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PubMed2002

Marginal zone B cells in neonatal rats express intermediate levels of CD90 (Thy-1).

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.

Animals↗
PubMed2006

Dissemination of a Sjögren's syndrome-associated extranodal marginal-zone B cell lymphoma: circulating lymphoma cells and invariant mutation pattern of nodal Ig heavy- and light-chain variable-region gene rearrangements.

OBJECTIVE: Both the genesis and outgrowth of extranodal marginal-zone B cell lymphomas (MZLs) of the mucosa-associated lymphoid tissue (MALT) type are generally thought to represent antigen-driven processes. We undertook this study to analyze lymphoma progression and dissemination outside of the MALT-type lesions. METHODS: Histopathologic and Ig heavy- and light-chain variable-region gene (V(H/L)) analyses were performed in sequential tissue samples from a patient with primary Sjögren's syndrome (SS) with glandular (parotid) manifestations and subsequent nodal dissemination of a low-grade MZL. RESULTS: This MZL expressed a CD20+,CD27+,sIgM/kappa+,IgD-,CD5-,CD10-,Bcl-6-,CD23-,p53-,p21-,MDM2- phenotype and mutated V(H)1-69/D2-21/J(H)4alpha-V(kappa)A27/J(kappa)2 Ig rearrangements. Notably, circulating lymphoma cells from the parotid glands occurred transiently in the patient's blood, as detected by single-cell polymerase chain reaction. In addition, 2 minor B cell clones (clones 2 and 3, with V(H)3-07/D3-22/J(H)3b-V(lambda)3L/J(lambda)2/3 and V(H)3-64/D3-03/J(H)2-V(kappa)A19/J(kappa)2 rearrangements, respectively) were also detected in the parotid glands and blood, and 1 of these (clone 2) was also detected in the lymph nodes. Ig V(H/L) analyses revealed ongoing (antigen-driven) mutations of the glandular lymphoma rearrangements, but an invariant mutation pattern of their nodal counterparts. CONCLUSION: These data indicate coexpansion and transient (re)circulation of the lymphoma clone and 2 additional glandular B cell clones in a primary SS-associated extranodal MZL. Combined histologic and molecular features of the nodal lymphoma subclone reflect a process of "follicular colonization" that eventually froze the mutation machinery after accumulation of additional (antigen-driven) Ig V(H/L) mutations.

Female↗
PubMed2005

TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production.

Bacterial DNA triggers B-cell proliferation and induces immunoglobulin secretion. Chromatin-IgG complexes activate autoreactive B cells by co-engaging B-cell receptor (BCR) and TLR-9, thus suggesting a role for innate signaling in systemic autoimmunity. Spleen cells from lupus prone Palmerston North (PN) mice produce several fold less IL-12p40 than controls in response to CpG-oligodeoxynucleotides (ODNs). Here we show that B cells are primarily responsible for this abnormality. The removal of B cells from PN cultures markedly increased IL-12p40. Moreover, the addition of purified B cells back to PN splenocyte cultures resulted in a B-cell number dependent/ IL-10-mediated suppression of IL-12p40. The B cells were the major source of IL-10. In response to CpG, B cells from several lupus strains produced twice as a much IL-10 as controls, but failed to produce IL-10 when stimulated through BCR or CD40. PN and control mice expressed IL-10R similarly, and the difference in IL-10 secretion remained when anti-IL-10R blocking antibodies were used. IFN-gamma and IL-4 regulated CpG-induced IL-10 secretion in opposite directions. The abnormal IL-10 response in lupus mice was derived from B cells with the marginal zone phenotype, and could be downregulated with inhibitory ODNs. We hypothesize that TLR-9 activated lupus B cells can modulate T-cell mediated inflammatory responses through IL-10 production. Therefore, B cells may contribute to the lupus pathogenesis in many different ways: as antigen-presenting cells for self antigens, as effector cells for autoantibody production, and as IL-10 secreting regulatory cells.

Animals↗
PubMed2006

Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation.

Non-Hodgkin lymphomas develop from nodal and extranodal lymphoid tissues. A distinct subset of extranodal lymphomas arising from B cells of the marginal zone (MZ) of mucosa-associated lymphoid tissue (MALT) or spleen has been individualized. Growing evidence indicates that MZ lymphomas are associated with chronic antigenic stimulation by microbial pathogens and/or autoantigens. The list of microbial species associated with MZ lymphoproliferations has grown longer with molecular investigations and now comprises at least 5 distinct members: H. pylori, C. jejuni, B. burgdorferi, C. psittaci, and hepatitis C virus (HCV), which have been associated with gastric lymphoma, immunoproliferative small intestinal disease, cutaneous lymphoma, ocular lymphoma, and spleen lymphoma, respectively. A pathophysiologic scenario involving chronic and sustained stimulation of the immune system leading to lymphoid transformation has emerged. It defines a distinct category of infection-associated lymphoid malignancies, in which the infectious agent does not directly infect and transform lymphoid cells, as do the lymphotropic oncogenic viruses Epstein-Barr virus (EBV), human herpesvirus 8 (HHV8), and human T-lymphotropic virus 1 (HTLV-1), but rather indirectly increases the probability of lymphoid transformation by chronically stimulating the immune system to maintain a protracted proliferative state.

Antigen Presentation↗
PubMed2005

Activation of marginal zone B cells from lupus mice with type A(D) CpG-oligodeoxynucleotides.

Several types of CpG-oligodeoxynucleotides (ODN) have been recently characterized. In mice, type A(D) CpG-ODNs primarily stimulate macrophages and dendritic cells, but fail to stimulate B cells. On the contrary, type B(K) CpG-ODNs are excellent B cell activators. Type C CpG-ODNs combine features of both types A(D) and B(K) CpG-ODNs. Despite cell type preferences, all CpG-ODNs require the presence of TLR9 for activation. In this study, we show that a subset of B cells from lupus mice responds to type A(D) CpG-ODN stimulation vigorously and directly with increased CD25 and CD86 expression and IL-10 secretion. Furthermore, these CpG-ODNs induce high surface IgM expression and promote 50- to 100-fold higher IgM and IgG3 secretion in lupus B cells than in controls. This response is similar to that seen with bacterial DNA stimulation of B cells. Type A(D)-responsive cells are enriched within lupus B cells with the marginal zone (MZ) phenotype. These cells are at least twice more numerous in lupus mice than in controls. The ability of lupus B cells to respond to type A(D) CpG-ODN stimulation is not due to differential TLR9 expression. Therefore, type A(D) CpG-ODNs may contribute to the lupus pathogenesis by inducing MZ-B cell activation, costimulatory molecule expression, and polyclonal Ig secretion. Through increased IL-10 secretion, MZ-B cells may also modify the activity of other cell types, particularly dendritic cells and macrophages.

Adjuvants, Immunologic↗
PubMed2002

Reduction of marginal zone B cells in CD22-deficient mice.

CD22 is a B cell-specific member of the immunoglobulin superfamily and binds to sialic acid. CD22 inhibits B cell receptor signaling. Mice deficient for CD22 show a largely normal B cell development. Here, we have performed a detailed analysis of the splenic B cell population and found that the subset of marginal zone (MZ) B cells was selectively reduced in CD22-deficient mice. CD22-deficient mice showed a lack of TNP-ficoll capturing cells in the MZ and a reduced response to TNP-ficoll, particularly when the antigen was applied intravenously. CD22-deficient B cells showed both enhanced motility as well as enhanced chemotaxis to certain chemokines. The altered chemokine responsiveness or the higher signaling capacity of CD22-deficient B cells may lead to the compromised MZ B cell compartment, as both processes have previously been shown to affect MZ composition.

Animals↗
PubMed2003

Transitional and marginal zone B cells have a high proportion of unmasked CD22: implications for BCR signaling.

CD22, a B cell-specific member of the Siglec family, is an important inhibitor of B cell signaling. The first Ig-like domain of CD22 specifically binds to alpha2,6-linked sialic acids. Through these interactions CD22 can mediate adhesion to other cells in trans, but can also bind endogenous ligands on the B cell surface in cis. Cis binding of CD22 to sialylated ligands enhances the efficiency of inhibition and thereby reduces the BCR signaling strength. In this study we used a newly developed oligomeric streptavidin-based sialylated probe as an artificial CD22 ligand. We found that CD22 is bound to ligands in cis on most B cells. However, there is a proportion of B cells with unbound (unmasked) CD22. The subpopulation with unmasked CD22 is 2-fold increased in transitional and marginal zone B cells in the spleen and on B1 cells in the peritoneum, when compared to mature B cells. Also, B cells with unmasked CD22 have an activated phenotype. Unmasking of CD22 could be functionally involved in lowering the signaling threshold on developmental checkpoints such as transitional B cells and during B cell activation or could be a consequence of such activation processes.

Animals↗
PubMed2005

Characterization of marginal zone B cell precursors.

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 CD21/35(high) 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 CD21/35(high) 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, CD21/35(high) 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 CD21/35(high) CD23(+) intermediates.

Animals↗
PubMed2005

Ocular adnexal marginal zone B cell lymphoma: a clinical and pathologic study of 23 cases.

To better characterize ocular adnexal marginal zone lymphoma of mucosa-associated lymphoid tissue (MZL-MALT), we analyzed the clinical and pathologic features of 23 patients (11 men, 12 women, median age 66 years). The tumor was confined to one ocular structure in 18 cases (conjunctiva, n=8; orbit, n=8; or lacrimal gland, n=2). Concurrent extraorbital disease was detected by the staging procedure in five patients, and preferentially involved other MALT sites. Histogenetic B cell marker studies, available in 13 cases, showed an early post-germinal center (GC) phenotype (BCL-6(-)/IRF4(+)/CD138(-)) (n=5) or a late post-GC phenotype (BCL-6(-)/IRF4(+)/CD138(+)) (n=8), which could be helpful for discrimination from other types of small-B cell lymphoma. BCL10 was positive in 12 of 13 patients tested, with nuclear (n=4) or cytoplasmic (n=8) immunoreactivity. These staining patterns ruled out t(1;14)(p22;q32) translocation. T(11;18)(q21;q21), another MZL-MALT-specific translocation, was detected by reverse transcriptase polymerase chain reaction in four of 15 patients tested. Clinical outcome was excellent but the overall relapse rate was 26.1% with a median follow-up of 39 months (range 6-132 months). Regardless of the disease stage at diagnosis, combined chemotherapy and radiotherapy seemed to be more effective than chemotherapy alone in ocular adnexal MZL-MALT, as persistent complete remission was achieved in nine patients receiving combination therapy, while six of 14 patients treated with chemotherapy alone relapsed.

Adult↗
PubMed2002

Adapter molecule Grb2-associated binder 1 is specifically expressed in marginal zone B cells and negatively regulates thymus-independent antigen-2 responses.

Grb2-associated binder 1 (Gab1) is a member of the Gab/daughter of sevenless family of adapter molecules involved in the signal transduction pathways of a variety of growth factors, cytokines, and Ag receptors. To know the role for Gab1 in hematopoiesis and immune responses in vivo, we analyzed radiation chimeras reconstituted with fetal liver (FL) cells of Gab1(-/-) mice, because Gab1(-/-) mice are lethal to embryos. Transfer of Gab1(-/-) FL cells of 14.5 days post-coitum rescued lethally irradiated mice, indicating that Gab1 is not essential for hematopoiesis. Although mature T and B cell subsets developed normally in the peripheral lymphoid organs, reduction of pre-B cells and increase of myeloid cells in the Gab1(-/-) FL chimeras suggested the regulatory roles for Gab1 in hematopoiesis. The chimera showed augmented IgM and IgG1 production to thymus-independent (TI)-2 Ag, although they showed normal responses for thymus-dependent and TI-1 Ags, indicating its negative role specific to TI-2 response. Gab1(-/-) splenic B cells stimulated with anti-delta-dextran plus IL-4 plus IL-5 showed augmented IgM and IgG1 production in vitro that was corrected by the retrovirus-mediated transfection of the wild-type Gab1 gene, clearly demonstrating the cell-autonomous, negative role of Gab1. Furthermore, we showed that the negative role of Gab1 required its Src homology 2-containing tyrosine phosphatase-2 binding sites. Cell fractionation analysis revealed that nonfollicular B cells were responsible for the augmented Ab production in vitro. Consistent with these results, the Gab1 gene was expressed in marginal zone B cells but not follicular B cells. These results indicated that Gab1 is a unique negative regulator specific for TI-2 responses.

Adaptor Proteins, Signal Transducing↗
PubMed2003

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.

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 gamma-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.

Animals↗
PubMed1985

The human gut contains a novel population of B lymphocytes which resemble marginal zone cells.

B cells in normal human Peyer's patches and in primary B cell lymphomas of the stomach have been characterized in terms of their cellular morphology and their reactivity with a panel of monoclonal antibodies. A population of B cells is present in normal and malignant gut-associated lymphoid tissue which is composed of neither mantle zone cells nor germinal centre cells. In Peyer's patches these cells surround the follicles merging with the mantle zone and extending both into the dome region, infiltrating between the epithelial cells and also towards the serosa. They are intermediate in size with irregular nuclear outlines and they resemble the centrocytes in the follicle centre. They are quiescent, expressing C3b- and C3d-receptors and surface IgM but not surface IgD. These centrocytes-like cells which are not seen in the peripheral lymph nodes are identical to the B cells in the marginal zone of the spleen according to all of the criteria employed in this study.

B-Lymphocytes↗
PubMed2005

Marginal zone B cell physiology and disease.

Mature B lymphocytes do not constitute a homogenous pool of cells, and it is now clear that several functionally and developmentally distinct subsets exist. Of these, marginal zone (MZ) B cells are a subset of peripheral B cells that respond vigorously to blood-borne infections, and play a vital role, particularly in host survival of infection by encapsulated bacteria. Their fast activation and differentiation to antibody-secreting plasma cells allows MZ B cells to bridge the gap between innate and adaptive immunity, effected mainly by the more prolific follicular B cells. Like other naturally activated lymphocytes, MZ B cells may also play a role in homeostasis and tolerance, apart from combating infection. Here we will review some of the extracellular signals that affect their development, selection and function. We conclude by examining how their repertoire, location and interactions with other cell types may be important in the induction of autoimmune disease.

Animals↗
PubMed1984

Marginal zone B cells express CR1 and CR2 receptors.

Opsonized yeast is known to bind strongly to the marginal zones in frozen sections of rat spleen (Kumararatne, D. S. et al., Eur. J. Immunol. 1981. 11: 858). This study reports an analysis of the cells involved in this binding. Sheep red cells coated respectively with C3b, C3bi or C3d were used as indicator cells. These showed homogeneous binding of both C3b and C3bi to marginal zones and germinal centers. C3d-coated red cells bound in a uniform speckled pattern to marginal zones. They also bound to germinal centers and the small lymphocyte zones of the follicles. Selective depletion experiments were undertaken to show that binding to marginal zones was a property of the IgM+ and IgD- B cells characteristic of this area. Binding to germinal centers was attributable to follicular dendritic cells. The C3d receptors in follicles were shown to be on IgM+ and IgD+ small B lymphocytes.

Animals↗
PubMed2004

Marginal zone B cell enrichment and strong follicular B cell reduction correlate with a delayed IgG response in a light chain diversity restricted mouse model.

Recently developed B6.kappa(-)lambda(SEG) mice (by crossing kappa(-) and C57BL/6 mice congenic for the wild Mus spretus SEG strain lambda locus lacking genes coding for lambda1 and lambda3) have a very reduced light chain diversity. B6.kappa(-)lambda(SEG) mice produce only lambda2 and lambdax light chains. Regardless of their Igh haplotype, B6.kappa(-)lambda(SEG) mice show a restricted B cell distribution by light chain subtype with lambdax dominance in all peripheral compartments except peritoneal cavity where lambda2 is dominant. This distribution suggests that selection mechanisms act differently in different B cell compartments on lambda2 and lambdax bearing B cells. Sequence analysis before or following immunization did not reveal unusual mechanisms of diversification. B6.kappa(-)lambda(SEG) mice still respond to various challenging antigens using new Ab patterns. In particular, regardless of Igh(a) or Igh(b) haplotypes, the anti-2,4-dinitrophenyl response is characterized by a restricted diversity for both heavy and light chains and a delayed IgG response when compared to B6 and B6.kappa(-) mice. We suggest that the delayed IgG response is due to the expansion of marginal zone B cells whereas follicular B cells are strongly reduced.

Amino Acid Sequence↗
PubMed2003

The selection of marginal zone B cells differs from that of B-1a cells.

Transgenic (Tg) L2 mice expressing high levels of the lambda2 (315) L chain contain only B cell populations involved in the first line of defense, i.e., B-1 and marginal zone (MZ) B cells. The strongly oligoclonal IgH chain repertoire of Tg B-1a cells in such mice was attributed to strong positive selection by autoantigens. In this study, we show that the MZ B cells of L2 mice correspond very closely to MZ B cells of normal mice, as revealed by surface marker expression and gene expression profiling. We demonstrate that the IgH chain repertoire of these Tg MZ B cells is extremely heterogeneous. This is in sharp contrast to the oligoclonality found in B-1a cells of the same mice, which was attributed to strong positive selection mediated by autoantigens. Therefore, the strong positive selection of the IgH chain repertoire in L2 mice is B-1a specific. Thus, our data demonstrate that despite common functional properties, MZ B and B-1a cells exhibit striking differences in their selection and/or maintenance requirements.

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↗