scholarly journals Gap-Junction Communication Pathways in Germinal Center Reactions

1998 ◽  
Vol 6 (1-2) ◽  
pp. 111-118 ◽  
Author(s):  
Tibor Krenacs ◽  
Martin Rosendaal
Keyword(s):  
B Cells ◽  
Gap Junctions ◽  
B Cell ◽  
Germinal Center ◽  
Lucifer Yellow ◽  
Cell Communication ◽  
Germinal Centers ◽  
Lymphoid Tissues ◽  
Human Tonsil ◽  
Cell Fractions

Intercellular channels called gap junctions enable multicellular organisms to exchange information rapidly between cells. Though gap junctions are held to be ubiquitous in solid tissues, we have only recently found them in the lymphoid organs. Functional direct cell-cell communication has now been confirmed by us and other groups in bone marrow, thymus, and in secondary lymphoid tissues. What functions do they serve in the lymphoreticular system where, so far, only cytokines/growth factors and adhesion molecules have been considered as regulators? Here we show evidence for and refer to published work about functional direct cellcell communication through gap junctions in germinal center reactions and make proposals for their role in the immune response.We found a large amount of the connexin43 (Cx43) gap junctions in the germinal centers of secondary lymphoid follicles. Ultrastructurally and immunohistologically, most of the junctions were detected on the processes of follicular dendritic cells (FDC) enveloping nondividing centrocytes in the light zone of germinal centers where B-cell selection is thought to take place. Further support for this finding came by revealing the Cx43 mRNAin situat the same location as the protein. On antigen challenge, gap junctions appeared on the FDC as they formed meshworks in germinal centers. In order to find out which germinal center cells communicate directly, we separated FDC-rich, low-density, B-cell fractions from human tonsil. In culture, we injected single FDC with the low-molecular-weight fluorescent dye, Lucifer Yellow (Mr 457 Da), which passed between adjacent FDC and sometimes from FDC to B cells.Based on these findings and their assigned functions in other tissues, gap junctions may contribute to germinal center reactions in the following ways: (1) they may regulate follicle pattern formation by controlling FDC growth, (2) they may be involved in FDC-B-cell signaling contributing to the final rescue of selected B cells from apoptosis, and (3) they may enable FDC to work as a functional syncytium providing a cellular internet for integrating germinal center events. Data supporting these interpretations are briefly discussed.

scholarly journals Telomerase activation in normal B lymphocytes and non-Hodgkin's lymphomas

Blood ◽  
1996 ◽  
Vol 88 (1) ◽  
pp. 222-229 ◽  
Author(s):  
KF Norrback ◽  
K Dahlenborg ◽  
R Carlsson ◽  
G Roos
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Telomerase Activity ◽  
Lymphoid Tissues ◽  
Low Grade ◽  
Malignant Lymphomas ◽  
Hodgkin's Lymphomas ◽  
Germinal Center B Cells

Abstract Activation of telomerase seems to be a prerequisite for immortalization and is found in permanent cell lines and most malignant tumors. Normal somatic cells are generally telomerase negative, except for bone marrow stem cells. Weak activity is also present in peripheral blood cells. In the present study strong telomerase activity was demonstrated in vivo in normal mature cells of the immune system, as well as in malignant lymphomas. Benign lymph nodes had lower telomerase activity than benign tonsils, which exhibited intermediate to high activity comparable with findings in malignant lymphomas. In benign tonsils the activity seemed to be restricted to germinal center B cells. In benign lymphoid tissues telomerase activity correlated with B-cell numbers and cell proliferation, but this was not observed in the lymphoma group. High- grade lymphomas exhibited higher levels of telomerase compared with low- grade cases. The data showed that in vivo activation of telomerase is a characteristic feature of germinal center B cells. Different signals for activation of telomerase are likely to exist, one of them being immune stimulation. The data suggest that telomerase activity in malignant lymphomas can be explained by an “induction and retention” model, ie, transformation occurs in a normal, mature B cell with reactivated telomerase, which is retained in the neoplastic clone.

scholarly journals Bcl-x rather than Bcl-2 mediates CD40-dependent centrocyte survival in the germinal center

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1359-1364 ◽  
Author(s):  
JM Tuscano ◽  
KM Druey ◽  
A Riva ◽  
J Pena ◽  
CB Thompson ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Protein Levels ◽  
Staphylococcus Aureus Cowan ◽  
A Cell ◽  
Tonsil Tissue ◽  
Cell Fractions ◽  
Selection Of

Both rapid B-cell proliferation and programmed cell death (PCD) occur during the differentiation and selection of B cells within the germinal center. To help elucidate the role of Bcl-x in B-cell antigen selection and PCD within the germinal center, we examined its expression in defined B-cell populations and by immunochemistry of tonsil tissue. Purified B-cell fractions enriched for centrocytes express high amounts of Bcl-x and relatively low amounts of Bcl-2, whereas fractions enriched for centroblasts lack significant levels of both proteins. Consistent with this observation, immunocytochemistry localized Bcl-x within cells scattered throughout the germinal center. Stimulation of tonsil B cells with either CD40 or Staphylococcus aureus Cowan increase bcl-x mRNA and protein levels. Treatment of a cell line with a germinal center phenotype (RAMOS) or the tonsillar B-cell centroblast fraction with CD40 rapidly increased Bcl-x levels and partially rescued B cells from PCD. These data suggest that Bcl-x rather than Bcl-2 may rescue centrocytes during selection in the germinal center.

scholarly journals K21-Antigen: A Molecule Shared by the Microenvironments of the Human Thymus and Germinal Centers

1998 ◽  
Vol 6 (1-2) ◽  
pp. 41-52 ◽  
Author(s):  
Nesrina Imami ◽  
Heather M. Ladyman ◽  
Bjarne Vincents ◽  
Abdulhamid Al-Tubuly ◽  
Jona Freysdóttir ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Intracellular Localization ◽  
Flow Cytometric Analysis ◽  
Germinal Centers ◽  
Lymphoid Cells ◽  
Thymic Epithelial Cells ◽  
Lymphoid Tissues ◽  
Human Thymus

The mouse IgG1 monoclonal antibody (mAb) K21 recognizes a 230-kD molecule (K21-Ag) on Hassall's corpuscles in the human thymus. This mAb also stains cultured thymic epithelial cells as well as other epithelial cell lines, revealing a predominant intracellular localization. Further analysis with mAb K21 on other lymphoid tissues showed that it also stains cells within the germinal centers of human tonsils, both lymphoid (B) cells and some with the appearance of follicular dendritic cells. Double immunostaining of tonsil sections shows that K21-Ag is not expressed by T cells, whereas staining with anti-CD22 and -CD23 mAb revealed some doublepositive cells. A subpopulation of the lymphoid cells express the K21-Ag much more strongly. This K21++/CD23++subpopulation of cells is localized in the apical light zone of germinal centers, suggesting that K21-Ag may be an important marker for the selected centrocytes within germinal centers and may play a role in B-cell selection and/or development of B-cell memory. Flow cytometric analysis showed that K21-Ag is expressed on the surface of a very low percentage of thymocytes, tonsillar lymphocytes, and peripheral blood mononuclear cells. Analysis of purified/separated tonsillar T and B lymphocytes showed that T cells do not express the K21-Ag; in contrast, B cells express low levels of the K21-Ag, and this together with CD23 is upregulated after mitogenic stimulation. Our data therefore raise the possibility that the K2l- Ag may play a role in B-lymphocyte activation/selection.

miRNA Profiling of B Cell Subsets: Specific miRNA Profile for Germinal Center B Cells with a Marked Variation Between Centroblast and Centrocytes.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1459-1459
Author(s):  
Lu Ping Tan ◽  
Miao Wang ◽  
Jan-Lukas Robertus ◽  
Rikst Nynke Schakel ◽  
Johan H Gibcus ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Germinal Centers ◽  
Memory B Cells ◽  
Mirna Profile ◽  
Mantle Zone ◽  
Tissue Sections ◽  
Germinal Center B Cell ◽  
Germinal Center B Cells

Abstract MiRNAs are a new class of small RNAs, of 19–23 nucleotides that were discovered less than two decades ago. These tiny RNAs can negatively regulate genes at the post-transcriptional level by either triggering translational repression or direct cleavage of mRNAs. It has become evident that miRNAs are involved in hematopoiesis and that the aberrant expression of miRNAs may give rise to hematopoietic malignancies. The aim of our study was to characterize the miRNA profile of naïve, germinal center and memory B cells sorted from tonsils and review expression of selected miRNAs in tonsils and in B cell malignancies by miRNA in situ hybridization (ISH). Quantitative (q)RT-PCR profiling revealed that several miRNAs were elevated in germinal center B cells, including miR-17–5p, miR-106a and miR-181b. miR-150 was one of the most abundant miRNAs in all subsets, but the expression level was more than 10 fold lower in germinal center B cell as compared to the other two subsets. MiRNA ISH on tonsillar tissue sections confirmed findings from the profiling work, and at the same time depicted differences in staining intensities within germinal centers. According to miRNA ISH, expression levels of miR-17-5p, miR-106a, and miR-181b were indeed higher in germinal center B cells as compared to naïve and memory B cells in the mantle zone. Surprisingly, we also observed gradual decrease of miR-17-5p, miR-106a, and miR-181b staining from dark to light zone in the germinal centers. Moreover, miRNA ISH with a probe for miR-150 demonstrated an interesting staining pattern in lymph node tissue sections. Naïve and memory B cells located in the mantle zone showed a higher miR-150 expression as compared to most of the cells in the germinal centers. However, within the germinal centers a minority of cells showed a much stronger cytoplasmic staining in part of the blasts located specifically in the dark zone. This indicated that part of the centroblasts have a high expression level of miR-150. The level of miR-150 was surprisingly low in 22 B cell lymphoma cell lines, irrespective of germinal center or non germinal center B cell origin. This seemingly negative association of miR-150 with proliferation suggests a role in B cell growth/death. We observed an inverse expression pattern of miR-150 and Survivin in the germinal centers by miRNA ISH and immunohistochemistry. Moreover, induction of miR-150 using synthetic mature miR-150 duplex resulted in reduced Survivin expression levels. Our results suggested that aside the experimentally proven target c-Myb, Survivin may also be regulated by miR-150. In conclusion, we have revealed a unique miRNA profile of naïve, germinal center and memory B cells sorted from normal tonsils and the results were confirmed by miRNA ISH. Within the germinal centers a marked difference was observed between the light zone and the dark zone.

scholarly journals Germinal Centers without T Cells

2000 ◽  
Vol 191 (3) ◽  
pp. 485-494 ◽  
Author(s):  
Carola García de Vinuesa ◽  
Matthew C. Cook ◽  
Jennifer Ball ◽  
Marion Drew ◽  
Yvonne Sunners ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
High Efficiency ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
High Affinity ◽  
Safe Mechanism ◽  
Germinal Center Formation

Germinal centers are critical for affinity maturation of antibody (Ab) responses. This process allows the production of high-efficiency neutralizing Ab that protects against virus infection and bacterial exotoxins. In germinal centers, responding B cells selectively mutate the genes that encode their receptors for antigen. This process can change Ab affinity and specificity. The mutated cells that produce high-affinity Ab are selected to become Ab-forming or memory B cells, whereas cells that have lost affinity or acquired autoreactivity are eliminated. Normally, T cells are critical for germinal center formation and subsequent B cell selection. Both processes involve engagement of CD40 on B cells by T cells. This report describes how high-affinity B cells can be induced to form large germinal centers in response to (4-hydroxy-3-nitrophenyl) acetyl (NP)-Ficoll in the absence of T cells or signaling through CD40 or CD28. This requires extensive cross-linking of the B cell receptors, and a frequency of antigen-specific B cells of at least 1 in 1,000. These germinal centers abort dramatically at the time when mutated high-affinity B cells are normally selected by T cells. Thus, there is a fail-safe mechanism against autoreactivity, even in the event of thymus-independent germinal center formation.

scholarly journals Coupled Antigen and BLIMP1 Asymmetric Division With a Large Segregation Between Daughter Cells Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells and a DZ-to-LZ Ratio in the Germinal Center

2021 ◽  
Vol 12 ◽  
Author(s):  
Elena Merino Tejero ◽  
Danial Lashgari ◽  
Rodrigo García-Valiente ◽  
Jiaojiao He ◽  
Philippe A. Robert ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Germinal Centers ◽  
Memory B Cells ◽  
Plasma Cell Differentiation ◽  
Daughter Cells

Memory B cells and antibody-secreting plasma cells are generated within germinal centers during affinity maturation in which B-cell proliferation, selection, differentiation, and self-renewal play important roles. The mechanisms behind memory B cell and plasma cell differentiation in germinal centers are not well understood. However, it has been suggested that cell fate is (partially) determined by asymmetric cell division, which involves the unequal distribution of cellular components to both daughter cells. To investigate what level and/or probability of asymmetric segregation of several fate determinant molecules, such as the antigen and transcription factors (BCL6, IRF4, and BLIMP1) recapitulates the temporal switch and DZ-to-LZ ratio in the germinal center, we implemented a multiscale model that combines a core gene regulatory network for plasma cell differentiation with a model describing the cellular interactions and dynamics in the germinal center. Our simulations show that BLIMP1 driven plasma cell differentiation together with coupled asymmetric division of antigen and BLIMP1 with a large segregation between the daughter cells results in a germinal center DZ-to-LZ ratio and a temporal switch from memory B cells to plasma cells that have been observed in experiments.

scholarly journals Engaging CD19 or target of an antiproliferative antibody 1 on human B lymphocytes induces binding of B cells to the interfollicular stroma of human tonsils via integrin alpha 4/beta 1 and fibronectin.

1995 ◽  
Vol 182 (5) ◽  
pp. 1191-1199 ◽  
Author(s):  
S Behr ◽  
F Schriever
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Tyrosine Kinases ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Lymphoid Tissues ◽  
Human Tonsil ◽  
Humoral Immune ◽  
Secondary Lymphoid Organs

Adhesion of B lymphocytes within the different compartments of secondary lymphoid organs is essential for the function of the humoral immune response. It is not currently known how the temporary immobilization of B cells in distinct areas of this complex microenvironment is regulated. The present study aimed at defining B cell antigens that initiate binding of B cells to human tonsil sections in situ. Engaging the B cell antigens CD19 and target of an antiproliferative antibody 1 (TAPA-1) with monoclonal antibodies induced adhesion of these B cells to the interfollicular stroma. This binding occurred through the integrin alpha 4 beta 1 on the B cell surface and via the extracellular matrix protein fibronectin expressed in the interfollicular compartment of the tonsil. Signaling through either antigen, CD19 or TAPA-1, depended on tyrosine kinases. Binding induced by engaging CD19 required an intact cytoskeleton, whereas TAPA-1-transmitted adhesion did not. We suggest that CD19 and TAPA-1 have a novel and unique function by regulating an alpha 4 beta 1/fibronectin-mediated binding of B cells to the interfollicular stroma of lymphoid tissues.

scholarly journals A novel human B cell subpopulation representing the initial germinal center population to express AID

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2545-2552 ◽  
Author(s):  
Grant R. Kolar ◽  
Darshna Mehta ◽  
Rosana Pelayo ◽  
J. Donald Capra
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Cell Subpopulation ◽  
Human Tonsil ◽  
Germinal Center Reaction ◽  
Cell Subpopulations ◽  
Human B Cell

Abstract We have identified a novel mature human B-cell subpopulation in the human tonsil that has characteristics of both naive B cells and germinal center B cells including the expression of activation-induced cytidine deaminase (AID), which is essential for the process of immunoglobulin somatic hypermutation and class-switch recombination. These cells are clearly somatically hypermutated, albeit modestly. Their phenotype (IgD+CD38−CD23−FSChiCD71+) is unique and suggests they may be intermediate between both naive and germinal center cells. Morphologically they are also distinct from other B-cell subpopulations. The evidence presented suggests these cells may be the founder cells of the germinal center reaction (a pro-GC cell) and may be the normal counterpart of the mantle cell lymphoma cell.

scholarly journals Association of Ig/BCL6 translocations with germinal center B lymphocytes in human lymphoid tissues: implications for malignant transformation

Blood ◽  
2006 ◽  
Vol 108 (6) ◽  
pp. 2006-2012 ◽  
Author(s):  
Xuwei Yang ◽  
Koutetsu Lee ◽  
Jonathan Said ◽  
Xun Gong ◽  
Ke Zhang
Keyword(s):  
B Cells ◽  
B Cell ◽  
Malignant Transformation ◽  
Germinal Center ◽  
Lymphoid Tissues ◽  
Healthy Humans ◽  
Human B Cells ◽  
Per Se ◽  
Cell Subpopulations ◽  
Follicular Lymphomas

Abstract Chromosomal translocations (CTs) between immunoglobulin (Ig) genes and the BCL6 proto-oncogene are frequently associated with diffuse large B-cell lymphomas (DLBCLs) and follicular lymphomas (FLs) and are implicated in the development of these lymphomas. However, whether Ig/BCL6 translocation per se is sufficient to drive malignant transformation is not clear. To understand the biology of Ig/BCL6-translocated cells prior to their malignant transformation, we developed a system capable of detecting 1 to 3 Igμ/BCL6 CT cells in 1 million mixed cells through the detection of chimeric Iμ-BCL6E2 and BCL6E1-Cμ1 transcripts that reflect reciprocal Igμ/BCL6 translocations. The chimeric transcripts that existed in the vast majority of normal lymphoid tissues are due to Igμ/BCL6 CT and were not generated from trans-splicing. Both Iμ-BCL6E2 and BCL6E1-Cμ1 transcripts were coexpressed in the same cell populations. The Ig/BCL6 recombination junctions themselves were isolated from B-cell subpopulations expressing the Iμ-BCL6 transcripts. The appearance of Igμ/BCL6 CT was associated with cells expressing germinal center but not naive B-cell markers. This study shows that Ig/BCL6 translocations occur in germinal center–stage B cells in healthy humans, and that Ig/BCL6 CTs per se are not likely sufficient to cause the malignant transformation in the context of human B cells.

scholarly journals Very Low Affinity B Cells Form Germinal Centers, Become Memory B Cells, and Participate in Secondary Immune Responses When Higher Affinity Competition Is Reduced

2002 ◽  
Vol 195 (9) ◽  
pp. 1215-1221 ◽  
Author(s):  
Joseph M. Dal Porto ◽  
Ann M. Haberman ◽  
Garnett Kelsoe ◽  
Mark J. Shlomchik
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
B Lymphocytes ◽  
Germinal Center ◽  
Germinal Centers ◽  
Association Constants ◽  
Memory B Cells ◽  
B Cell Antigen Receptor ◽  
The Relationship

To understand the relationship between the affinity of the B cell antigen receptor (BCR) and the immune response to antigen, two lines of immunoglobulin H chain transgenic (Tg) mice were created. H50Gμa and T1(V23)μa mice express μ H chain transgenes that associate with the λ1 L chains to bind the (4-hydroxy-3-nitrophenyl)acetyl hapten with association constants (Kas) of only 1.2 × 105 M−1 and 3 × 104 M−1, respectively. Both lines mounted substantial antibody-forming cell (AFC) and germinal center (GC) responses. H50Gμa Tg mice also generated memory B cells. T1(V23)μa B cells formed AFC and GCs, but were largely replaced in late GCs by antigen-specific cells that express endogenous BCRs. Thus, B lymphocytes carrying BCRs with affinities previously thought to be irrelevant in specific immune responses are in fact capable of complete T cell–dependent immune responses when relieved of substantial competition from other B cells. The failure to observe such B cells normally in late primary responses and in memory B cell populations is the result of competition, rather than an intrinsic inability of low affinity B cells.

Sign in / Sign up

Export Citation Format

Share Document