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PubMed2001

Cells of the marginal zone--origins, function and neoplasia.

Splenic marginal zone B cells of humans and mice are anatomically positioned with specialized macrophages, dendritic and endothelial cells. Together, they function as the first line of defense against blood borne pathogens with a low triggering threshold for B cells providing a rapid proliferative and antibody response to infections. In humans, B cells with similar cytology and physical relations to follicles are found in lymph nodes and Peyer's patches. However, they also develop in mucosa-associated lymphoid tissue (MALT) and other sites, such as the thyroid and salivary gland, that normally lack organized lymphoid tissue. Chronic antigenic stimulation at these sites or in response to infection with Hepatitis C provides the milieu for mutations at FAS, API2/ML, TP53 and INK4a/p19ARF and the development of marginal zone lymphomas (MZL) in node, spleen and MALT. Only splenic MZL are seen in mice. A reduced threshold for triggering to proliferation may predispose the marginal zone B cell to neoplasia with mutations in genes regulating apoptosis playing a leading role.

Animals↗
PubMed2003

Nodal marginal zone B-cell lymphoma with a novel t(X;5)(q28;q22): conventional and molecular cytogenetic analysis.

Cytogenetic studies provide important information for the diagnosis and classification of malignant lymphomas that in some cases also has prognostic significance. Furthermore, the investigation of isolated novel cytogenetic findings in malignant lymphoma has led to the discovery of many important oncogenes and tumor suppressor genes. For this reason, a case of nodal marginal zone B-cell lymphoma in a 72-year-old woman is described in which analysis by conventional and molecular cytogenetic techniques demonstrated the presence of a t(X:5)(q28;q22) as the sole chromosomal abnormality. This translocation has not been previously reported in the literature.

Aged↗
PubMed2001

Homeostasis of peripheral B cells in the absence of B cell influx from the bone marrow.

To study homeostasis of peripheral B lymphocytes in the absence of B cell influx from the bone marrow, we generated a mouse mutant in which the recombination-activating gene (RAG)-2 can be inducibly deleted. When RAG-2 was deleted at the age of 8-10 wk, splenic naive follicular B cells were gradually lost over a year of observation, with a half-life of approximately 4.5 mo. By contrast, the pool of marginal zone B cells in the spleen and of B-1 cells in the peritoneal cavity were kept at normal level. In lymph nodes, approximately 90% of the B cells were lost within 4 mo, and B cell numbers remained constant thereafter. Mice in which RAG-2 was deleted at birth maintained a small population of activated B cells with an increased proportion of marginal zone B cells. Additionally, an increase of the pool of IgM secreting cells and B-1a cells was observed.

Animals↗
PubMed2003

Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone.

The marginal zone of the spleen is a precisely ordered region that contains specialized subsets of B lymphocytes and macrophages. Disruption of the negative signaling inositol phosphatase, SH2-containing inositol-5-phosphatase 1 (SHIP), results in the loss of marginal zone B cells (MZBs) with reorganization of marginal zone macrophages (MZMOs) to the red pulp of the spleen. This primary macrophage defect, as revealed by selectively depleting SHIP in myeloid cells shows that MZMOs are specifically required for the retention of MZBs. The MZMO phenotype was reverted in SHIP/Bruton's tyrosine kinase (Btk) double knockout mice, thus identifying the Btk activating pathway as an essential component being regulated by SHIP. Furthermore, we identified a direct interaction between the MARCO scavenger receptor on MZMOs and MZBs. Activation or disruption of this interaction results in MZB migration to the follicle. The migration of the MZMOs was further studied after the response to Staphylococcus aureus, which induced MZMOs to move into the red pulp while MZBs migrated into the follicular zone. The marginal zone is therefore a dynamic structure in which retention and trafficking of B cells requires specific macrophage-B cell interactions.

Animals↗
PubMed1998

Characterization of the lymphoid infiltrate in Hashimoto thyroiditis by immunohistochemistry and polymerase chain reaction for immunoglobulin heavy chain gene rearrangement.

A close relationship between Hashimoto thyroiditis (HT) and low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) has been shown. We used immunohistochemistry to study paraffin sections from 40 unselected cases of HT and scored cases according to the lymphoid infiltrate and presence of lymphoepithelial lesions (LELs). Clonality was assessed by kappa/lambda immunohistochemistry and polymerase chain reaction for immunoglobulin heavy chain gene rearrangement (IgH PCR). Histologic findings were compared with 2 cases of primary thyroid MALT-type lymphoma. In HT, the lymphoid infiltrate consisted predominantly of T cells in all cases; B cells, associated with germinal centers, did not have the appearance of marginal zone cells. All cases had identifiable T-cell LELs; immunohistochemistry confirmed inconspicuous, rare B-cell LELs in 13 of 40 cases. In all cases, plasma cells were polyclonal and IgH PCR showed a polyclonal pattern. Clinical follow-up was available for 34 patients. Lymphoma developed in none. In contrast, a B-cell predominant infiltrate of marginal zone cells was present in the MALT-type lymphomas that was not confined to germinal centers. Cytokeratin stains demonstrated severe loss of epithelial elements and destructive LELs. LELs are not, in isolation, a useful criterion for distinguishing low-grade MALT-type lymphoma of the thyroid from HT. Features associated with low-grade MALT-type lymphoma include a predominance of B cells, marked loss of epithelial elements, and destructive LELs composed of marginal zone B cells. Unselected cases of HT do not contain monoclones detectable by IgH PCR.

Adult↗
PubMed1998

[A case of marginal zone B-cell lymphoma].

A 60-year-old woman had an abnormal shadow in the right lower lung field on chest roentgenogram. Transbronchial lung biopsy revealed findings consistent with malignant lymphoma, and a right middle lobectomy was performed. Pathological findings showed that tumor cells had infiltrated the epithelium, forming so-called lymphoepithelial lesions. Flow cytometric analysis of the resected specimen revealed that B-cell associated antigens (CD 19, 20) were expressed, and that the tumor cells were CD 5-, CD 10-. A marked increase in the number of lymphocytes with an IgM kappa component suggested monoclonal origin for the tumor cells in the resected specimen. Southern blot analysis showed clonal rearrangement of the heavy chain of the immunoglobulin gene. A diagnosis of malignant lymphoma of bronchus-associated lymphoid tissue was made. This tumor was defined according to the revised European. American classification of lymphoid neoplasms as a marginal zone B-cell lymphoma.

Antigens, CD19↗
PubMed1986

Antigen-driven selection of virgin and memory B cells.

This review has summarized the evidence indicating that far more B cells are produced in adult bone marrow than are required to maintain B cell numbers in the periphery. It is shown that most if not all these newly-formed B cells have the potential to become mature peripheral B cells. However, to do this they need to receive an appropriate signal in secondary lymphoid organs. Cells failing to receive such a signal die after a brief period. Two separate situations have been identified which result in recruitment of newly-formed virgin B cells into the peripheral B-cell pool: Following activation by antigen. When the peripheral B-cell pool has been depleted. It is proposed that the first of these signals requires T help and is initiated by antigen presented on interdigitating cells in extrafollicular areas of secondary lymphoid organs. This process seems to be confined to periods immediately following administration of antigen and does not continue in established immune responses to thymus-dependent antigens. It seems probable that continued B cell activation, occurring during long term antibody responses, takes place in the follicles of secondary lymphoid organs and is driven by antigen presented on follicular dendritic cells. Indirect evidence is cited which suggests that somatic mutation in rearranged immunoglobulin V-region genes occurs mainly following B-cell activation in follicles and not during primary B lymphopoiesis. It is suggested that this may involve a hypermutation process which is switched on in activated B cells in germinal centers. Evidence is presented suggesting that plasma cells generated from B cells activated early in immune responses have an average life-span of less than 3 d. However, plasma cells generated in established responses appear to have an average life-span in excess of 20 d. Later sections in the review consider how B-cell recruitment in thymus-independent antibody responses differs markedly from recruitment during thymus-dependent responses. The possible role of splenic marginal zone B cells in some thymus-independent antibody responses is discussed and the evidence indicating that SIgM + ve, IgD-ve marginal zone B cells develop as a distinct population from recirculating SIgM + ve, IgD + ve B cells is summarized.

Adult↗
PubMed2003

Cutaneous marginal zone B-cell lymphoma: a case accompanied by massive plasmacytoid cells.

A 36-year-old man presented with a red nodule on his left shoulder. Histologically, there were variously sized, irregularly shaped nests throughout the dermis partly extending into the subcutaneous tissue. Masses of centrocyte-like cells were situated in the center of the tumor nests and accompanied by adjacent secondary follicle structures. Partial follicular colonization was seen. Massive plasmacytoid cells were located in the papillary dermis and the periphery of the tumor nests. Immunohistochemically, these centrocyte-like cells were positive for CD19 and alkaline phosphatase, and negative for CD5 and CD10. Cytoplasm of the plasmacytoid cells was positive for IgG and lambda-light chain, and negative for IgM, IgA, and kappa-light chain. Monotypic immunoglobulin staining including light chain restriction was shown. Clonal immunoglobulin heavy chain gene rearrangement by Southern blot analysis was shown in the tumor tissue. Morphologic, immunohistochemical, and molecular studies revealed that this patient had a cutaneous marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type. Electron beam (total 40 Gy) irradiation was applied. The tumor disappeared completely. Neither local recurrence or metastasis have appeared during 3 years of follow-up.

Adult↗
PubMed1990

A study of the properties of a low-grade mucosal B-cell lymphoma using a monoclonal antibody specific for the tumour immunoglobulin.

Primary low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) are tumours with distinctive clinico-pathological characteristics, two of which are studied in this paper, namely the tendency of the tumours to remain localized and the morphologic and phenotypic resemblance of the malignant cells to splenic marginal zone B cells. We have made a detailed study of a small intestinal lymphoma and a gastric lymphoma, which together with the spleen were resected from the same patient. Using a monoclonal antibody (7G3) raised against a unique determinant on the small intestinal tumour, we were able to detect disseminated small intestinal tumour cells in the stomach and spleen. The tumour in the stomach was genetically related, but non-identical to that in the small intestine, and was not recognized by 7G3. Lymphocytes expressing the marker of the small intestinal tumour (7G3) were present in lymphoid nodules in the stomach, and 7G3+ plasma cells were present beneath the gastric epithelium. In the spleen, cells expressing 7G3 were present in the marginal zone and plasma cells expressing the same marker were present in the red pulp. These findings suggest that low-grade MALT lymphomas may migrate beyond the primary tumour site, but that tumour cells distant to the primary site may differentiate into mature, non-dividing plasma cells. The localization of small intestinal tumour cells in the splenic marginal zones reinforces the suggestion of lineage homology between these populations of cells.

Antibodies, Monoclonal↗
PubMed2005

The role of host CD4 T cells in the pathogenesis of the chronic graft-versus-host model of systemic lupus erythematosus.

Systemic lupus erythematosus is characterized by production of autoantibodies and glomerulonephritis. The murine chronic graft-vs-host (cGVH) model of systemic lupus erythematosus is induced by allorecognition of foreign MHC class II determinants. Previous studies have shown that cGVH could not be induced in CD4 knockout (CD4KO) mice. We have further explored the role of host CD4 T cells in this model. Our studies now show that B cells in CD4KO mice have intrinsic defects that prevent them from responding to allohelp. In addition, B cells in CD4KO mice showed phenotypic differences compared with congeneic C57BL/6 B cells, indicating some degree of in vivo activation and increased numbers of cells bearing a marginal zone B cell phenotype. The transfer of syngeneic CD4 T cells at the time of initiation of cGVH did not correct these B cell abnormalities; however, if CD4 T cells were transferred during the development and maturation of B cells, then the B cells from CD4KO mice acquire the ability to respond in cGVH. These studies clearly indicate that B cells need to coexist with CD4 T cells early in their development to develop full susceptibility to alloactivation signals.

Adoptive Transfer↗
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↗
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↗
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↗