Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Marginal zone B cells”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources
PubMed2005

An antibody VH gene that promotes marginal zone B cell development and heavy chain allelic inclusion.

The Ig heavy (H) chain plays a pivotal role in the regulation of primary B cell development through its association with a variety of other proteins including Igalpha and Igbeta, the surrogate light chain components and bona fide L chains, to form transmembrane signaling complexes. Little is known about how alterations in the structure of the H chain variable region influence association with these proteins, or the signaling capacity of the complexes that form. Here we describe a line of VH 'knockin' mice in which the transgene-encoded VH region differs by eight amino acid residues from the VH region in a VH knockin line we previously constructed and characterized. The transgenic H chain locus in the line of mice we characterized earlier efficiently promotes H chain allelic exclusion and all phases of primary B cell development, resulting in the generation of mature B1, marginal zone (MZ) and follicular (FO) B cell compartments. In contrast, the transgenic H chain locus in the new line fails to enforce allelic exclusion, as evidenced by the majority of peripheral B cells expressing two H chains on their surfaces. Moreover, this locus inefficiently drives bone marrow B lymphopoiesis and FO B cell development. However, this H chain locus does promote MZ B cell development, from precursors that appear to be generated during fetal and neonatal life. We discuss these data in the context of previous findings on the influence of Ig H chain structure on primary B cell development.

Animals↗
PubMed2002

CD1d on antigen-transporting APC and splenic marginal zone B cells promotes NKT cell-dependent tolerance.

CD1d-reactive NKT cells are required for the development of antigen-specific T regulatory (Tr) cells responsible for mediating systemic tolerance induced through an immune privileged site such as the eye. The aim of this study was to elucidate the cellular source of CD1d needed for NKT cell activation. Transforming growth factor beta (TGF beta)-2-treated peritoneal exudate cells (PEC) functionally resemble "eye-derived" antigen-presenting cells (APC) and contribute to the generation of Tr cells both in vitro and in vivo. However, when TGF beta-2-treated PEC were pretreated with CD1d-specific antibodies or lacked CD1d expression they failed to induce Tr cells. In addition, we show that the subpopulation of marginal zone (MZ) B cells within the spleen is necessary for induction of Tr cells and that they also must express CD1d. The role of MZ B in tolerance is novel and previously unexplored. Thus, CD1d is necessarily expressed on putative eye-derived APC and splenic MZ B cells for efficient generation of Tr cells in CD1d-reactive NKT cell-dependent tolerance.

Adoptive Transfer↗
PubMed2003

The Yaa mutation promoting murine lupus causes defective development of marginal zone B cells.

The accelerated development of systemic lupus erythematosus (SLE) in BXSB male mice is associated with the presence of an as yet unidentified mutant gene, Yaa (Y-linked autoimmune acceleration). In view of a possible role of marginal zone (MZ) B cells in murine SLE, we have explored whether the expression of the Yaa mutation affects the differentiation of MZ and follicular B cells, thereby implicating the acceleration of the disease. In this study, we show that both BXSB and C57BL/6 Yaa mice, including two different substrains of BXSB Yaa males that are protected from SLE, displayed an impaired development of MZ B cells early in life. Studies in bone marrow chimeras revealed that the loss of MZ B cells resulted from a defect intrinsic to B cells expressing the Yaa mutation. The lack of selective expansion of MZ B cells in diseased BXSB Yaa males strongly argues against a major role of MZ B cells in the generation of pathogenic autoantibodies in the BXSB model of SLE. Furthermore, a comparative analysis with mice deficient in CD22 or expressing an IgM anti-trinitrophenyl/DNA transgene suggests that the hyperreactive phenotype of Yaa B cells, as judged by a markedly increased spontaneous IgM secretion, is likely to contribute to the enhanced maturation toward follicular B cells and the block in the MZ B cell generation.

Animals↗
PubMed2002

Expansion of marginal zone B cells is not sufficient for the development of renal disease in NZBxNZW F1 mice.

The mechanisms which govern the production of autoantibodies and of tissue damage during systemic lupus (SLE) are still unclear. In the NZBxNZW F1 (BW) model of SLE glomerulonephritis, the activation and commitment of B cells are thought to play a major role in disease progression. Previous analysis has suggested that these mice have a substantial increase of marginal zone (MZ) B cells before the occurrence of the disease. Owing to the probable role of this B cell subset in autoantibody production, it was important to define the possible link between this abnormality and the occurrence of kidney damage. Using cytofluorometry analysis, we followed the splenic MZ B cell phenotype in different series of mice with shared autoimmune genetic background and histologically defined renal status. By comparing BW females and BW males, NZB and NZW mice, we confirm that BW mice have an increase in MZ B cells but this MZ B cells expansion is not directly linked to tissue lesions. Genetically modified BW female mice with a restricted repertoire of B and T cell antigen receptors, and which do not develop nephritis, exhibit the same increase of MZ B cells, suggesting that this increase does not depend on a specific set of antigens. Moreover, our analysis brings to light a pre-disease state in BW males, with autoantibody production and mesangial deposits.

Animals↗
PubMed1997

Marginal zone B-cell lymphomas including mucosa-associated lymphoid tissue type lymphoma (MALT), monocytoid B-cell lymphoma and splenic marginal zone cell lymphoma and their relation to the reactive marginal zone.

The marginal zone of the B follicle represents a well-defined compartment of the B area. Its cellular composition is distinct from that of the follicle centre, from which it also differs in its functional role in the immune response. Several newly identified lymphoma entities, e.g. extranodal MALT type lymphoma, nodal monocytoid B-cell lymphoma and splenic marginal zone B-cell lymphoma, display in common a very peculiar organoid growth pattern reminiscent of the marginal zone. Moreover, their neoplastic components share morphologic and phenotypic similarities to the cellular components of the marginal zone. The clinical characteristics of these various marginal zone cell lymphomas may differ depending of the organ which is involved. Nevertheless, they all share common cytogenetic abnormalities suggesting a common pathogenesis.

Humans↗
PubMed2005

Crk-associated substrate lymphocyte type is required for lymphocyte trafficking and marginal zone B cell maintenance.

The lymphocyte-specific Cas family protein Cas-L (Crk-associated substrate lymphocyte type) has been implicated to function in lymphocyte movement, mediated mainly by integrin signaling. However, its physiological role is poorly understood. In this study we analyzed the function of Cas-L in lymphocytes using gene-targeted mice. The mutant mice showed a deficit of marginal zone B (MZB) cells and a decrease of cell number in secondary lymphoid organs. An insufficient chemotactic response and perturbed cell adhesion were observed in Cas-L-deficient lymphocytes, suggesting that the aberrant localization was responsible for the deficit of MZB cells. Moreover, we found that lymphocyte trafficking was altered in Cas-L-deficient mice, which gave a potential reason for contraction of secondary lymphoid tissues. Thus, Cas-L affects homeostasis of MZB cells and peripheral lymphoid organs, which is considered to be relevant to impaired lymphocyte migration and adhesion.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Development of nephritis but not sialadenitis in autoimmune-prone BAFF transgenic mice lacking marginal zone B cells.

B cell-activating factor belonging to the TNF family (BAFF) is a B cell survival factor required for B cell maturation. BAFF transgenic (Tg) mice develop autoimmune disorders characterized by autoantibody production, which leads to nephritis and salivary gland destruction (sialadenitis), features reminiscent of systemic lupus erythematosus and Sjögren's syndrome (SS), respectively. Disease in BAFF Tg mice correlates with the expansion of the marginal zone (MZ) B cell compartment and the abnormal presence of MZ-like B cells in the blood, LN and inflamed salivary glands, suggesting a role for these cells in BAFF-induced autoimmunity. Lymphotoxin-beta (LTbeta)-deficient mice show disrupted splenic architecture, lack MZ B cells and some peripheral LN, and are unable to mount T cell-dependent immune responses. BAFF Tg mice lacking LTbeta (LTbetaDelta-BTg) retained these defects, yet still developed nephritis associated with the presence of B-1 B cells in the kidneys. However, in contrast to old BAFF Tg mice, aging LTbetaDelta-BTg mice no longer developed sialadenitis. Thus, autoimmune disorders in BAFF Tg mice are possibly events coordinated by MZ and B-1 B cells at separate anatomical sites.

Animals↗
PubMed2005

Splenic marginal zone B cells in humans: where do they mutate their Ig receptor?

Human IgM+ IgD+ CD27+ B cells have mutated Ig genes and harbor a splenic marginal zone (MZ) phenotype. In this issue, the group of R. Küppers has studied the expression of the enzyme activation-induced cytidine deaminase (AID) in human spleen samples by immunocytochemistry and failed to detect a significant AID-expressing subset in the MZ region. The consequences on the possible origin of these cells are discussed.

Animals↗
PubMed2005

Sphingosine 1-phosphate receptor agonist FTY720-phosphate causes marginal zone B cell displacement.

FTY720 is an immunosuppressive agent that modulates lymphocyte trafficking. It is phosphorylated in vivo to FTY720-phosphate (FTY-P) and binds to a family of G protein-coupled receptors recognizing sphingosine 1-phosphate (S1P) as the natural ligand. It has previously been reported that FTY-P blocks egress of lymphocytes from the thymus and lymph nodes, resulting in peripheral blood lymphopenia. We now report that FTY-P also causes displacement of marginal zone (MZ) B cells to the splenic follicles, an effect that is similar to that observed after in vivo administration of lipopolysaccharide. This effect is specific to B cells in the MZ, as treatment with FTY-P does not cause redistribution of the resident macrophage population. A small but statistically significant decrease in the expression of beta1 integrin on MZ B cells was observed with FTY-P treatment. The redistribution of MZ B cells from the MZ sinuses does not abolish the ability of these cells to respond to the T-independent antigen, trinitrophenol-Ficoll. It has been proposed that the displacement of MZ B cells to the follicles is an indication of cell activation. Consistent with this, FTY-P caused an increase in percentage of MZ B cells expressing activation markers CD9, CD1d, and CD24. These results suggest that S1P receptors on MZ B cells are responsible for their mobilization to follicles.

Animals↗
PubMed2000

Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response.

The lymphoid organs contain specialized microanatomic structures composed of lymphoid, myeloid and stromal cells that are vital to the generation of an effective adaptive immune response. Although the existence of these specialized structures has been known for over a century, the developmental signals that generate them and the specific roles of these structures in the immune response have remained largely elusive. Because of their position adjacent to the marginal sinuses, marginal zone B (MZB) cells are amongst the first population of cells seen by blood born antigens and are presumed to have a critical role in host defense against bacterial pathogens. Here we demonstrate that a deficiency of the tyrosine kinase (Pyk-2) results in a cell autonomous defect of MZB cell production. In response to repetitive polysaccharide antigens (T-independent type II (TI-II)) Pyk-2-deficient mice displayed marked suppression of IgM, IgG3 and IgG2a production. Furthermore, complement receptor engagement proved necessary for the specific targeting of polysaccharide antigens to MZB cells. These results suggest how innate immune responses mediated through complement coupling are translated into an adaptive response by MZB cells, and provide a potential mechanism for the T cell independence of humoral responses to polysaccharide antigens.

Animals↗
PubMed2005

Infection-induced marginal zone B cell production of Borrelia hermsii-specific antibody is impaired in the absence of CD1d.

Ab that arise in the absence of T cell help are a critical host defense against infection with the spirochetes Borrelia burgdorferi and Borrelia hermsii. We have previously shown that CD1d-deficient (CD1d(-/-)) mice have impaired resistance to infection with B. burgdorferi. In mice, CD1d expression is highest on marginal zone B (MZB) cells, which produce Ab to blood-borne Ag. In this study we examined MZB cell activation and Ab production in mice infected with B. hermsii, which achieve high levels of bacteremia. We show by flow cytometry that MZB cells associate with B. hermsii and up-regulate the activation markers syndecan I and B7.1 within 16 h of infection. By 24 h, MZB cells secrete B. hermsii-specific IgM, coinciding with the loss of activation marker expression and the reduction in spirochete burden. In contrast, MZB cells from CD1d(-/-) mice remain activated for at least 96 h of infection, but produce only minimal B. hermsii-specific IgM in vivo and ex vivo; pathogen burden in the blood also remains elevated. Wild-type mice depleted of MZB cells using mAb to LFA-1 and alpha(4)beta(1) integrin have reduced serum levels of B. hermsii-specific IgM and increased pathogen burden, similar to B. hermsii-infected CD1d(-/-) mice. Passive transfer of immune mouse serum, but not naive mouse serum, into infected CD1d(-/-) mice leads to down-regulation of activation markers and clearance of B. hermsii from the MZB cells. These results demonstrate that blood-borne spirochetes activate MZB cells to produce pathogen-specific IgM and reveal a role for CD1d in this process.

Animals↗
PubMed2000

Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and btk.

Using immunoglobulin heavy chain transgenic mice, we show that B cell clones reaching the long-lived pool are heterogeneous: some are enriched in the CD21(high) compartment (mostly marginal zone [MZ]), others reside primarily in the follicles (FO). Altering the composition of the B cell receptor through N region additions decreases the rate of clonal production and the MZ enrichment. This process can be recapitulated by purified CD21(low) B cells and is due to a preferential clonal survival that requires a functional btk tyrosine kinase. We also show that generation of the MZ population is dependent on CD19. These findings suggest that the MZ B cell repertoire is positively selected and have functional implications for antigenic responses effected by B cells from this microenvironment.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2005

Human splenic marginal zone B cells lack expression of activation-induced cytidine deaminase.

It has been speculated that somatic hypermutation of rearranged immunoglobulin variable (V) region genes does not only take place in the germinal center (GC) microenvironment, but also in the marginal zone (MZ) of the spleen, and that human peripheral blood IgM-positive B cells with somatically mutated V region genes may derive from mutating MZ B cells. As somatic hypermutation is strictly dependent on the enzyme activation-induced cytidine deaminase (AID), we used an AID-specific monoclonal antibody that is suitable for immunohistochemical staining to analyze human splenic MZ cells for AID expression. Analysis of tissue sections from 29 spleens revealed only very rare MZ cells (approx. 0.05%) showing AID staining, whereas in 25 of the spleen samples strong AID staining of GC B cells was observed. Thus, there are virtually no AID-expressing MZ B cells, indicating that somatic hypermutation does not take place at a significant level in the MZ. Consequently, it appears unlikely that the somatically mutated IgM B cells are generated in the splenic MZ. Moreover, the lack of AID-positive MZ B cells questions the recent speculation that B cell chronic lymphocytic leukemias with mutated V genes are derived from mutating MZ B cells.

Adolescent↗
PubMed1996

Sequence analysis of rearranged IgVH genes from microdissected human Peyer's patch marginal zone B cells.

The Peyer's patches of the terminal ileum are a source of IgA plasma cells in the intestinal lamina propria of experimental animals. They are also thought to harbour IgA memory cells. However, the microanatomical location of Peyer's patch memory cells, and whether they are also present in man is not known. Human Peyer's patches have a pronounced marginal zone (MGZ) of sIgD-negative B cells. In this study we analysed the sequence of polymerase chain reaction-amplified, rearranged IgVH genes from microdissected MGZ B cells, to determine whether this is a site of B-cell memory in Peyer's patches. We observed that the majority of Peyer's patch MGZ B cells contain heavily mutated IgVH genes and are therefore clearly memory B cells. Sequences of rearranged mutated genes in the MGZ have a pattern of replacement and silent mutations expected of selected products of the affinity maturation process. Related clones, with identical CDR3 but different patterns of mutation, are seen. This suggests that either these memory cells are formed as the germinal centre selection process proceeds, or a memory cell has re-entered the germinal centre for further rounds of mutation. Interestingly, in one patient, the MGZ in the Peyer's patches also contains a proportion of B cells with unmutated IgVH 4.21 genes.

Aged↗
PubMed2006

Autoreactive marginal zone B cells are spontaneously activated but lymph node B cells require 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.

Animals↗
PubMed2004

Marginal zone B cells transport and deposit IgM-containing immune complexes onto follicular dendritic cells.

Secreted IgM and complement are important mediators in the optimal initiation of primary T-dependent humoral immune responses. Secreted IgM serves as a natural adjuvant by enhancing the immunogenicity of protein antigens, perhaps as a result of IgM's ability to facilitate antigen deposition onto follicular dendritic cells (FDCs) and promote rapid germinal center (GC) formation. To understand how IgM enhances adaptive immune responses, we investigated the mechanism by which IgM-containing immune complexes (IgM-IC) are transported to FDCs as a first step in GC formation. We demonstrate that IgM-IC localize first to the splenic marginal zone (MZ) where the IgM-IC bind MZ B cells in a complement and complement receptor (CR1/2) dependent process. MZ B cells then transport the IgM-IC into the follicle for deposition onto FDCs. Mice with reduced numbers of MZ B cells trap IgM-IC on FDC less efficiently, whereas mice with reduced numbers of follicular B cells trap IgM-IC normally. The functional elimination of MZ B cells abrogates the ability of FDCs to trap IgM-IC. Transfer of B cells with associated IgM-IC into naive mice results in deposition of IgM-IC onto FDC by MZ B cells. The results demonstrate an IgM and complement-dependent role for MZ B cells in the fate of antigen early in the initial phases of T-dependent immune responses. The data also establish an important role for CR1/2 on MZ B cells in the efficient binding and transport of IgM-IC to FDCs, which we suggest is an important first step in initiating adaptive immune responses.

Animals↗