versus Common: Disease-Biased Immunoglobulin Gene Repertoires Along with Public Antigen Receptor Stereotypes in Marginal Zone B-Cell Lymphoproliferations." Blood 126, no. 23 (December 3, 2015): 1479. http://dx.doi.org/10.1182/blood.v126.23.1479.1479.
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Abstract B cells residing the marginal zone (MZ) provide a first line of defense against blood borne pathogens, producing the greater part of circulating natural antibodies conferring protection against infection. Dysregulated homeostasis and function of MZ B cells has been implicated in a wide range of B lymphoproliferations, encompassing the distinct MZ lymphomas recognized by the WHO Classification, the related provisional entities and even chronic lymphocytic leukemia (CLL), for which a MZ derivation has been proposed. Here, taking advantage of a large multi-institutional series, we aimed at obtaining insight into the ontogenetic relationship of MZ lymphoproliferations, related entities and CLL through cross-comparison of their B cell receptor immunoglobulin (BcR IG) gene repertoires. Our sequence dataset included 3660 unique IGHV-IGHD-IGHJ gene rearrangement sequences from our collaborative centers and/or public databases derived from: (1) MZ lymphomas: splenic (SMZL), n=379; nodal (NMZL), n=37; extranodal (ENMZL), n=95; (2) provisional entities of postulated MZ origin, including splenic diffuse red pulp lymphoma (SDRL, n=16) and clonal B cell lymphocytosis of MZ origin (CBL-MZ, n=60); (3) persistent polyclonal B cell lymphocytosis (PPBL), n=286 (from 2 cases); (4) MZ cells isolated from six spleen specimens free of neoplastic cells at histological inspection (non-malignant MZ), obtained at surgery for cancer, n=489; (5) autoimmune conditions, n=1243; (6) various types of normal B cells, n=1055. The most pronounced IG gene repertoire skewing was observed in SMZL with the IGHV1-2*04 gene accounting for 26% of cases. Restrictions, though less striking, were also identified in the other MZ lymphomas as well: (i) the IGHV4-34 gene predominated in NMZL (14.3%); and, (ii) the IGHV1-69 gene predominated in ENMZL (14.6%), albeit with significantly different distribution depending on the primary site of involvement, ranging from 38% in salivary ENMZL to 11% in gastric ENMZL to 4% in ocular adnexa ENMZL (p<0.01). The vast majority of MZL cases showed at least some impact of somatic hypermutation (SHM), with the proportion of cases lacking any SHM ranging from 0% in salivary ENMZ to only 13% in SMZL. Following established bioinformatics approaches, we searched for stereotyped BcR IG sequences i.e. IGHV-IGHD-IGHJ gene rearrangements with restricted antigen-binding site sequence motifs. For the purposes of this analysis, the present sequence dataset was cross-compared to a large dataset of 20451 IGHV-IGHD-IGHJ gene rearrangement sequences from CLL patients from the IMGT/CLL-DB. Overall, 6437 different clusters with stereotyped BcR IG sequences were identified in the merged dataset, including from only 2 to more than 350 sequences. Two categories of clusters with stereotyped BcR IG were identified: disease-specific (n=4813) and 'mixed' (n=1624) i.e. comprised of cases with different diagnosis. The great majority of clusters in the former category concerned exclusively CLL and corresponded to well-established CLL stereotyped subsets, while only a small minority concerned exclusively MZ lymphomas, all with a diagnosis of SMZL. Mixed clusters were relatively small in size, with only 4 populated by more than 10 cases; of these, 2 utilized the IGHV1-69 gene, while the remaining 2 utilized the IGHV3-7 and IGHV4-59 gene, respectively. They comprised rearrangements from various entities, including SMZL, ENMZL (gastric, salivary gland, ocular adnexa), CLL, hepatitis C virus-associated diffuse large B cell lymphoma (DLBCL), but also rheumatoid factors and non-malignant spleen MZ cells. Notably, shared (recurrent) amino acid changes introduced by SHM (i.e. the same amino acid replacement at the same position) were identified in each mixed cluster. In conclusion, we document different immunogenetic signatures for MZ lymphomas, with limited overlap both amongst the various distinct and provisional WHO entities but also versus CLL. These findings indicate distinct antigen exposure histories and/or different (micro)environments underlying the ontogeny of MZ lymphomas. That said, the existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms, may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Disclosures Ghia: Janssen Pharmaceuticals: Research Funding.
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Tusche, Michael W., Lesley A. Ward, Frances Vu, Doug McCarthy, Miguel Quintela-Fandino, Jurgen Ruland, Jennifer L. Gommerman, and Tak W. Mak. "Differential requirement of MALT1 for BAFF-induced outcomes in B cell subsets." Journal of Experimental Medicine 206, no. 12 (November 16, 2009): 2671–83. http://dx.doi.org/10.1084/jem.20091802.
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B cell activation factor of the TNF family (BAFF) activates noncanonical nuclear factor κB (NF-κB) heterodimers that promote B cell survival. We show that although MALT1 is largely dispensable for canonical NF-κB signaling downstream of the B cell receptor, the absence of MALT1 results in impaired BAFF-induced phosphorylation of NF-κB2 (p100), p100 degradation, and RelB nuclear translocation in B220+ B cells. This corresponds with impaired survival of MALT1−/− marginal zone (MZ) but not follicular B cells in response to BAFF stimulation in vitro. MALT1−/− MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor–mediated signaling, and TRAF3 was found to interact with MALT1. Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numbers, elevated serum immunoglobulin titers, and spontaneous germinal center formation, were found to be dependent on B cell–intrinsic MALT1 expression. Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction.
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Gorelik, Leonid, Kevin Gilbride, Max Dobles, Susan L. Kalled, Daniel Zandman, and Martin L. Scott. "Normal B Cell Homeostasis Requires B Cell Activation Factor Production by Radiation-resistant Cells." Journal of Experimental Medicine 198, no. 6 (September 15, 2003): 937–45. http://dx.doi.org/10.1084/jem.20030789.
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The cellular source of B cell activation factor (BAFF) required for peripheral B cell survival/maturation is unknown. To determine the nature of BAFF-producing cells we established and analyzed reciprocal bone marrow (BM) chimeras with wild-type (WT) and BAFF-deficient mice. The results revealed that BAFF production by radiation-resistant stromal cells is completely sufficient to provide a necessary signal for B cell survival/maturation, as BAFF−/− BM cells transferred into lethally irradiated WT mice gave rise to normal numbers of follicular (FO) and marginal zone (MZ) B cell subpopulations. On the other hand, transfer of WT BM into BAFF−/− lethally irradiated mice resulted only in minimal reconstitution of mature FO B cells and no restoration of MZ B cells. Thus, in the absence of BAFF+/+ stromal cells, BAFF production by BM-derived cells, presumably by macrophages, dendritic cells, and/or neutrophils, was not at all sufficient to support normal B cell homeostasis. Interestingly, immunization of both types of chimeras stimulated high levels of antigen-specific antibody secretion, indicating that either stromal cell– or hematopoietic cell–derived BAFF is sufficient for B cell antibody responses.
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Wang, Hongsheng, Jianxun Feng, Chang Hoon Lee, and Herbert Morse. "B Cell Lineage-Specific Deletion of Icsbp/IRF8 Reveals Roles for IRF8 in the Regulation of Marginal Zone and Follicular B Cell Development." Blood 110, no. 11 (November 16, 2007): 1334. http://dx.doi.org/10.1182/blood.v110.11.1334.1334.
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Abstract Interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein (ICSBP), is a transcription factor that expresses in T cells, B cells and macrophages and plays a role in myeloid development. Targeted deletion of IRF8 in mice (IRF8−/−) induced progressive increase in the numbers of granulocytes in various lymphoid organs and development of a syndrome similar to human chronic myelogenous leukemia. In addition to defective development of macrophages and dendritic cells, B cell development was also impaired in IRF8−/− mice. This includes decreased numbers of early B cells, expanded marginal zone (MZ) B cells and diminished follicular (OF) B2 cells. Because abnormal myeloid cells could alter microenvironment required for normal B cell development, we have generated IRF8 conditional knockout mice to specifically investigate the function of IRF8 in B lineage cells. Mice were engineered to have exon 2, encoding the DNA binding domain of IRF8, flanked by loxP sites (designated IRF8f/+). These mice were then crossed with the CD19Cre strain in which the expression of Cre-recombinase is controlled by the endogenous CD19 locus. Homozygous mice (designated (IRF8f/f x Cre)F1) underwent germline excision of IRF8 in CD19+ B lineage cells. As a result, there was no detectable mRNA and protein of IRF8 in their splenic B cells. Flow cytometry analysis revealed expanded MZ B cells and reduced OF B2 cells in the spleen of (IRF8f/f x Cre)F1 mice. Interestingly, the expression level of CD23 on OF B cells was significantly decreased in (IRF8f/f x Cre)F1 mice, indicating that IRF8 is required for maintaining a normal OF phenotype. In the peritoneum of (IRF8f/f x Cre)F1 mice, while the numbers of B1a and B2 cells were slightly decreased, the number of B1b cells was slightly increased. Furthermore, BXH2 mice carrying a mutation (C915T) in the Icsbp1 gene exhibited similar expansion of MZ B cells and low expression of CD23 in OF B cells. Taken together, these analyses indicate that IRF8 is required for development of normal MZ and B2 cells.
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Attygalle, Ayoma D., Hongxiang Liu, Sima Shirali, Timothy C. Diss, Christoph Loddenkemper, Harald Stein, Ahmet Dogan, Ming-Qing Du, and Peter G. Isaacson. "Atypical marginal zone hyperplasia of mucosa-associated lymphoid tissue: a reactive condition of childhood showing immunoglobulin lambda light-chain restriction." Blood 104, no. 10 (November 15, 2004): 3343–48. http://dx.doi.org/10.1182/blood-2004-01-0385.
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Abstract Mucosa-associated lymphoid tissue (MALT) lymphomas usually arise at sites of acquired MALT and are uncommon in native MALT (eg, Peyer patches and tonsil). Malignancy in these low-grade lymphomas is often inferred by immunoglobulin light-chain restriction and expression of CD43; molecular genetic evidence is sought only if these are in doubt. We report 6 cases (4 tonsils, 2 appendixes) of marginal zone (MZ) hyperplasia in children aged 3 to 11 years that, despite histologic and immunophenotypic features indicative of lymphoma, were polyclonal by molecular analysis. No lymphoma-directed therapy was given and patients remain alive and well (5 cases, median follow-up 35.3 months). The involved tonsil and appendix showed florid MZ hyperplasia with prominent intraepithelial B cells (IEBCs). The MZ B cells and IEBCs showed a high-proliferation fraction and a CD20+, CD21+, CD27-, immunoglobulin (Ig) superfamily receptor translocation-associated 1-positive (IRTA-1+), CD43+, multiple myeloma oncogene 1 (MUM-1), IgM+D+ phenotype. Polymerase chain reaction (PCR), cloning, and sequencing of rearranged IgH and Igλ genes (whole tissue sections [6 cases]; microdissected cells [2 cases]) showed that the MZ B cells and IEBCs were polyclonal and the IgH genes nonmutated. In contrast, MZ (intraepithelial) B cells of 6 control tonsils had a similar immunophenotype, except for expression of CD27 and polytypic light chains, whereas molecular studies showed that they were polyclonal with mutated Ig genes. (Blood. 2004;104:3343-3348)
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Chen, Yan, Yishu Yang, Min Sun, Zhuohong Yan, Xiaoli Cui, Ge Zhang, Stephan W. Morris, and Quangeng Zhang. "Inhibition of Caspase-8 Activity Caused by Overexpression of BCL10 Contributes to the Pathogenesis of High-Grade MALT Lymphoma,." Blood 118, no. 21 (November 18, 2011): 3694. http://dx.doi.org/10.1182/blood.v118.21.3694.3694.
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Abstract Abstract 3694 Mucosa-associated lymphoid tissue (MALT) lymphoma comprises approximately 8% of all non-Hodgkin lymphomas and is the most common lymphoma in the gastrointestinal tract. B-cell lymphoma/leukemia 10 (BCL10) overexpression and nuclear expression has been associated with high-grade MALT lymphomas unresponsive to H. pylori eradication treatment. To explore the molecular mechanism of BCL10 overexpression on the pathogenesis and malignant phenotype of MALT lymphoma, we generated EμSR-BCL10 transgenic mice. Results in our previous report showed that predisposition to marginal zone B-cell lymphoma (MZL) development was enhanced in these transgenic mice. MALT lymphoma precursor cells - marginal zone (MZ) B cells - are expanded in BCL10 transgenic mice. Constitutive activation of both canonical and noncanonical NF-κB pathways was identified in these MZ B cells. Elevated expression of BAFF, a NF-κB downstream gene, may be in part responsible for increased tumor cell survival in MALT lymphomas. In this continuing study, quantitative analysis of BCL10 protein levels and the extent of MZ B cell expansion in heterozygous (Tg/+) and homozygous (Tg/Tg) EμSR-BCL10 transgenic mice demonstrated a direct pathogenic effect of BCL10 protein on MALT lymphomagenesis. The activities of caspase-8 and caspase-3, but not caspase-9, were inhibited with increasing BCL10 protein levels in a dose-dependent manner. Apoptosis induced by anti-IgM was selectively inhibited in MZ B cells from transgenic mice, but no differences were observed following treatment with dexamethasone, γ-irradiation or anti-CD95, implying that overexpressed BCL10 exerts anti-apoptotic effects through the B-cell antigen receptor pathway. Expression of API2, another NF-κB downstream gene, was also elevated in a dose-dependent manner with BCL10 protein level in the MZ B cells. Overexpressed BCL10 protein co-immunoprecipitated with caspase-8 and API2, suggesting an in vivo interaction leading to inhibition of caspase-8 activity. Our current data suggests a novel effect of overexpressed BCL10 in the pathogenesis of high-grade MALT lymphoma by increasing expression of API2 and recruitment of API2 and caspase-8 to form a protein complex leading to the suppression of caspase-8 activity in MZ B cells. Disclosures: No relevant conflicts of interest to declare.
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Fontaine, Julie, Josiane Chagnon-Choquet, Han Sang Valcke, Johanne Poudrier, and Michel Roger. "High expression levels of B lymphocyte stimulator (BLyS) by dendritic cells correlate with HIV-related B-cell disease progression in humans." Blood 117, no. 1 (January 6, 2011): 145–55. http://dx.doi.org/10.1182/blood-2010-08-301887.
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AbstractIn view of assessing the possible contribution of dendritic cells (DCs) to HIV-related B-cell disorders, we have longitudinally measured B lymphocyte stimulator (BLyS) surface expression by myeloid DCs (mDCs) and concentrations of B-cell growth factors in the blood of subjects undergoing primary HIV infection with different rates of disease progression. We report that BLyS surface expression by mature mDCs and precursors as well as blood levels of BLyS, a proliferation-inducing ligand (APRIL), interleukin-6 (IL-6), and IL-10 increased above normal levels in both rapid and normal HIV progressors as quickly as in the acute phase of infection and persisting throughout the course of disease despite successful therapy. Consequently, hyperglobulinemia and high blood levels of circulating activated mature B cells and precursor/activated marginal zone (MZ)–like B cells were found throughout follow-up for both rapid and normal progressors. In contrast, mDC cell-surface expression of BLyS as well as blood levels of BLyS, immunoglobulin, activated mature B cells, and precursor/activated MZ-like B cells in aviremic slow progressors were similar to those observed in healthy donors. Interestingly, the levels of mature MZ B cells were significantly reduced in slow progressors. Our results suggest that DCs might modulate the outcome of the HIV-related B-cell disease progression through the expression of BLyS.
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Seo, Sachiko, Takashi Asai, Toshiki Saito, Takahiro Suzuki, Motoshi Ichikawa, Seishi Ogawa, Mineo Kurokawa, Shigeru Chiba, and Hisamaru Hirai. "Cas-L/Hef1 Is Required for Marginal Zone B Cell Maintenance and Lymphocyte Trafficking." Blood 106, no. 11 (November 16, 2005): 3920. http://dx.doi.org/10.1182/blood.v106.11.3920.3920.
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Abstract Cas-L (Crk-associated substrate lymphocyte type) which is also known as Hef1 (human enhancer of filamentation 1) was first identified as a protein tyrosine-phosphorylated upon stimulation of b1 integrin. Cas-L possesses a single Src homology (SH) 3 domain and multiple YXXP motifs (substrate domain) as a member of Cas protein family, and is well expressed in peripheral lymphocytes. Previous studies suggest that Cas-L might be involved in Bcr-Abl positive leukemia and adult T cell leukemia. However, the biological function of Cas-L in lymphocytes is little known. We generated Cas-L-deficient mice using a gene targeting strategy. The mice showed a deficit of marginal zone (MZ) B cells and a decrease of cell number in secondary lymphoid organs. To elucidate the mechanism of the MZ B cell defect, the reciprocal bone marrow transfer assays were performed. The results revealed that the defect of MZ B cells in Cas-L-deficient mice is cell autonomous. Next, we analyzed B cell receptor signaling by measurement of intracellular Ca2+ concentration and lymphocyte proliferation. However, we could not find any significant differences between wild type and Cas-L-deficient mice. Cas-L-deficient lymphocytes showed reduced chemotactic response to CXCL12 and CXCL13. The adhesion assay also showed the decreased adhesiveness to VCAM-1 and ICAM-1, which are important for retention of MZ B cells in spleen. Moreover, we found that the lymphocyte trafficking to spleen and lymph nodes was altered in Cas-L-deficient mice. Thus, Cas-L affects homeostasis of MZ B cells and peripheral lymphoid organs, which is considered to be relevant to impaired lymphocyte migration and adhesion.
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Amezcua Vesely, María C., Daniela A. Bermejo, Carolina L. Montes, Eva V. Acosta-Rodríguez, and Adriana Gruppi. "B-Cell Response during Protozoan Parasite Infections." Journal of Parasitology Research 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/362131.
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In this review, we discuss how protozoan parasites alter immature and mature B cell compartment. B1 and marginal zone (MZ) B cells, considered innate like B cells, are activated during protozoan parasite infections, and they generate short lived plasma cells providing a prompt antibody source. In addition, protozoan infections induce massive B cell response with polyclonal activation that leads to hypergammaglobulnemia with serum antibodies specific for the parasites and self and/or non related antigens. To protect themselves, the parasites have evolved unique ways to evade B cell immune responses inducing apoptosis of MZ and conventional mature B cells. As a consequence of the parasite induced-apoptosis, the early IgM response and an already establish humoral immunity are affected during the protozoan parasite infection. Moreover, some trypanosomatides trigger bone marrow immature B cell apoptosis, influencing the generation of new mature B cells. Simultaneously with their ability to release antibodies, B cells produce cytokines/quemokines that influence the characteristic of cellular immune response and consequently the progression of parasite infections.
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Chen, Yuhong, Mei Yu, Andrew Podd, Renren Wen, Magdalena Chrzanowska-Wodnicka, Gilbert C. White, and Demin Wang. "A critical role of Rap1b in B-cell trafficking and marginal zone B-cell development." Blood 111, no. 9 (May 1, 2008): 4627–36. http://dx.doi.org/10.1182/blood-2007-12-128140.
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Abstract B-cell development is orchestrated by complex signaling networks. Rap1 is a member of the Ras superfamily of small GTP-binding proteins and has 2 isoforms, Rap1a and Rap1b. Although Rap1 has been suggested to have an important role in a variety of cellular processes, no direct evidence demonstrates a role for Rap1 in B-cell biology. In this study, we found that Rap1b was the dominant isoform of Rap1 in B cells. We discovered that Rap1b deficiency in mice barely affected early development of B cells but markedly reduced marginal zone (MZ) B cells in the spleen and mature B cells in peripheral and mucosal lymph nodes. Rap1b-deficient B cells displayed normal survival and proliferation in vivo and in vitro. However, Rap1b-deficient B cells had impaired adhesion and reduced chemotaxis in vitro, and lessened homing to lymph nodes in vivo. Furthermore, we found that Rap1b deficiency had no marked effect on LPS-, BCR-, or SDF-1–induced activation of mitogen-activated protein kinases and AKT but clearly impaired SDF-1–mediated activation of Pyk-2, a key regulator of SDF-1–mediated B-cell migration. Thus, we have discovered a critical and distinct role of Rap1b in mature B-cell trafficking and development of MZ B cells.
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Chorny, Alejo, Sandra Casas-Recasens, Jordi Sintes, Meimei Shan, Nadia Polentarutti, Ramón García-Escudero, A. Cooper Walland, et al. "The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells." Journal of Experimental Medicine 213, no. 10 (September 12, 2016): 2167–85. http://dx.doi.org/10.1084/jem.20150282.
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Pentraxin 3 (PTX3) is a fluid-phase pattern recognition receptor of the humoral innate immune system with ancestral antibody-like properties but unknown antibody-inducing function. In this study, we found binding of PTX3 to splenic marginal zone (MZ) B cells, an innate-like subset of antibody-producing lymphocytes strategically positioned at the interface between the circulation and the adaptive immune system. PTX3 was released by a subset of neutrophils that surrounded the splenic MZ and expressed an immune activation–related gene signature distinct from that of circulating neutrophils. Binding of PTX3 promoted homeostatic production of IgM and class-switched IgG antibodies to microbial capsular polysaccharides, which decreased in PTX3-deficient mice and humans. In addition, PTX3 increased IgM and IgG production after infection with blood-borne encapsulated bacteria or immunization with bacterial carbohydrates. This immunogenic effect stemmed from the activation of MZ B cells through a neutrophil-regulated pathway that elicited class switching and plasmablast expansion via a combination of T cell–independent and T cell–dependent signals. Thus, PTX3 may bridge the humoral arms of the innate and adaptive immune systems by serving as an endogenous adjuvant for MZ B cells. This property could be harnessed to develop more effective vaccines against encapsulated pathogens.
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Pirgova, Gabriela, Anne Chauveau, Andrew J. MacLean, Jason G. Cyster, and Tal I. Arnon. "Marginal zone SIGN-R1+macrophages are essential for the maturation of germinal center B cells in the spleen." Proceedings of the National Academy of Sciences 117, no. 22 (May 18, 2020): 12295–305. http://dx.doi.org/10.1073/pnas.1921673117.
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The mechanisms that regulate germinal center (GC) B cell responses in the spleen are not fully understood. Here we use a combination of pharmacologic and genetic approaches to delete SIGN-R1+marginal zone (MZ) macrophages and reveal their specific contribution to the regulation of humoral immunity in the spleen. We find that while SIGN-R1+macrophages were not essential for initial activation of B cells, they were required for maturation of the response and development of GC B cells. These defects could be corrected when follicular helper T (Tfh) cells were induced before macrophage ablation or when Tfh responses were enhanced. Moreover, we show that in the absence of SIGN-R1+macrophages, DCIR2+dendritic cells (DCs), which play a key role in priming Tfh responses, were unable to cluster to the interfollicular regions of the spleen and were instead displaced to the MZ. Restoring SIGN-R1+macrophages to the spleen corrected positioning of DCIR2+DCs and rescued the GC B cell response. Our study reveals a previously unappreciated role for SIGN-R1+macrophages in regulation of the GC reaction and highlights the functional specification of macrophage subsets in the MZ compartment.
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Meyer-Bahlburg, Almut, Sarah F. Andrews, Karl O. A. Yu, Steven A. Porcelli, and David J. Rawlings. "Characterization of a late transitional B cell population highly sensitive to BAFF-mediated homeostatic proliferation." Journal of Experimental Medicine 205, no. 1 (January 7, 2008): 155–68. http://dx.doi.org/10.1084/jem.20071088.
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We have characterized a distinct, late transitional B cell subset, CD21int transitional 2 (T2) B cells. In contrast to early transitional B cells, CD21int T2 B cells exhibit augmented responses to a range of potential microenvironmental stimuli. Adoptive transfer studies demonstrate that this subset is an immediate precursor of both follicular mature and marginal zone (MZ) B cells. In vivo, a large percentage of CD21int T2 B cells has entered the cell cycle, and the cycling subpopulation exhibits further augmentation in mitogenic responses and B cell-activating factor of the TNF family (BAFF) receptor expression. Consistent with these features, CD21int T2 cells exhibit preferential responses to BAFF-facilitated homeostatic signals in vivo. In addition, we demonstrate that M167 B cell receptor (BCR) idiotypic-specific B cells are first selected within the cycling CD21int T2 population, ultimately leading to preferential enrichment of these cells within the MZ B cell compartment. These data, in association with the coordinate role for BAFF and microenvironmental cues in determining the mature BCR repertoire, imply that this subset functions as a unique selection point in peripheral B cell development.
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Erdogan, S., M. Erlandsson, N. Oparina, C. Lundquist, C. Wasen, M. Svensson, M. Bemark, K. M. Andersson, and M. I. Bokarewa. "OP0026 IGF1R DEPENDENT CELL INTERACTION AND REGULATION OF AUTOANTIBODY PRODUCTION IN RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 14.2–14. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2440.
Full textAbstract:
Background:The insulin-like growth factor 1 receptor (IGF1R) signalling mediates numerous developmental processes acting through downstream adaptor molecules IRS1/2, which activate Akt and inhibit the family of forkhead box class O (FoxO). Inhibition of IGF1R signalling alleviates rheumatoid arthritis (RA) (Erlandsson et al., 2017), however, the role of IGF1R signalling in the regulation of immune function is poorly understood.Objectives:To investigate the link between IGF1R signalling and antigen presentation in experimental arthritis.Methods:Arthritis was induced by immunising Balb/c mice with methylated bovine serum albumin (mBSA, n=18) and DBA/1 mice with type II collagen (CII, n=18). The mice were treated with a synthetic IGF1R inhibitor NT157 or with short hairpin RNA targeting IGF1R (shIGF1R) from the day prior to immunisation. Controls were treated with cyclodextrine vehicle/ non-targeting (nt)RNA, respectively. Flow cytometry was used for spleen cell phenotype. Antibody levels were measured by ELISA. Immunohistochemistry (IHC) of spleen was performed for assessment of marginal zone (MZ) and location of pS612IRS1+ and pS256FoxO1+ cells. IHC images were acquired by fluorescent confocal microscopy, and analysed using ZEN2009 and Cell Profiler soft ware.Results:The inhibition of IGF1R resulted in an 80% increase in MZ area in NT157-treated mice compared to controls (p=0.0001). This was supported by a significant increase of CD21+ (p=0.034) and CD23+ cell populations (p=0.00059), both among the CD19+ B cells and antigen-presenting MHCII+CD19- cells, implying that IGF1R expression regulates the populations of MZ and follicular cells. Additionally, there was a strong positive correlation between the decrease of IGF1R+ and ICOSL+ population on CD21+ cells (r=0.70, p=0.0071), which retained them in the MZ and prolonged communication with macrophages. Insufficient feedback from ICOSL- B cells limited expression of CXCR5 on CD4 cells. The IHC analysis displayed that, IGF1R inhibition led to abundance of inactivate pS612IRS1+ and pS256FoxO1+ cells within the MZ, compared with controls (p=0.0002). Alongside the increase of IgM+ B cell population (p=0.0022), we observed significant increase in number of antigen-presenting F4/80+ cells (p=0.043) and MARCO expression (p=0.043) after IGF1R intervention. Finally, the NT157- treated mice displayed a significant pleiotropic increase in IgM autoantibody production, with anti-CCP IgM (p=0.027), RF-IgM (p=0.0085), anti-DNA IgM (p=0.066) and in total IgM (p=0.027) levels, which correlated positively with pS256FoxO1+ cells (r=0.51, p=0.03). Levels of IgG were not changed.Conclusion:We show that IGF1R signalling is important for immune cell communication after antigen challenge. IGF1R controls ICOSL dependent trafficking of B cells through the MZ and facilitates interaction with T cells. Retention of B cells in the MZ tips the balance from T cell to macrophage-dependent processes, which permits the formation of autoantibody producing B cells.References:[1]Erlandsson, M., et.al., 2017. IGF-1R signalling contributes to IL-6 production and T cell dependent inflammation in rheumatoid arthritis. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1863(9), pp.2158-2170.Disclosure of Interests:None declared