Ligation of tumour-produced mucins to CD22 dramatically impairs splenic marginal zone B-cells

2009 ◽  
Vol 417 (3) ◽  
pp. 673-683 ◽  
Author(s):  
Munetoyo Toda ◽  
Risa Hisano ◽  
Hajime Yurugi ◽  
Kaoru Akita ◽  
Kouji Maruyama ◽  
...  
Keyword(s):  
Sialic Acid ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Signalling ◽  
Negative Regulator ◽  
Mammary Adenocarcinoma ◽  
Marginal Zone B Cells ◽  
Tumour Bearing

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.

scholarly journals Autoreactive marginal zone B cells are spontaneously activated but lymph node B cells require T cell help

2006 ◽  
Vol 203 (8) ◽  
pp. 1985-1998 ◽  
Author(s):  
Laura Mandik-Nayak ◽  
Jennifer Racz ◽  
Barry P. Sleckman ◽  
Paul M. Allen
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
B Cell Tolerance ◽  
Marginal Zone B Cells ◽  
T Cell Help

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.

RhoH-Deficient Mice Show Altered B Cell Populations In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2307-2307
Author(s):  
Abel Sanchez-Aguilera ◽  
Jose Cancelas ◽  
David A. Williams
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Receptor ◽  
Wild Type ◽  
Marginal Zone B Cells

Abstract RhoH is a GTPase-deficient, hematopoietic-specific member of the family of Rho GTPases (Li et al, 2002). RhoH has been described as regulating proliferation and engraftment of hematopoietic progenitor cells (Gu et al, 2005) and integrin-mediated adhesion in T cells (Cherry et al, 2004). Additionally, RhoH plays a critical role in T-cell development and T-cell receptor signaling (Gu et al, 2006; Dorn et al, 2007). However, the potential role of RhoH in the differentiation and biological functions of B cells are unknown. To answer these questions, we analyzed the B-cell phenotype of RhoH−/− mice and the in vitro properties of RhoH-deficient splenic B cells compared to their wild-type counterparts. RhoH−/− mice showed increased B-cell numbers in the bone marrow, mainly due to an increase in the number of pro-B, pre-B and immature B cells. In the spleen, lymph nodes and peripheral blood, RhoH−/− mice showed a significant decrease in the number of follicular (B-2) cells (B220+ CD93– IgDhigh CD21low). The number of splenic marginal zone B cells (B220+ CD93– IgDlow CD21high), plasma cells (CD93– CD38+ CD138+) in bone marrow and spleen, and B-1 cells (IgM+ CD5+) in peritoneal cavity were not significantly different from those in wild-type animals. These alterations have functional significance, since the serum concentrations of IgM and IgG1 were significantly lower in RhoH−/− mice. However, splenic B cells isolated from RhoH−/− mice did not show any significant differences in their in vitro activation by anti-IgM, CD40 ligation or IL-4 stimulation, nor did they differ in their proliferative response to lipopolysaccharide. In vitro migration of RhoH-deficient B cells in response to CXCL12 or CXCL13 was similar to that of wild-type B cells. Given the important role of RhoH in signal transduction downstream the T cell receptor, we investigated the possible role of RhoH in B cell receptor signaling. Although total splenic B cells from RhoH−/− mice showed markedly increased phosphorylation of SYK and ERK after anti-IgM stimulation compared to wild-type B cells, sorted populations of splenic B-2 and marginal zone B cells from RhoH−/− and wild-type animals did not differ in the activation of these kinases, suggesting that the observed difference can be attributed to the different cellular composition of the B cell compartment (i.e. B-2 vs marginal zone B cells) in RhoH−/− mice. These data imply that the phenotype observed in RhoH−/− mice may not reflect an intrinsic defect in B cells but may be attributed to crosstalk between B cells and other hematopoietic cell populations. Composition of B cell subsets in wild-type and RhoH−/− mice (total cell number ×106, ± standard deviation, N=9) Bone marrow Spleen (*) indicates p<0.05; (**), p<0.01; (***), p<0.005 RhoH+/+ RhoH−/− RhoH+/+ RhoH−/− total B cells 7.8±1.8 11.0±2.4 (**) total B cells 31.7±10.1 25.4±8.8 pro-B 0.12±0.03 0.15±0.04 (*) transitional 8.7±1.2 8.6±2.8 pre-B 2.6±0.6 3.8±0.8 (***) B-2 11.6±4.1 7.6±2.5 (*) immature 1.5±0.4 2.1±0.5 (*) marginal 3.2±1.1 3.9±1.6 mature 1.4±0.7 1.7±0.9

scholarly journals CD40 Ligand and Autoantigen Are Involved in the Pathogenesis of Low-Grade B-Cell Lymphomas of Mucosa-Associated Lymphoid Tissue

1998 ◽  
Vol 6 (3-4) ◽  
pp. 187-196 ◽  
Author(s):  
A. Greiner ◽  
C. Knörr ◽  
Y. Qin ◽  
A. Schultz ◽  
A. Marx ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lymphoid Tissue ◽  
Marginal Zone ◽  
Cd40 Ligand ◽  
Cell Interaction ◽  
Low Grade ◽  
Antigen Specificity ◽  
Marginal Zone B Cells

Low-grade MALT-type lymphomas are malignancies of mucosal marginal-zone B cells and preceded by reactive inflammatory lymphoid tissue. Experimental observations suggest that antigen and CD40 Ligand act during cognate T/B cell interaction and are crucial for germinal center B-cell maturation generating marginal-zone B cells. To investigate the mechanisms underlying the development of extranodal MALT-type lymphomas, the immunoglobulin receptor was sequenced and analyzed for antigen specificity using heterohybridoma technology. Furthermore, CD40 ligand expression was evaluated by immunohistochemistry and by semiquantitative RT-PCR, and ligand binding to the CD40 of tumor B cells was studied using the CD40 system. Hypermutations were found in low-grade lymphomas throughout CDR1- CDR3 suggestive of positive selection through their antigen receptor. Different VH families were used and more than 69% of tumor immunoglobulins bound different mucosal antigens. CD40L expression was found in the tumor marginal zone in substantial amounts. Thein vitroproliferation response of all low-grade MALT-type lymphomas was dependent on anti-CD40- mediated signals and cytokines. Our data provide evidence that autoantigen as well as the CD40L expressed by activated nonneoplastic T cells may drive the evolution of low-grade MALT-type lymphomas either directly or by paracrine mechanisms and that antigen may contribute to lymphoma pathogenesis.

scholarly journals Morphologic and Functional Effects of Gamma Secretase Inhibition on Splenic Marginal Zone B Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Maria Cristina de Vera Mudry ◽  
Franziska Regenass-Lechner ◽  
Laurence Ozmen ◽  
Bernd Altmann ◽  
Matthias Festag ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Nuclear Translocation ◽  
Recovery Period ◽  
Functional Characterization ◽  
Notch Receptor ◽  
Marginal Zone B Cells ◽  
Cell Fate Decisions

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.

Vav proteins regulate peripheral B-cell survival

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2391-2398 ◽  
Author(s):  
Elena Vigorito ◽  
Laure Gambardella ◽  
Francesco Colucci ◽  
Simon McAdam ◽  
Martin Turner
Keyword(s):  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Receptor ◽  
Cross Linking ◽  
Marginal Zone B Cells ◽  
Survival Signal ◽  
B Cell Survival ◽  
Follicular B Cells ◽  
Deficient Mice

AbstractMice lacking all 3 Vav proteins fail to produce significant numbers of recirculating follicular or marginal zone B cells. Those B cells that do mature have shortened lifespans. The constitutive nuclear factor-kappaB (NF-κB) activity of resting naive B cells required Vav function and expression of cellular reticuloendotheliosis (c-Rel). Rel-A was reduced in Vav-deficient B cells. Furthermore, expression of the NF-κB-regulated antiapoptotic genes A1 and Bcl-2 was reduced in mature Vav-deficient B cells. Overexpression of Bcl-2 restored the number of mature follicular B cells in the spleens of Vav-deficient mice. When activated by B-cell receptor (BCR) cross-linking, Vav-deficient B cells failed to activate NF-κB. Vav proteins thus regulate an NF-κB-dependent survival signal in naive B cells and are required for NF-κB function after BCR cross-linking.

Marginal Zone B Cells Mediate a CD4 T Cell Dependent Extrafollicular Antibody Response Following RBC Transfusion in Mice

Blood ◽  
2021 ◽  
Author(s):  
Patricia E Zerra ◽  
Seema R Patel ◽  
Ryan Philip Jajosky ◽  
Connie M Arthur ◽  
James W McCoy ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Antibody Response ◽  
B Cell ◽  
T Cell Activation ◽  
Antibody Formation ◽  
Marginal Zone ◽  
Cd4 T Cell ◽  
Marginal Zone B Cells ◽  
Rbc Transfusion

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 and ovalbumin fused to human 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 co-localize with marginal zone (MZ) B cells. Depletion of MZ B cells inhibited IgM and IgG anti-HOD antibody formation, while 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 MZ B cells can initiate and then contribute to RBC alloantibody formation, highlighting a unique immune pathway that can be engaged following RBC transfusion.

scholarly journals NR4A Expression by Human Marginal Zone B-Cells

Antibodies ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 50
Author(s):  
Kim Doyon-Laliberté ◽  
Josiane Chagnon-Choquet ◽  
Michelle Byrns ◽  
Matheus Aranguren ◽  
Meriam Memmi ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Population ◽  
Human Blood ◽  
Marginal Zone ◽  
Ex Vivo ◽  
Transcriptome Profiling ◽  
Marginal Zone B Cells ◽  
Healthy Donors ◽  
And Function

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.

Analysis of IgVH, BCL-6, PIM, RHO/TTF and PAX5 Mutational Status in Splenic and Nodal Marginal Zone B Cell Lymphoma Suggests a Particular B Cell Origin.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 162-162 ◽  
Author(s):  
Alexandra Traverse-Glehen ◽  
Aurelie Verney ◽  
Lucille Baseggio ◽  
Pascale Felman ◽  
Evelyne Callet-Bauchu ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Mutations ◽  
Marginal Zone ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Marginal Zone B Cells ◽  
Mutational Status ◽  
Frequent Absence

Abstract Background and Objectives Splenic and nodal marginal zone B cell lymphoma (SMZL and NMZL) have been recently identified as distinct clinicopathological entities in the WHO classification. These lymphomas entities may have a common origin in the marginal B-cell compartment of the lymphoid organs. However the precise cell of origin of marginal zone B cells, its status in the B cell differentiation pathway and the mechanisms involved in lymphomagenesis remain unclear. The most widely held view is that marginal zone B cells are mostly memory B cells. But the origin of these cells, especially the transit through germinal center pathway, remains contradictory. Somatically mutated variable-region of immunoglobulin genes and bcl-6 gene represent at this time faithful markers for exposure to the germinal center. In addition, aberrant somatic hypermutations have been suggested to contribute to the development of B-cell lymphomas, occurring in the 5′ sequence of several proto-oncogenes. Interestingly those mutation do not occur in normal germinal center B cells. Design and Methods: IgVH, BCL-6, PIM1, Rho/TTF and PAX 5 genes, highly mutated in DLBCL and other indolent lymphoma such as B-CLL, were analysed for the presence of somatic mutations from 50 marginal zone lymphoma tissue and blood samples (21 NMZL and 29 SMZL including 10 cases with numerous villous lymphoma cells in peripheral blood). According to the morphological and immunophenotypical analysis, the fraction of malignant cells in the specimen was 70% or more in all cases. Mutational analysis was restricted to the regions previously shown to contain more than 95% of mutations in DLBCL. PCR products were directly sequenced on both sides and perfomed in duplicate in two independent reactions. Results: Out of 18 NMZL cases analysed for IgVH mutational status (3 cases not analysed for IgVH) 15 cases were mutated and 21 out of 28 in SMZL cases. Mutation of BCL-6 was detected in only 1 NMZL patients (1/21) and 1 SMZL patients (1/29). For RhoH/TTF, PIM1, PAX5 the mutation average was also low with only 1 case mutated per group and per gene, with a different case mutated in each for each gene. Conclusion In summary, we demonstrate the low frequency of aberrant somatic mutations in SMZL and NMZL, suggesting that this process is probably not a major contributor to lymphomageneis. However the frequent absence of mutation in BCL6 suggest a particular differentiation pathway, as suggested before in normal marginal zone B cells, possibly without transit through the germinal center. Interestingly the relatively high frequency of VH mutated cases compared with the frequent absence of mutation of BCL6, considered as a specific germinal center tag, could suggest somatic hypermutation outside the germinal center. In addition the absence of hypermutation could be linked with the absence of recurrent translocation in SMZL and NMZL, the translocation process haveing been associated with somatic hypermutation dysfunction.

B Cells with BCL2/IGH Translocation Compose a Distinctive Cell Population That May Serve as a Reservoir of Lymphoma of Germinal Center B-Cell Type.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2050-2050
Author(s):  
Tomomi Sakai ◽  
Momoko Nishikori ◽  
Masaharu Tashima ◽  
Ryo Yamamoto ◽  
Toshio Kitawaki ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Marginal Zone ◽  
Terminal Differentiation ◽  
Follicular Dendritic Cells ◽  
Marginal Zone B Cells ◽  
Germinal Center B Cell ◽  
Follicular B Cells

Abstract BCL2/IGH translocation is a hallmark of follicular lymphoma and diffuse large B-cell lymphoma of germinal center B-cell type. Although being a strong determinant of these histological subtypes, this translocation is considered to be insufficient by itself and further gene alterations are necessary for cellular transformation. In Eμ-BCL2 transgenic (Tg) mice, B-lineage cells are increased by several-fold compared to wild-type (WT) mice, but only 5–15 % of them develop disease in the first year of life. To clarify how the BCL2 translocation contributes to the development of specific lymphoma subtypes, we created two types of chimeric mouse models to characterize the biological features of BCL2-overexpressing B cells in normal individuals. First, we introduced CD19 promoter-driven BCL2 and its mutant genes to a minor population of murine bone marrow cells by using a lentiviral vector system and transplanted into irradiated mice. BCL2-overexpressing B cells showed increased follicular and reduced marginal zone populations. The same phenotypic shift was observed in B cells introducing BCL2-Y28F mutant that retained anti-apoptotic function, but a defective mutant BCL2-G142A and a mock vector did not affect B-cell phenotype. Additionally, BCL2-introduced B cells showed decreased cell size compared to those introduced BCL2-G142A and mock vectors. To assess the functional alteration of BCL2-overexpressing B cells, TNP-Ficoll binding experiment was performed. The result showed diminished T-cell independent response in parallel with decreased marginal zone B cells. The low transformation frequency of B cells in Eμ-BCL2 Tg mice has been partly explained by their propensity to reside in the G0 phase of the cell cycle (reviewed in Oncogene, 18:5268,1999). We hypothesized that the microenvironment of B cells in Eμ-BCL2 Tg mice might be altered by abnormal B cells themselves. To evaluate the influence of the different microenvironments on BCL2-overexpressing B cells, we next made Eμ-BCL2/CAG-GFP double Tg mice and transferred their bone marrow mononuclear cells into WT or Eμ-BCL2 Tg mice. Blastic cell population of BCL2+GFP+ B cells was larger in those transferred to WT mice compared to those transferred to Eμ-BCL2 Tg mice, regardless of the same phenotypic preference toward follicular B cells. BrdU uptake experiments demonstrated continuous cell cycle progression of the BCL2+GFP+ B cells in WT mice but repressed cell cycle of those in Eμ-BCL2 Tg mice. In immunohistochemical analysis, splenic follicles were disorganized with reduced follicular dendritic cells and inadequate T cell accumulation in Eμ-BCL2 Tg mice. Functional impairment of splenic follicles in Eμ-BCL2 Tg mice might be caused by decreased marginal zone B cell subset, as the antigen capture and delivery by marginal zone B cells was reported to play an important role in the development of follicular dendritic cells. To understand the fate of BCL2-overexpressing B cells after stimulation, we finally assessed their terminal differentiation capacity in vitro. Plasma cell differentiation was suppressed in B cells derived from Eμ-BCL2 Tg mice under either LPS or anti-IgM antibody stimulation. BCL2 is reported to impede the activity of transcription factor NF-AT (Proc Natl Acad Sci93:9545,1996; Nature386:728,1997), and we found that calcineurin inhibitor FK506 suppressed plasma cell differentiation of WT B cells. Gene regulation patterns of the Eμ-BCL2+ B cells were similar to B cells stimulated in the presence of FK506 as well, suggesting that repressed terminal differentiation in Eμ-BCL2+ B cells was partly caused by the suppressed activity of NF-AT. In summary, BCL2-deregulated B cells preferentially differentiate into follicular B cells, and as a result of decreased terminal differentiation in addition to their anti-apoptotic property, they may be obliged to survive and recirculate as memory B cells, and accumulate genetic abnormalities while they repeatedly pass through the germinal center. As the germinal center is the particular site where they can counterbalance the cell cycle-retarding effect of BCL2, it may be a specific place for generating lymphoma triggered by BCL2/IGH translocation. Our results emphasize the importance of the microenvironment of pre-malignant cells during transformation process, and suggest that a simple transgenic mouse model may not be always appropriate for the study of oncogenesis.

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