Germinal centers and the B-cell system: B cell differentiation in rabbit appendix germinal centers.
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Animals↗
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Early ontogeny of germinal center formation in the chicken.
Germinal center formation was studied in the spleen of young chickens immunized in ovo and at the time of hatching. When immunization was performed on day 18 in ovo and on the day of hatching, the first germinal centers were observed at 4 days. This is markedly earlier than in unimmunized chickens, where the first germinal centers appear at the age of 10 days or later. Germinal center formation preceded significant antibody production. The possible role of germinal centers in the generation of immunological memory is discussed in the light of these and earlier observations.
Aging↗
An ultrastructure study on antibody production of the lymph nodes of rats with special reference to the role of germinal centers.
Antibody-containing cells in lymph nodes, expecially in germinal centers, and in thoracic duct of rats sensitized by injection of horseradish peroxidase were studied with the immunoperoxidase method. In the primary response the large germinal center cells began to produce antibody on the 9th day and predominated thereafter in germinal centers ,added by intercellular antibody deposition in its late stage. The "ordinary" medium-sized germinal center cells were a minor component. In the secondary response, the intracellular antibody positivity disappeared immediately after the antigenic rechallenge but reappeared from 6 hours later in the large germinal center cells which further transformed from 48 to 72 hours into the "specifically differentiated" medium-sized germinal center cells that disappeared by 96 hours after the secondary injection to enter the thoracic duct. Antibody-containing cells outside the germinal centers appeared 5 to 6 days after the primary injection and were mainly comprised of plasmocytic cell series which was classified into interfollicular large cells, proplasmocytes and plasmocytes. Some results conflicting with the cytological identity of both cell series were presented.
Animals↗
An ultrastructural study with enzyme-labeled antibody technique on immunoglobulin-containing cells in human tonsils, especially in germinal centers.
Localization of IgG, IgA and IgM in human palatine tonsils, especially in germinal centers, was studied with the electron microscopical enzyme-labeled antibody method. The large germinal center cells differentiate into two kinds of cells within the germinal center; one was the medium-sized germinal center cells not engaging in intracytoplasmic production of immunoglobulins and another was the immature cells producing at least one of the three classes of immunoglobulins, especially IgM. The latter continued to maturate and developed into the intermediate-matured cells and probably into the plasmocytes. The three classes of immunoglobulins were also deposited in the form of admixtures in the intercellular spaces among the constituent cells of the germinal centers, mainly attaching on the cell membrane of desmodendric cells. In addition, some of the deposits were found freely in the intercellular spaces. Some differences between the immunoglobulin-containing cells outside and within the germinal centers were pointed out.
Child↗
Structure of the germinal centers in the chicken caecal tonsil: light and electron microscopic and autoradiographic studies.
The light and electron microscopic structure of the germinal center of chicken caecal tonsils were studied. Two kinds of germinal centers were revealed; the first was located deep in the lymphatic tissue close to the muscle layer of the caeca. These germinal centers frequently have an incomplete capsule, and are not, therefore, separated from the diffuse lymphatic tissue. The second kind of germinal center was located closer to the epithelium and had a complete capsule separating it from the diffuse lymphatic tissue. Both germinal centers possessed an outer dark cortical zone which contained smaller lymphoblasts (of less than 10 micron in diameter) and a central medullary area which contained larger lymphoblasts (up to 16 micron). Autoradiographic studies revealed that the small lymphoblasts of the outer cortical zone are concerned with cell generation and that the large lymphoblasts of the medullary area may have derived from the small lymphocytes. Within the medullary area of the germinal center are cells which are embedded in an intercellular substance of high density. We propose that the intercellular substance may be a product of this cell. For discussion purposes we have called this cell a secretory cell. The secretory cell may originate from a small lymphocyte-like cell.
Aging↗
Peritoneal macrophages introduced into mouse foot pads enter the germinal center of regional lymph nodes nonspecifically.
Male mice were injected into their foot pads with sheep erythrocytes (SRBC) to form lymph follicles in the germinal centers in the popliteal lymph nodes. 4 weeks later, peritoneal macrophages labeled with carbon from syngeneic donors sensitized with SRBC or typhoid-paratyphoid bacilli (TAB) were separately injected into the foot pads as well. The popliteal lymph nodes were histologically examined at 6 h to 5 days after injection. Labeled macrophages appeared in the marginal sinus, migrated straight across the cortex from the marginal sinus to the lymph follicles and then entered the germinal centers. There was no difference in the mode of appearance, migration and localization of labeled macrophages in the regional lymph nodes between the mice given labeled macrophages from SRBC-sensitized donors and those given macrophages from TAB-sensitized donors. The entrance of lymph macrophages into the germinal centers of the regional lymph nodes would be immunologically nonspecific. After the injection of Pelikan ink into the foot pads, the macrophages which have taken up carbon in the peripheral tissue reached the regional lymph nodes via the afferent lymphatics and then entered the germinal centers, mainly through the medullary pole of the lymph follicles, after migrating along their immediate exterior from their marginal sinus to their medullary pole.
Animals↗
Histocompatibility requirements for cellular cooperation in the chicken: generation of germinal centers.
Cyclophosphamide-treated newly hatched chicks were transplanted with histocompatible, semiallogeneic and allogeneic combinations of B (bursa) and T (thymus) cells from newly hatched donors. At the age of 5 weeks the birds were studied for an anti-SRBC response and for the generation of germinal centers in the spleen. The results of these experiments are summarized as follows. i) Allogeneic bursal stem cells have the capacity to restore the bursal structures of CY-treated recipients, but not the germinal center or anti-SRBC formation. ii) When allogeneic B cells are combined with T cells histocompatible or semiallogeneic with them, a restoration of the germinal center formation is achieved, but not to the same level as observed in normal birds or in CY-treated birds transplanted with histocompatible or semiallogeneic B cells. iii) Allogeneic B cells, even when complemented with T cells histocompatible with them, fail to restore the antibody production against SRBC; this is achieved only after transplantation of B cells histocompatible or semiallogeneic with the recipient. These findings indicate that germinal center formation is dependent on cooperation of histocompatible or semiallogeneic B and T cells, and furthermore, that an additional factor provided by the host is involved. Studies with transplantation of histocompatible and histoincompatible 'empty' splenic stromata revealed that the additional factor is not related to the splenic stroma.
Animals↗
Germinal center formation in BSA-tolerant chickens.
In chickens rendered neonatally tolerant to BSA the germinal center formation was significantly decreased after stimulation with BSA at the age of 3 weeks. At the breakdown of tolerance after the age of 6 weeks the IgG antibody formations recovered before the IgM production. Stimulation of tolerant birds with unrelated antigens resulted in slightly decreased antibody response but the germinal center formation was on the same level as in normal controls.
Aging↗
Survival with mammary cancer related to the interaction of germinal center hyperplasia and sinus histiocytosis in axillary and internal mammary lymph nodes.
In a review of the histologic sections of axillary and internal mammary lymph nodes removed during surgery for invasive ductal carcinoma of the breast, we found that 16 of 17 patients in whom sinus histiocytosis was the dominant lymphoid proliferative reaction are alive with no evidence of cancer 5 or more years after operation. In contrast, 5 of 6 patients in whom germinal center hyperplasia was the only significant reaction found died of cancer in less than 5 years. Patients with both sinus histiocytosis and germinal center hyperplasia in significant amounts had survival that was intermediate; 17 of 25 of these patients are currently alive and apparently free of cancer. In addition, 5 of 6 patients in whom no evidence was found of any lymphoid proliferative reaction and 3 of 3 patients with diffuse cortical hyperplasia in their axillary lymph nodes died of cancer in less than 5 years. Germinal center hyperplasia was associated with nodal metastases anatomically in individual lymph nodes and statistically in the series of cases. The internal mammary lymph nodes of most cases showed less proliferative reaction to tumor than the axillary lymph nodes. The pattern of proliferative reactions in lymph nodes and its correlation with survival after surgery suggest that different immune reactions may either suppress or enhance the growth of carcinoma of the breast.
Axilla↗
Non-endemic Burkitt's lymphoma. A B-cell tumor related to germinal centers.
To investigate the nature of non-endemic Burkitt's lymphoma, we examined neoplastic cells from eight American patients for receptors for sheep erythrocytes (E), complement (EAC), and Fc fragment of lgG (igGEA), and for surface immunoglobulins (Slg) and hydrolytic enzymes. In addition, we reviewed 47 biopsies and 17 autopsies from American patients to ascertain patterns of involvement by tumor in lymph nodes, spleens and Peyer's patches. Neoplastic cells in all cases studies bore monoclonal surface immunoglobulins of the igM class. Receptors for EAC and igGEA were identified on a minority of the cells. Little or no hydrolytic enzyme activity was demonstrable. These results indicate that, like Burkitt's lymphoma in Africans, this histologically identical tumor in American patients consists of B lymphocytes. In 10 biopsies and two autopsies, germinal centers were selectively involved by tumor, suggesting that these neoplastic cells may be related to some B lymphocytes of normal germinal centers.
Africa↗
Spatial proximity sequencing maps developmental dynamics in the germinal center.
Spatial profiling of proteins and protein interactions facilitates understanding of cell functions within tissues and is essential for studies in signaling, immunity, and cancer. We present spatial proximity sequencing (Sprox-seq) for simultaneous profiling of surface proteins, protein complexes, and mRNAs, recording the tissue location of each molecule. Sprox-seq profiled 32 proteins, 528 pairwise interactions, and thousands of mRNAs with spatial resolution across human tonsils and germinal centers. Mapping tissue-wide protein interactions recapitulated RNA-defined tissue architecture but also revealed higher interaction complexity in the light zone. Protein-interaction trajectories uncovered a B cell state transition distinct from that inferred by RNA. Integrated protein-complex and mRNA analysis related spatially enriched complexes with mitotic pathways. Sprox-seq captured cell-cell interactions, such as B cell-follicular dendritic cell interactions mediated by the receptor complex VLA-4-VCAM1. Sprox-seq provides a spatially resolved multi-modal view of cell states and an integrated study of protein and cellular interactions across tissues.
Humans↗
Anatomy of germinal centers in mouse spleen, with special reference to "follicular dendritic cells".
Lymphocyte proliferation in germinal centers (GC's) is thought to be triggered by antigen retained extracellularly on the surface of special "dendritic" cells. The anatomy and function of these cells have not been studied directly or in detail. We therefore examined mouse spleen GC's developing in response to sheep erythrocyte stimulation. We found that distincitve "follicular dendritic cells" (FDC's) were present in both the GC and adjacent mantle region of secondary follicles. The large, irregularly shaped nucleus, containing little heterochromatin, allowed for the light microscope (LM) identification of FDC's. By EM, the cell was stellate in shape sending out long, thin sheets of cytoplasm which could fold and coil into complex arrays. The processes were coated extracellularly by an amorphous electron-dense material of varying thickness, as well as particulates including variable numbers of virions. The FDC cytoplasm lacked organelles of active secretory and endocytic cells, such as well-developed rough endoplasmic reticulum (RER) and lysosomes. These anatomical features readily distinguished FDC's from other cell types, even those that were extended in shape. To pursue these descriptive findings, we injected three electron-dense tracers i.v. and sacrificed the mice 1 h-10 days thereafter. Colloidal carbon, colloidal thorium dioxide (cThO2), and soluble horseradish peroxidase (HRP) were actively sequestered into the vacuolar system of macrophages but were interiorized only in trace amounts by FDC's. Therefore, FDC's are not macrophages by cytologic and functional criteria. FDC's did display a unique property. Both colloidal carbon and thorium dioxide, which are nonimmunogens, could be visualized extracellularly on the cell surface for several days. The meaning of this is unclear, but the association of colloid with FDC's appeared to slow the movement of particulates through the extracellular space into the GC proper. FDC's were not readily identified in splenic white pulp lacking GC's. They must develop de novo then, possibly from novel dendritic cells that we have identified in vitro (Steinman, R. M., and Z. A. Cohn. 1973. J. Exp. Med. 137:1142-1162).
Animals↗
Nodular paragranuloma and progressively transformed germinal centers. Ultrastructural and immunohistologic findings.
Ultrastructural and immunohistologic findings in a nodular variant of Hodgkin's disease with lymphocytic predominance, called nodular paragranuloma, are presented and compared with those in so-called progressively transformed germinal centers. These are large follicles with numerous lymphocytes which can be found not only in nonspecific lymphadenitis, but also in lymph nodes from patients with nodular paragranuloma. The immunoperoxidase technique was applied on paraffin sections to detect intracytoplasmic immunoglobulin and lysozyme. The so-called L & H type Sternberg-Reed cells contained IgG and one type of light chain per cell, suggesting that such cells produce immunoglobulin. The ultrastructure of the L & H type Sternberg-Reed cells favored the immunoblastic nature of these cells. It is concluded that nodular paragranuloma differs from other types of Hodgkin's disease by its localization in B-cell areas and the presence of atypical B immunoblasts.
B-Lymphocytes↗
[Comparative histological-morphometric study of the marginal zone and the germinal center of the rat spleen after endotoxin injection (author's transl].
Basing on the knowledge of structure and function of the marginal zone of the lymph follicle of the spleen in correlation with migration of lymphocytes to the red pulp and from there back to the lymph follicle (filtration of lymphocytes, so-called marginal zone bridging channel, role of the marginal sinus) a comparative study on the size of the marginal zone and germinal center following endotoxin-injection is presented.
Animals↗
Definition of germinal center cell-derived lymphomas by analysis of complement receptor subtypes and morphological criteria.
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Binding Sites↗
Temporal decrease of germinal centers during the secondary immune response in the chicken spleen.
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Animals↗
Morphologic and cell kinetic investigations of the spleen after repeated in situ freezing of liver and kidney.
In order to evaluate a possible primary or secondary immunologic response of the spleen after single or repeated in situ freezing of parenchymal organs such as liver and kidney within a four week period, light microscopic and cell kinetic investigations with tritiated thymidine were performed on spleens of non-germfree rats. Sham operations served as controls. The sham operations did not induce any significant morphological or cell kinetic changes in the splenic white pulp. After cryolesions were produced in the liver and kidney, the percentages of activated germinal centers, labeled germinal center cells, and cells in the perifollicular area of the lymphatic mantle and marginal zones increased, with maxima during the first 3 days. The investigations show that the cellular reaction of the spleen starts earlier and is more prominent after repeated in situ freezing than after a single cryolesion. These findings point to an immunologic response of the anamnestic type, and correspond to results after repeated freezing of normal and malignant tissue of the urogenital tract. These cell kinetic results are important in the evaluation of further immunologic studies involving the cryotherapy of malignant tissues.
Animals↗
Demonstration of immunoglobulin production by tumor cells in non-Hodgkin's and Hodgkin's malignant lymphomas and its significance for their classification.
Combined application of morphologic, immunochemical, and immunologic methods has led to a reinterpretation of non-Hodgkin's lymphomas and to the establishment of the Kiel classification. In the present paper, the main Ig-producing entities are considered. These are: 1. Chronic lymphocytic leukemia of the B-type (B-CLL)--a proliferation of lymphocytes and a few so-called prolymphocytes and lymphoblasts. The mean tissue IgM value is slightly increased; the serum IgM level is normal or reduced. The tumor cells bear SIg, and a majority of them have a receptor for C3d but always lack CIg and are usually devoid of receptors for C3b. 2. Lymphoplasmacytoid immunocytoma--a mixed proliferation of lymphocytes and centrocytes, blast cells, plasma cells, or plasmacytoid cells. The tissue Ig content is most often (91%) and most highly increased in this group, whereas the serum Ig level is increased in only 20% of the cases. The tissue IgM of 17 cases was shown to be monoclonal by IEF. Most tumor cells have SIg and a variable numbear CIg. The tumor cells bear both complement receptor subtypes, only a receptor for C3b, or no complement receptors at all. 3. Centroblastic/centrocytic lymphoma--usually a follicular proliferation of abundant small germinal center cells (centrocytes) and some large germinal center cells (centroblasts). The tumor cells bear SIg and both complement receptor subtypes. The C3b- and C3d-positive cells are located in the follicles, as in nonneoplastic lymphatic tissue. 4. Centrocytic lymphoma--a purebred, diffuse proliferation of the small germinal center cells (centrocytes). These cells bear SIg and receptors for C3b and C3d but usually lack CIg. 5. Centroblastic lymphoma--a proliferation of the large germinal center cells (centroblasts). 6. Lymphoblastic lymphoma of Burkitt's type. 7. Immunoblastic lymphoma--a diffuse proliferation of large basophillic cells resembling immunoblasts. The tissue IgM content is increased in 60% of the cases. It proved to be monoclonal with IEF in all five cases studied. The cells of five cases with increased tissue Ig content bore SIg. Nearly half of the cases studied showed CIg. Besides non-Hodgkin's lymphomas, paraffin sections of 87 biopsies from Hodgkin's disease were investigated for CIg in Hodgkin's and Sternberg-Reed cells. These cells stained positively in 68 cases, most often for IgG, followed by IgD. In five cases of the lymphocyte-depleted type, the staining of the Hodgkin's and Sternberg-Reed cells was restricted to one light chain type.
Burkitt Lymphoma↗