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PubMed2006

Higher-order CpG-DNA stimulation reveals distinct activation requirements for marginal zone and follicular B cells in lupus mice.

Mouse follicular B cells express TLR9 and respond vigorously to stimulation with single-stranded CpG-oligodeoxynucleotides (ODN). Surprisingly, follicular B cells do not respond to direct stimulation with other TLR9 ligands, such as bacterial DNA or class A(D) CpG-ODN capable of forming higher-order structures, unless other cell types are present. Here, we show that priming with interferons or with B cell-activating factor, or simultaneous co-engagement of the B cell receptor for antigen (BCR), can overcome this unresponsiveness. The effect of interferons occurs at the transcriptional level and is mediated through an autocrine/paracrine loop, which is dependent on IRF-1, IL-6 and IL-12 p40. We hypothesize that the lack of bystander activation of follicular B cells with more complex CpG ligands may be an important safety mechanism for avoiding autoimmunity. This will prevent resting B cells from responding to foreign or self-derived hypomethylated double-stranded CpG ligands unless these ligands are either delivered through the B cell receptor or under conditions where B cells are simultaneously co-engaged by activated plasmacytoid dendritic cells or TH1 cells. A corollary is that the heightened responsiveness of lupus B cells to TLR9-induced stimulation cannot be ascribed to unprimed follicular B cells, but is rather mediated by hypersensitive marginal zone B cells.

Adjuvants, Immunologic↗
PubMed2005

Indolent lymphoplasmacytic and marginal zone B-cell lymphomas: absence of both IRF4 and Ki67 expression identifies a better prognosis subgroup.

BACKGROUND AND OBJECTIVES: Small B-cell indolent lymphomas postulated to be of a post-germinal center origin include marginal zone lymphomas of the spleen (S-MZL) or lymph nodes (N-MZL) and mucosa-associated lymphoid tissue (MALT) lymphomas and lymphoplasmacytic lymphomas (LPL). The existence of rather aggressive cases stresses the need for new biological prognostic markers. DESIGN AND METHODS: We analyzed 90 tumors (20 LPL, 41 MALT lymphomas, 12 N-MZL, 17 S-MZL), investigating the expression of CD5, CD10, CD20, CD23, CD27, CD38, CD79a, CD138, Bcl6, cyclin D1, IRF4 and Ki67 antigens by immunohistochemistry. Results were compared to the histology, the standard clinical and biological parameters, and the global survival. RESULTS: Tumors were all positive for CD20 and CD79a, occasionally positive for CD5, CD23, CD138 and cyclin D1, and all negative for Bcl-6 and CD10. CD38, CD27 and IRF4 expression was heterogeneous. IRF4 expression was correlated with plasma-cell differentiation (p=0.0017). Ki67 expression was increased mainly in N-MZL (66%) and LPL (45%). In terms of overall survival, Ki67, IRF4 and C-reactive protein levels were found to be the 3 independent parameters associated with a worse outcome. Lack of both Ki67 and IRF4 expression was associated with a longer survival (median overall survival 9.8+/-1.1 years versus 3.6+/-1.3 years in the other group) (p=0.0011). INTERPRETATIONS AND CONCLUSIONS: Absence of expression of both Ki67 and IRF4 is likely to define a group of memory B-cell lymphomas with a better prognosis. This may have an important impact in the staging of patients since expression of these markers is easily assessed in routine diagnosis.

Adult↗
PubMed2005

Lymphocyte-expressed BILL-cadherin/cadherin-17 contributes to the development of B cells at two stages.

The gene encoding BILL-cadherin/cadherin-17, a nonclassical cadherin expressed on B lymphocytes in a stage-and-site-specific manner, was inactivated by targeted disruption of its transmembrane/cytoplasmic portion-encoding parts. BILL-cadherin deficiency caused a threefold proB cell accumulation, as well as a reduction to half of the numbers of immature B cells in bone marrow. In spleen, CD21(hi)CD23(lo) marginal zone B cells were found reduced and the structure of the marginal zone was impaired. In addition, the size and number of germinal center as well as the number of PNA(+) cells were significantly reduced in BILL-cadherin-deficient mice. In the peritoneal cavity of mutant mice IgM(+)Mac-1(+)CD5(+) B1a cell, that express high BILL-cadherin in wild-type mice, was also reduced in number. The IgG1 and IgG3 antibody response to the T-independent antigen, TNP-Ficoll, was impaired in the mutant mice. These results indicate that BILL-cadherin participates in B lymphocyte development at least at two stages, first at the transition of pro/preB-I cells to preB-II cells possibly in association with surrogate light chain in bone marrow, and later at the point of development, accumulation and reactiveness of immature B cells in spleen.

Animals↗
PubMed2003

From the yolk sac to the spleen: New roles for Notch in regulating hematopoiesis.

Although Notch receptors are widely expressed during hematopoiesis, their roles outside of the T cell lineage are not well characterized. Two reports in this issue of Immunity show that Notch1 and Notch2, respectively, are required to generate the earliest embryonic hematopoietic stem cells and splenic marginal zone B cells. Thus, different Notch receptors have specific and nonoverlapping functions that influence multiple hematopoietic lineages at various stages of development.

Animals↗
PubMed2006

Fatalities in natalizumab treatment--a 'no go' for leukocyte recirculation approaches?

Natalizumab (Tysabri), Biogen Idec/Elan) is a humanised neutralising antibody directed against alpha4 integrin expressed by leukocytes. Although it is an effective therapy for multiple sclerosis (MS), the serious adverse effect of progressive multifocal leukoencephalopathy (PML) resulted in its voluntary withdrawal from the market by Biogen Idec/Elan in February 2005. This has raised debates on whether PML was caused by blocking leukocyte trafficking-mediated immune suppression or by other effects through targeting alpha4 integrin per se. The authors propose that natalizumab-associated PML is a target-specific side effect predominantly due to the combination of: i) blocking leukocyte trafficking to peripheral organs resulting in reduced immune surveillance; ii) mobilisation of PML-causative JC virus-carrying bone marrow precursor cells and splenic marginal zone B cells; and iii) migration of these cells to sites of inflammation such as the brain. Therefore, combination of these effects is, so far, specific for the target alpha4 integrin and should not occur in general when interfering with other targets involved in leukocyte trafficking.

Antibodies, Monoclonal↗
PubMed1981

Marginal zones: the major B cell compartment of rat spleens.

The marginal zones of rat and human spleens are a broad band of cells, which surround the small lymphocyte area of the white pulp. Staining for acid phosphatase and alpha-naphthyl acetate esterase activity indicates that the majority of cells in this compartment are intermediate-sized lymphocytes. Macrophages only form a minor component. Using quantitative histology, it is shown that the marginal zones are the largest white pulp compartment in terms of volume. They contain approximately as many lymphocytes as the small lymphocyte zones. The cells of the marginal zone are strongly C3- and Fc receptor-positive. While the cells of this zone have demonstratable surface membrane Ig, it is difficult to exclude that this is not passively absorbed. Other means were therefore sought to determine the lineage of lymphocytes in this area. First, the cells in this zone do not bear appreciable quantities of the rat T cell selective antigen detected by the monoclonal antibody W313. Second, marginal zone cells are present in normal numbers in congenitally athymic "nude" rats. Finally, marginal zones do not become populated with lymphocytes in rats treated from birth with anti-mu antibody. Further experiments showed that marginal zone lymphocytes do not recirculate.

Animals↗
PubMed2003

After chemotherapy, functional humoral response capacity is restored before complete restoration of lymphoid compartments.

Chemotherapy has, besides the beneficial effects, several adverse effects. Suppression of the immune system is one of the most important problems. Infections caused by encapsulated bacteria like Streptococcus pneumoniae are responsible for a major part of infectious problems during and after treatment. The splenic marginal zone is essential in the initiation of an immune response to encapsulated bacteria. In this study, we analysed the effects of three different cytostatic agents on humoral immune responses. We found a reduced, but detectable immune response capacity at two days after treatment although the marginal zone B cell population is severely reduced at this time point. Twenty-four days after cessation of treatment, the immune response capacity was largely restored although lymphoid compartments were still not completely restored at that time point. Apparently, the presence of only few marginal zone B cells is sufficient to evoke a rise in antibody titres and although antibody titre increases are low, even small rises are most likely clinically relevant.

Animals↗
PubMed2002

Extranodal marginal zone B-cell lymphoma of the lacrimal gland associated with crystal-storing histiocytosis.

OBJECTIVE: Crystal-storing histiocytosis (CSH) is a very rare immunoglobulin (Ig) deposition disorder that can be associated with B-cell neoplasms as well as some reactive Ig-secreting lymphoproliferative disorders. This article reports the clinical, histopathologic, and molecular biologic findings of CSH in association with an extranodal marginal zone lymphoma (EMZL) of the lacrimal gland. DESIGN: Interventional case report with clinicopathologic correlation. INTERVENTION: Treatment consisted of conjunctival and orbital biopsies, as well as low-dose radiation of the left orbit. METHODS: Histopathologic findings of the conjunctival and orbital biopsies were compared. Further, extensive immunohistochemistry, polymerase chain reaction (PCR) for the detection of Ig heavy chain (IgH) gene rearrangement, Gene Scan analysis, and DNA sequencing were performed on all tissues. RESULTS: The tumor manifestations in the specimens demonstrated a similar morphologic and immunophenotypic characteristics consistent with the diagnosis of EMZL. Immunoglobulin H PCR and Gene Scan analysis showed B cells derived from the same clone. In association with the orbital EMZL were large accumulations histiocytes filled with refractile crystals, consistent with the diagnosis of CSH. CONCLUSIONS: The current case describes an EMZL of the lacrimal gland appearing 5 years after excision and low-dose radiation of a conjunctival lymphoma. The orbital recurrence was associated with surrounding CSH, a rare Ig storage disorder more often reported in patients with multiple myeloma or lymphoplasmacytic lymphoma or immunocytoma. Ophthalmic pathologists should be aware of the diagnosis when reviewing orbital biopsies, because difficulties may arise when the crystal-storing macrophages occupy more tissue space than the Ig-secreting cells or when they resemble cell types such as rhabdomyoblasts.

Antigens, CD↗
PubMed2006

Lysophospholipids control integrin-dependent adhesion in splenic B cells through G(i) and G(12)/G(13) family G-proteins but not through G(q)/G(11).

Integrin-mediated adhesion is a crucial step in lymphocyte extravasation and homing. We show here that not only the chemokines CXCL12 and CXCL13 but also the lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) enhance adhesion of murine follicular and marginal zone B cells to ICAM-1 in vitro. This process involves clustering of integrin LFA-1 and is blocked by pertussis toxin, suggesting that G(i) family G-proteins are involved. In addition, lysophospholipid-induced adhesion on ICAM-1 depends on Rho and Rhokinase, indicative of an involvement of G(12)/G(13), possibly also G(q)/G(11) family G-proteins. We used G(12)/G(13)- or G(q)/G(11)-deficient B cells to study the role of these G-protein families in lysophospholipid-induced adhesion and found that the pro-adhesive effects of LPA and S1P are completely abrogated in G(12)/G(13)-deficient marginal zone B cells, reduced in G(12)/G(13)-deficient follicular B cells, and normal in G(q)/G(11)-deficient B cells. We also show that loss of lysophospholipid-induced adhesion results in disinhibition of migration in response to the follicular chemokine CXCL13, which might contribute to the abnormal localization of splenic B cell populations observed in B cell-specific G(12)/G(13)-deficient mice in vivo. Taken together, this study shows that lysophospholipids regulate integrin-mediated adhesion of splenic B cells to ICAM-1 through G(i) and G(12)/G(13) family G-proteins but not through G(q)/G(11).

Animals↗
PubMed2001

Novel genomic imbalances in B-cell splenic marginal zone lymphomas revealed by comparative genomic hybridization and cytogenetics.

Splenic marginal zone lymphoma (SMZL) has recently been recognized in the World Health Organization classification of hematological diseases as distinct type of non-Hodgkin's lymphoma. In contrast to the well-established chromosomal changes associated with other B-cell non-Hodgkin's lymphoma, few genetic alterations have been found associated with SMZL. The aim of our study was to analyze by comparative genomic hybridization (CGH) the chromosomal imbalances in 29 patients with SMZL and to correlate these findings with clinical and biological characteristics and patient outcome. In 21 cases, cytogenetic studies were simultaneously performed. Most of the patients (83%) displayed genomic imbalances. A total of 111 DNA copy number changes were detected with a median of four abnormalities per case (range, 1 to 12). Gains (n = 92) were more frequent than losses (n = 16), while three high-level amplifications (3q26-q29, 5p11-p15, and 17q22-q25) were observed. The most frequent gains involved 3q (31%), 5q (28%), 12q and 20q (24% each), 9q (21%), and 4q (17%). Losses were observed in 7q (14%) and 17p (10%). SMZL patients with genetic losses had a shorter survival than the remaining SMZL patients (P < 0.05). In summary, chromosomal imbalances in regions 3q, 4q, 5q, 7q, 9q, 12q, and 20q have been detected by CGH in SMZL. Patients with SMZL displaying genetic losses by CGH had a short survival.

Adult↗
PubMed1998

Detection of CD5 antigen on B cell lymphomas in fixed, paraffin embedded tissues using signal amplification by catalyzed reporter deposition.

CD5 surface antigen is expressed on some categories of B cell lymphomas. The detection of CD5 coexpression on malignant B cell infiltrates, particularly in small biopsy specimens, is useful in distinguishing between small lymphocytic lymphoma, mantle cell lymphoma, low grade marginal zone B cell lymphoma, and follicular small cleaved cell lymphoma. However, conflicting results have been reported with regard to the detection of CD5 antigen expression on B cell non-Hodgkin's lymphomas (B-NHLs) in fixed, paraffin embedded tissues using routine immunohistochemical (IHC) staining techniques. We used catalyzed reporter deposition (CARD) as a strategy to amplify the IHC signal and consequently increase the sensitivity of antigen detection. CARD improved detection of CD5 antigen without sacrificing specificity of the test. In our study, virtually all malignant B-NHLs with CD5 antigen expression showed strong immunoreactivity for a commercially available anti-CD5 monoclonal antibody using CARD, whereas the majority of the same lymphomas did not label for CD5 using routine IHC without CARD amplification. The concordance between CD5 antigen detection by immunophenotyping of fresh or frozen tissues and immunostaining with CARD amplification on paraffin fixed tissue sections was 100%. It appears that this method can be applied in the diagnostic evaluation of B-NHLs or in other situations that a weak antigen signal is present.

Biotin↗
PubMed2000

Primary splenic B-cell lymphoma (marginal zone lymphoma). Clinicopathological evaluation of 10 cases.

SMZL has been included in the REAL classification of lymphoid neoplasms (1994) as an entity. It affects middle aged adults presenting with splenomegaly, mild lymphocytosis and in 40% of cases with the presence of monoclonal paraprotein. Our material includes 10 patients (6 women + 4 men). In all patients bone marrow biopsy was the initial material for histopathological examination. With characteristic intertrabecular nodular interstitial infiltrates of CD20+ small lymphocytes and corresponding clinical data (splenomegaly, lymphocytosis in peripheral blood and sporadic elevation of IgM levels) it was very suggestive of SMZL diagnosis. Splenectomy was the treatment of choice. The spleen showed micronodular white foci in all cases. Morphologically the pattern of white pulp involvement was observed with lymphoma infiltrates as well as small foci in the red pulp. The white pulp showed follicles surrounded by a wide marginal zone, resembling reactive splenic follicles. A corona-like rim consisted of medium size cells with abundant clear cytoplasm, resembling monocytoid B cells, often with plasmacytoid differentiation, or centrocyte-like cells. Smaller aggregates of these cells were present in the red pulp. Lymphoma cells were CD20+, bcl-2 and IgM+. In all cases monoclonal kappa light chains were found. Although SMZL is a disseminated lymphoma at diagnosis, its course is indolent and splenectomy is the treatment of choice. Clinical and histopathological differential diagnoses include hairy cell leukemia and secondary involvement of the spleen by infiltrates of nodal B-cell lymphomas.

Aged↗
PubMed1997

Lymphomas in patients with Sjogren's syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses.

The occurrence of non-Hodgkin's lymphoma (NHL) is the most serious complication of Sjogren's syndrome (SS). We performed a study of 16 NHLs occurring in patients with an underlying SS. These lymphomas arose not only in salivary glands (7 cases) but also in other mucosal extranodal sites (the stomach [4 cases], the lung [3 cases], the skin [3 cases], the buccal mucosa [1 case], the thymus [1 case]) and in nodal sites (8 cases). Low-grade marginal zone lymphomas (MZL) were diagnosed in 12 of the 16 patients, 9 of mucosa-associated lymphoid tissues (MALT) type in mucosal sites and 3 exclusively nodal. The 4 other patients presented with a high-grade B-cell lymphoma that was probably a histological transformation of an underlying low-grade MZL at least in 3 of the cases involving skin, stomach, and parotid, respectively. A t(14;18) translocation was detected in 1 of 8 lymphomas tested. We detected serum anti-p53 antibodies in 2 of the 14 studied patients. p53 protein was detected in 1 of 11 lymphomas tested. LMP protein and Eber RNAs of Epstein-Barr virus (EBV) were not detected in the 16 NHL biopsies. Using polymerase chain reaction, EBV was never detected except in 1 of 4 parotid lymphomas. No human T-lymphotropic virus 1 or human herpes virus 8 DNAs were detected in NHL biopsies. None of the patients had hepatitis C virus infection found using serological methods. Chemotherapy was usually efficient. In conclusion, lymphomas occurring in patients with an underlying SS are in most cases MZL. These lymphomas are not associated with viruses known to be present in other types of lymphomas. Some of the translocations or mutations of oncogenes or antioncogenes described in other lymphomas are detected in SS-associated lymphomas.

Adolescent↗
PubMed1976

T- and B-areas in immune reactions. Volume changes in T and B cell compartments of the rat spleen following intravenous administration of a thymus-dependent (SRBC) and a thymus-independent (paratyphoid vaccin-endotoxin) antigen. A histometric study.

In the white pulp of rat spleens cell numbers were studied in the different compartments following intravenous administration of comparable doses of paratyphoid vaccine (PTV, thymus-independent) and sheep red blood cells (SRBC, thymus-dependent). In the periarteriolar lymphatic sheaths (PALS) both cell concentration and volume were measured. For the follicles and the marginal zone only volume was recorded in the first 5 days following antigen administration. Additionally, histologic observations were made. In the thymus-dependent area PTV caused oedema 12-24 hours after administration. Following SRBC administration an increase in lymphocyte numbers occurred until the second day, probably representing an influx of T cells from the recirculating pool. Both antigens gave rise to a plasmacellular reaction in the peripheral PALS (2nd-4th day). In the bone marrow-dependent areas a massive shift of medium-sized lymphocytes from the marginal zone to the follicles took place in the first 24 hours following PTV administration. These cells subsequently transformed into blasts. After SRBC (6 and 12 hours) only a few marginal zone lymphocytes seemed to migrate into the follicles. It is aruged that the endotoxin present in PTV is responsible for the fact that, following administration of the antigen, all marginal zone (B) cells responded. Endotoxin stimulation might provide a model for the fate of marginal zone cells stimulated by other agents, such as antigen (stimulating antigen binding B cells) or antigen-antibody complexes (stimulating Fc-receptor B cells).

Animals↗
PubMed1985

Marginal zone macrophages identified by a monoclonal antibody: characterization of immuno- and enzyme-histochemical properties and functional capacities.

In the present study, the non-lymphoid cell of the marginal zone is described: the marginal zone macrophage, identified by a monoclonal antibody, ERTR9. The characteristics of these cells were investigated by use of a two-step immunoperoxidase method (on light and ultrastructural level) in combination with enzyme-cytochemical techniques and functional tests. The marginal zone macrophage appears to be a large cell with close contacts between its cell processes and surrounding marginal zone B cells, and with a well-developed phagocytic capacity. These ERTR9-positive macrophages are capable of selective uptake and retention of i.v. injected FITC-Ficoll and are negative for Ia antigen as well as for the macrophage-related F4/80 antigen. By these characteristics, they constitute a subpopulation of non-lymphoid cells of spleen unique for the marginal zone.

Animals↗
PubMed2006

Confounding B-cell defences: lessons from a staphylococcal superantigen.

Studies of microbial superantigens that target large clonal sets of B cells through conserved antigen-receptor-variable-region sites are providing new insights into the mechanisms of B-cell activation-induced cell death. These investigations have shown differences between the clonal regulation of follicular B cells (B2 cells) and the innate-like marginal-zone B cells and B1 cells, and have also shown how B-cell superantigens can affect specialized host defences against infection. Agents designed to emulate the properties of B-cell superantigens might also provide new approaches for the treatment of B-cell-mediated autoimmune and neoplastic diseases.

Animals↗