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PubMed2006

IgD positive L&H cells identify a unique subset of nodular lymphocyte predominant Hodgkin lymphoma.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare B-cell lymphoma considered to be of germinal center (GC) derivation. Studies on immunoglobulin expression have been few, and post-switch immunoglobulin (IgG) has been identified in the majority of cases examined thus far. We reviewed 180 cases of NLPHL and observed the unexpected expression of IgD in 27% of cases. IgD is usually coexpressed with IgM in naive B cells but can also be seen as IgD-only in centroblasts (CD38-positive) or memory B cells (CD27-positive). We asked whether IgD-positive NLPHL differed from cases of NLPHL negative for IgD. Clinically, the IgD-positive cases presented at a younger median age (21 vs. 44 years) and had a striking male predominance (male-to-female ratio, 23:1 vs. 1.5:1). Cervical lymph nodes were more frequently involved (56% vs. 18.2%). L&H cells were localized in a predominantly extrafollicular distribution in the majority of IgD-positive cases (69%). The IgD-positive cases did not coexpress IgM or CD27 (a marker associated with memory B cells), and nearly all (93%) were weakly positive for CD38, supporting a GC derivation. The expression of Bcl-6, BOB.1, Oct2, and SWAP-70 was similar in the two groups. However, PU.1 expression was seen in 60% of the IgD-positive cases in contrast to 86% of the IgD-negative cases. The absence of PU.1 staining correlated with more L&H cells in an extrafollicular distribution, weakening the use of this marker in the differential diagnosis with T-cell rich/histiocyte rich B-cell lymphomas. To study IgD expression in "de-novo" T-cell rich/histiocyte rich B-cell lymphomas, we analyzed 20 cases and all but one were negative. In conclusion, cases of IgD-positive NLPHL do not differ from IgD-negative cases regarding cellular derivation and most other immunophenotypic characteristics. However, IgD-positive NLPHL exhibits distinctive clinical features, and more often involves the interfollicular region in a background relatively rich in T cells. IgD positivity may represent an additional useful marker in the diagnosis of NLPHL.

Adolescent↗
PubMed1997

Dendritic cells enhance growth and differentiation of CD40-activated B lymphocytes.

After antigen capture, dendritic cells (DC) migrate into T cell-rich areas of secondary lymphoid organs, where they induce T cell activation, that subsequently drives B cell activation. Here, we investigate whether DC, generated in vitro, can directly modulate B cell responses, using CD40L-transfected L cells as surrogate activated T cells. DC, through the production of soluble mediators, stimulated by 3- to 6-fold the proliferation and subsequent recovery of B cells. Furthermore, after CD40 ligation, DC enhanced by 30-300-fold the secretion of IgG and IgA by sIgD- B cells (essentially memory B cells). In the presence of DC, naive sIgD+ B cells produced, in response to interleukin-2, large amounts of IgM. Thus, in addition to activating naive T cells in the extrafollicular areas of secondary lymphoid organs, DC may directly modulate B cell growth and differentiation.

Animals↗
PubMed1997

Apoptosis and the B cell response to antigen.

The primary B cell response to T cell dependent antigens comprises two pathways of differentiation; one resulting in formation of foci of antibody forming cells in the extrafollicular regions of secondary lymphoid organs and the other giving rise to germinal centers within the follicles. Foci of antibody forming cells are detectable for only a limited time, before involuting due to apoptosis of the plasma cells. Similarly in the germinal center, regulation of cell number, selection of high affinity variants generated by somatic hypermutation, and the resolution of the germinal center itself all involve the death of unwanted B cells. In this review we describe recent experiments which have allowed determination of the role of certain forms of apoptosis in the B cell response to antigen.

Animals↗
PubMed2006

B cell clones that sustain long-term plasmablast growth in T-independent extrafollicular antibody responses.

Some antigens induce Ab responses without T lymphocyte help. Among these, many polysaccharide-based antigens cause marginal zone B cells to proliferate and differentiate into plasma cells. B1 cells also respond to some of these antigens. In this article, we report that antigen-specific B1b cells, in response to the T-independent antigen (4-hydroxy-3-nitrophenyl)-acetyl (NP)-Ficoll, develop into clones that sustain Ab production for months with continued production of plasma cells and the accumulation of antigen-specific B cells in follicles. The persistence of this T-independent plasmablast response contrasts with the short-term plasmablast growth associated with T-dependent extrafollicular responses. The nature of the cells responding to NP-Ficoll was probed by using chimeras that have B1 cells but lack primary B lymphopoietic capacity and have very few B2 cells or T cells. The chimeras were constructed by transferring 10(5) IgM(+) IgD(-) peritoneal exudate cells into mice unable to produce their own T and B cells because of deficiency in recombinase-activating gene 1 (RAG-1). The chimeras mounted sustained IgM and IgG3 anti-NP Ab responses to NP-Ficoll. This finding was associated with continued NP-specific extrafollicular plasmablast growth and the accumulation of NP-specific B cells in follicles. B cells were not found in the marginal zones of chimeras, and they also lacked recirculating IgD(+) cells and CD3(+) cells. The absence of B2 and T cells confirms that hemopoietic cell chimerism leading to primary lymphopoiesis had not been established.

Animals↗
PubMed1997

Human interdigitating dendritic cells directly stimulate CD40-activated naive B cells.

Human interdigitating dendritic cells (IDC) were isolated from tonsils based on their CD40+ lineage-negative expression in situ. Isolated IDC displayed a phenotypic profile similar to that of IDC in tonsils and spleen in situ, characterized by high-level expression of major histocompatibility complex class II, the co-stimulatory molecules B7.1 (CD80) and B7.2 (CD86), expression of the late DC maturation marker CD83, and no expression of CD1a, CD13, or CD33. IDC also showed weak nonspecific esterase staining and had the ability to induce an allogeneic mixed lymphocyte reaction. In this study, we further show that in the presence of surrogate activated T cells in the form of CD40 ligation and IL-2, IDC enhance the proliferation of naive B cells and induce their differentiation into plasma cells producing IgM. Evidence for the anatomical co-localization of naive B cells and IDC in the T cell area together with the data obtained in vitro implies a role for IDC in the initiation of the extrafollicular reaction.

B-Lymphocytes↗
PubMed2006

Bovine early embryonic development and vitamin A.

Vitamin A and its derivatives, collectively termed as retinoids, have been paid attention in recent years because of their effects in bovine reproduction. However, the role of retinoids in the pre-implantation period continues to be largely unexplored, in contrast to later stages of development. Retinoids control cell growth, differentiation and death through binding to specific nuclear receptors by retinoic acid and other active metabolites. This paper reviews how retinoids can influence early embryonic development in cattle through their influence on the follicle, the extrafollicular oocyte and the pre-implantation embryo itself.

Animals↗
PubMed1998

An in vitro approach for the characterization of the cycling B cell response.

Because isolation of sufficient numbers of cycling, germinal center B cells from mice for biochemical characterization of BCR-derived signals can be problematic, we have designed an experimental approach for generating large numbers of cycling B cells for further study. In the experiments reported here, small, resting B cells were polyclonally stimulated with lipopolysaccharide (LPS), and cycling B cells isolated as two bands on three-step Percoll gradients. Cycling B cells isolated at Days 2, 4, or 6 of preactivation showed an increased expression of Fas receptor and peanut agglutinin binding, with a concomitant decrease in sIgD positivity. These cells phenotypically resembled extrafollicular or early germinal center B cells. These cycling B cells were used to study the functional consequences of differential signaling through the BCR. Strong cross-linking of BCR, by restimulation of cycling normal B cells with either immobilized or soluble F(ab')2 anti-mu and cycling hen egg lysozyme (HEL) transgenic B cells with either soluble or immobilized HEL, extended cellular proliferation by 2-3 d. In contrast, cycling B cells either restimulated with soluble, whole anti-mu (to mimic binding of soluble immune complexes) or cultured in the absence of restimulation (to mimic cycling B cells not competitive for antigen) resulted in the rapid exit of the cells from cycle. This system will enable the molecular and biochemical characterization of signal delivery to cycling B cells.

Animals↗
PubMed1992

[Expression of beta 1 integrins in normal B lymphocytes at different stages of development and in B cell neoplasias].

VLA-1 to -6 are cell surface molecules binding to matrix molecules such as collagen, fibronectin, epiligrin, and laminin. In addition, VLA-4 binds to VCAM-1 and ICAM-2, thus mediating intercellular adhesion prerogative for lymphocyte extravasation or "homing". Using frozen tissue of normal lymphoid organs and of 100 morphologically and immunologically typed B cell neoplasias, monoclonal antibodies to all six VLA-alpha subunits and to the common beta 1-chain were applied to serial sections. VLAs were found differentially expressed in cytologically and microtopographically defined B cell subsets [follicular mantle zone cells (MZ), follicular center cells (FC), extrafollicular cells (EF), and plasma cells (PC)] of normal spleen, lymph node, and thymic medulla (which contains an EF compartment). Thus, these cell types, which correspond to discrete stages of B cell development, can also be defined by their VLA status. Acute B lymphoblastic leukemia (ALL) was VLA-1-, 2-, 3 +/-, 4 +/-, 5 +/-, 6-. The VLA-1-, -2 +/-, -3+, -4+, -5+, -6- phenotype of chronic B lymphocytic leukemia (CLL) resembled that of MZ. Hairy cell leukemia (HCL) differed from CLL in its tendency to lack VLA-2, in its consistent lack of VLA-3, and altogether resembled splenic EF in its VLA profile. Mantle zone lymphoma (MZL) consistently expressed VLA-3 and -4 and frequently VLA-5. Nodal follicular center cell lymphomas (FCCL) were VLA-1- and -2- and very rarely expressed VLA-5 and -6. Thus, FCCL although roughly corresponding to FC, tended to aberrantly express VLA-3 and/or VLA-4. Burkitt's lymphoma resembled FCCL but expressed VLA-4 more frequently and at higher levels.(ABSTRACT TRUNCATED AT 250 WORDS)

B-Lymphocytes↗
PubMed1992

Adhesion molecules VLA-1 to VLA-6 define discrete stages of peripheral B lymphocyte development and characterize different types of B cell neoplasia.

VLA-1 to VLA-6 are cell-surface molecules binding to matrix molecules such as collagen, fibronectin, epiligrin, and laminin. In addition, VLA-4 binds to VCAM-1 and ICAM-2, thus mediating intercellular adhesion prerogative for lymphocyte extravasation or 'homing'. Using frozen tissue of normal lymphoid organs and of 100 morphologically and immunologically typed B cell neoplasias, monoclonal antibodies to all six VAL-alpha and to the common beta-chain were applied to serial sections. VLAs were found differentially expressed in cytologically and microtopographically defined B-cell subsets [follicular mantle zone cells (MZ), follicular center cells (FC), extrafollicular cells (EF), and plasma cells (PC)] of normal spleen, lymph node, and thymic medulla (which contains an EF compartment). Thus, these cell types, which correspond to discrete stages of B cell development, can also be defined by their VLA status. Acute B lymphoblastic leukemia (ALL) was VLA-1-, 2-, 3 +/-, 4 +/-, 5 +/-, 6-. The VLA-1-, -2 +/-, 3+, -4+, -5+, -6-phenotype of chronic B lymphocytic leukemia (CLL) resembled that of MZ. Hairy cell leukemia (HCL) differed from CLL in its tendency to lack VLA-2, in its consistent lack of VLA-3, and altogether resembled splenic EF in its VLA profile. Mantle zone lymphoma (MZL) consistently expressed VLA-3 and -4 and frequently VLA-5. Nodal follicular center cell lymphomas (FCCL) were VLA-1- and -2- and very rarely expressed VLA-5 and -6. Thus, FCCL although roughly corresponding to FC, tended to aberrantly express VLA-3 and/or VLA-4. Burkitt's lymphoma resembled FCCL but expressed VLA-4 more frequently and at higher levels. Mediastinal clear cell lymphoma of B-cell type differed from FCCL in its regular lack of VLA-3, -5, and -6 and in frequently lacking VLA-4. Medullary plasmacytoma was VLA-1-, -2-, -3 +/-, -4 +/-, -5-, -6+, thus being the only B cell neoplasia which was consistently VLA-6+. With respect to the well-known clinical characteristics of the B cell malignancies examined, the leukemic phenotype might crucially depend on the presence of VLA-5.

B-Lymphocytes↗
PubMed1991

Phenotype and topography of human thymic B cells. An immunohistologic study.

Using single and double labeling immunohistochemical techniques and a large panel of monoclonal antibodies against B-cell differentiation antigens, including those newly defined at the Fourth International Leucocyte Typing Workshop, we have examined the immunophenotype and tissue distribution of human thymic B-cells. The existence of a distinct B-cell population as a constant constituent of the thymic microenvironment has been noted only recently. We found a significant population of B-lymphocytes in the thymic medulla expressing the B-cell restricted antigens CD19, CD20, CD22, CD37, CD72, CD76 and IgM and IgD. As with other extrafollicular B-lymphocytes, they differ significantly from both follicle mantle and germinal center cells in morphology and immunophenotype, which points to alternative modes of B-cell differentiation. Thymic B-cells themselves show considerable heterogeneity and a subpopulation with dendritic features and the expression of CD23 has been referred to as "asteroid" cells. Their close association with T-cells and medullary epithelial cells points to a functional role for B-cells in the thymus. A second population of B-lymphocytes together with frequent lymph follicles is found within the extrathymic perviascular space. Though separated from the medulla by a layer of epithelial cells, a clear distinction between the B-cells of these two compartments is not always possible. The intramedullary B-cell compartment shows a parallel numeric increase with the occurrence of germinal centers in the perivascular space, mostly due to an accumulation of B-cells in the medulla adjacent to these lymph follicles. Thus a close relationship between the intra- and extramedullary B-cell population of the thymus seems likely.

Adolescent↗
PubMed1991

Expression of beta 1-integrins, H-CAM (CD44) and LECAM-1 in primary gastro-intestinal B-cell lymphomas as compared to the adhesion receptor profile of the gut-associated lymphoid system, tonsil and peripheral lymph node.

beta 1-Integrins (VLA-1 to -6) are cell-surface molecules binding to matrix molecules such as collagen, fibronectin and laminin. VLA-4 is the human homologue to the murine Peyer's patch homing receptor mediating cell/cell adhesion required for lymphocyte extravasation or "homing". Other structures which have a homing-receptor function through recognition of venular endothelium are H-CAM (CD44) and LECAM-1 (LAM-1, human MEL-14 equivalent). In order to elucidate whether these adhesion receptors are expressed in primary gastro-intestinal malignant B-cell lymphomas (GI BmL) which, in this case, might contribute to the initial confinement to this extranodal site, 31 extensively characterized tumors were examined together with reactive lymphoid tissues from small and large intestine, tonsil and lymph node using monoclonal antibodies (MAbs) against these receptors. All types of adhesion receptors were differentially expressed in the cytologically and microtopographically defined B-cell subsets [follicular center cells (FC), mantle-zone cells (MZ), extrafollicular cells (EF) and plasma cells (PC)] of the normal B-cell system. With the exception of differences in LECAM-1 levels among EF and PC of intestinal vs. nodal vs. tonsillar sites, receptor profiles were almost identical in different lymphoid organs. The expression pattern of these molecules in GI BmL was markedly heterogeneous, mimicking to some extent the receptor equipment of their reactive cellular counterpart. Thus, we failed to find a unifying adhesion receptor profile indicative of a tissue-specific homing of reactive and neoplastic B-cells.

Antibodies, Monoclonal↗
PubMed1997

Human dendritic cells skew isotype switching of CD40-activated naive B cells towards IgA1 and IgA2.

Within T cell-rich areas of secondary lymphoid organs, interdigitating dendritic cells recruit antigen-specific T cells that then induce B cells to secrete Igs. This study investigates the possible role(s) of dendritic cells in the regulation of human B cell responses. In the absence of exogenous cytokines, in vitro generated dendritic cells (referred to as Dendritic Langerhans cells, D-Lc) induced surface IgA expression on approximately 10% of CD40-activated naive sIgD+ B cells. In the presence of IL-10 and TGF-beta, a combination of cytokines previously identified for its capacity to induce IgA switch, D-Lc strongly potentiated the induction of sIgA on CD40-activated naive B cells from 5% to 40-50%. D-Lc alone did not induce the secretion of IgA by CD40-activated naive B cells, which required further addition of IL-10. Furthermore, D-Lc skewed towards the IgA isotype at the expense of IgG, the Ig production of CD40-activated naive B cells cultured in the presence of IL-10 and TGF-beta. Importantly, under these culture conditions, both IgA1 and IgA2 were detected. In the presence of IL-10, secretion of IgA2 by CD40-activated naive B cells could be detected only in response to D-Lc and was further enhanced by TGF-beta. Collectively, these results suggest that in addition to activating T cells in the extrafollicular areas of secondary lymphoid organs, human D-Lc also directly modulate T cell-dependent B cell growth and differentiation, by inducing the IgA isotype switch.

Antigens, CD34↗
PubMed1987

Cytoskeletal components of lymphoid organs. I. Synthesis of cytokeratins 8 and 18 and desmin in subpopulations of extrafollicular reticulum cells of human lymph nodes, tonsils, and spleen.

Using light and electron microscopic immunolocalization with antibodies to cytoskeletal proteins, we have characterized the nonlymphoid cells of various human lymphoid organs (lymph nodes, tonsils, spleen). In all these tissues, the lymphoid follicles contain a three-dimensional meshwork of "dendritic reticulum cells" which are characterized by the presence of desmosomal junctions, as demonstrated by positive punctate staining with antibodies to the desmosome-specific proteins desmoplakin I and desmoglein, and by intermediate-sized filaments (IFs) of the vimentin type only. In contrast, the extrafollicular regions are characterized by an extended meshwork of other types of reticulum cells, which also contain vimentin IFs but lack desmosomal proteins. In addition, a considerable, although variable proportion of these extrafollicular reticulum cells forms IFs containing cytokeratins 8 and 18 and/or desmin-containing IFs. The occurrence of cytokeratins 8 and 18 in lymph nodes has also been shown by gel electrophoresis and immunoblotting. Results of double-label immunolocalization indicate that some of the extrafollicular reticulum cells coexpress all three kinds of IF protein. A large proportion of these cells also synthesizes another marker of myogenic differentiation, i.e., the isoform of alpha-actin specific for smooth muscle. This proportion includes some cells that are negative for desmin. Comparison of the distribution of cells expressing cytokeratins and/or desmin with that of reticulum cells showing strong alkaline phosphatase activity (as a marker for the so-called "fiber-associated (fibroblastic) reticulum cells") suggests that the former represent a subset of the latter. The biological meaning of these different patterns of expression in reticulum cells and of the resulting cell-type heterogeneity as well as possible implications of these observations for tumor diagnosis, notably of lymph-node metastases and lymphomas, are discussed.

Adult↗
PubMed2005

PRDM1/Blimp-1 is expressed in human B-lymphocytes committed to the plasma cell lineage.

PRDM1/Blimp-1 (in human and mouse, respectively) has a central role in determining and shaping the secretory arm of mature B-cell differentiation. In this study, a mouse monoclonal antibody that recognizes PRDM1 was used to detail its distribution in normal human lymphoid tissue and in lymphoid neoplasms that correspond to different stages of B-cell differentiation. PRDM1 was expressed in germinal centre blasts that co-express Pax5, CD19, CD20, and CD10, but not BCL6 or MTA-3. Pax5 was downregulated and full plasma cell morphology and phenotype were acquired by PRDM1+, nuclear cREL-, pre-plasma cells upon exit from the germinal centre. Activated extrafollicular B-cells (CD30+, Pax5+) were largely PRDM1-. PRDM1 was also absent in tissue histiocytes and the majority of resting T-cells and S-100+ antigen-presenting cells. PRDM1 and CD138 were expressed simultaneously in human lymphomas with plasma cell differentiation, but not in marginal zone lymphomas or chronic lymphocytic leukaemias. A minority of diffuse large B-cell lymphomas expressed PRDM1 and Hodgkin lymphomas were largely PRDM1-. Infiltrating T-cells in PRDM1- B-cell lymphomas expressed PRDM1. In conclusion, PRDM1 staining is a reliable and informative assay to define plasma cell commitment and differentiation in human normal and neoplastic B-cell lineages.

Animals↗
PubMed2001

Changing responsiveness to chemokines allows medullary plasmablasts to leave lymph nodes.

During T cell-dependent antibody responses lymph node B cells differentiate either to plasmablasts that grow in the medullary cords, or to blasts that proliferate in follicles forming germinal centers. Many plasmablasts differentiate to plasma cells locally, but some leave the medullary cords and migrate to downstream lymph nodes. To assess the basis for this migration, changes in the responsiveness of B cells to a range of chemokines have been studied as they differentiate. Naive B cells express high levels of CCR6, CCR7, CXCR4 and CXCR5. When activated B cells grow in follicles the expression of these chemokine receptors and the responsiveness to the respective chemokines is retained. During the extrafollicular response, plasmablast expression of CXCR5 and responsiveness to B-lymphocyte chemoattractant (CXCR5) as well as to secondary lymphoid tissue chemokine (CCR7) and stromal cell-derived factor (SDF)-1 (CXCR4) are lost while a weak response towards the CCR6 chemokine LARC is maintained. Despite losing responsiveness to SDF-1, extrafollicular plasmablasts still express high levels of CXCR4 on the cell surface. These results suggest that the combined loss of chemokine receptor expression and of chemokine responsiveness may be a necessary prerequisite for cells to migrate to the medullary cords and subsequently enter the efferent lymph.

Animals↗
PubMed1995

Differential expression of cell adhesion molecules in the functional compartments of lymph nodes and tonsils.

Aims-To analyse the topographical distribution of adhesion molecules involved in lymphocyte recirculation in human lymph nodes and tonsils. The study focused on the expression of LECAM-1 (CD62L), VLA-alpha4 (CD49d), VLA-beta1 (CD29), LFA-1 alphaL (CD11a), LFA-beta2 (CD18), VCAM-1 (CD106), ICAM-1 (CD54), and H-CAM (CD44).Methods-Reactive lymph nodes and palatine tonsils were studied using immunofluorescence methods with fluorescein isothiocyanate (FITC) labelled monoclonal antibodies directed against cell adhesion molecules. To investigate the expression patterns of these molecules in the T and B cell populations, double labelling experiments were performed using Texas Red labelled antibodies against CD2 or CD19, respectively. The images from each fluorochrome were then simultaneously analysed using a laser scanning confocal microscope.Results-LECAM-1, VLA-alpha4 and H-CAM were predominantly expressed by mantle zone B cells, VCAM-1 and ICAM-1 by germinal centre cells, most of which exhibited a reticular staining pattern suggestive of follicular dendritic cells, whereas LFA-1 alphaL and LFA-beta2 were mainly found in extrafollicular and germinal centre T cells. All high endothelial venules expressed VLA-beta1 and ICAM-1, whereas VCAM-1 was present in only a few, with variable intensity.Conclusions-The data show that all of these adhesion molecules are differentially distributed within the distinct functional microenvironments of both organs. The differences observed in the expression patterns among the B and T cells belonging to different compartments probably depend on the momentum of cell traffic, the stage of maturation/activation, as well as on their functional role in the immune response.

Journal Article↗
PubMed1994

Lymphocytic infiltration in focal thyroiditis: an ultrastructural case study.

In autoimmune thyroiditis, infiltrating lymphocytes play an important role in the disease process since they are known to release cytokines which can alter thyroid functions. The degree and site of lymphocytic infiltration in the thyroid gland have been used to differentiate between Hashimoto's disease and focal lymphocytic thyroiditis. Intraluminal lymphocytes have been reported to be absent in focal thyroiditis but present in Hashimoto's disease. However, we demonstrate here by transmission electron microscopy, that extrafollicular and intrafollicular lymphocytes could be present in focal lymphocytic thyroiditis. This seems to support the notion that focal lymphocytic thyroiditis could represent part of the spectrum of autoimmune thyroiditis and Hashimoto's thyroiditis.

Adult↗