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.
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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.
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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↗
Nodular lymphoma: an ultrastructural study of its relationship to germinal centers and a correlation of light and electron microscopic findings.
This study describes the ultrastructural findings in 16 cases of nodular lymphoma, and compares these with normal germinal centers in order to determine the possible germinal center origin of the lymphomas. Long branching desmosome-associated dendritic reticulum cells, characteristic of germinal centers, were found in all 16 cases of nodular lymphoma. Desmosomes were observed only between dendritic cells and not between lymphoid cells, and they were seen in only 1 of 7 cases of diffuse lymphoma. Cells comprising the nodular lymphomas share cytologic features, such as nuclear blebs and marked nuclear indentations, with germinal center cells. It appears that nodular lymphomas have a close anatomical relationship to germinal centers, although their actual origin from these sites is not established by this study. They are composed of lymphoid cells; we have no evidence to confirm the view that nodular lymphomas are derived from dendritic cells. Light and electron microscopic findings have been compared in order to establish the nature of large "histiocyte-like" cells in the nodular lymphomas. Many of these cells appear to represent transformed lymphocytes rather than histiocytes. They are more numerous in so-called mixed "histiocytic" lymphocytic lymphomas than in poorly differentiated lymphocytic lymphomas, which otherwise are ultrastructurally similar. This study casts doubt upon the existence of a mixed lymphocytic and histiocytic lymphoma within the spectrum of the nodular lymphomas, and indicates that a cytologic continuum exists between cells interpreted as poorly differentiated lymphocytes and those heretofore identified as histiocytes.
Adult↗
Lymph macrophages enter the germinal center of lymph nodes of guinea pigs.
To determine the fate of macrophages within the afferent lymph stream, the popliteal lymph nodes at various times (3 h to 6 months) after subcutaneous injection of india ink into the footpads of guinea pigs were examined. Two types of cells which had phagocytized india ink were observed in the germinal centers. A small number of type I phagocytes (engulfing india ink as small particles which were often found together with tingible bodies in their cytoplasm) were scattered through the germinal center. A large number of type II phagocytes (packed full of india ink) presented preferentially in the medullary portion of the germinal center, together with many pyroninophil lymphoblastoid cells. In the second experiment, the afferent lymphatics of the popliteal lymph node were ligated 15-20 min after india ink injection. Although the type I phagocytes were distributed as in the first experiment, the type II phagocytes were scanty. In the third experiment, the afferent lymphatics of the popliteal lymph node were ligated 7 days after india ink injection. The type II phagocytes disappeared rapidly from the germinal center, whereas the type I phagocytes remained and were not affected by ligature. These results suggest that the type I phagocytes are the fixed macrophages or tingible body macrophages in the germinal center, and that the type II phagocytes are the macrophages migrating from the peripheral tissues. It was also shown that many macrophages reaching the regional node via afferent lymphatics entered the germinal center through the medullary pole where the cap of small lymphocytes became thinner or disappeared.
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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.
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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.
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Epitheloid germinal centers: an acquired immunologic deficit?
The histologic structure of lymphoid tissue in cases of fatal infection was reviewed, and epithelioid germinal centers, completely devoid of the usual dark zone of rapidly dividing blast cells, were found in 16 infants and children, one of whom also had Reye's syndrome. Epithelioid change has been previously reported to occur in various childhood infections and in the sudden infant death syndrome. All reported cases have been fatal. In four additional cases there was toxic follicle alteration, or massive necrosis of germinal center cells. Toxic follicle alteration and epithelioid change have been found in childhood infections and sudden infant death syndrome, and some evidence of a pathogenetic relationship between the two was found in this study. It is concluded that epithelioid change represents a definite pathologic alteration of germinal centers associated with total destruction of a whole population of cells. It probably represents an acutely acquired immunologic deficit and therefore may well contribute to the thus far uniformly fatal outcome of the associated diseases.
Humans↗
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.
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L-Asparaginase: effect on 7S gamma globulin extents and germinal centers in spleen and lymph-nodes.
Administration of L-asparaginase may cause remission in a high percentage of acute lymphocytic leukemias and lymphomas, either in experimental animals or in human beings. This enzyme is able to depress immune reactions like lymphocyte blastogenesis and delayed hypersensitivity, and to impair gamma-globulin synthesis. L-asparaginase also has antigenic properties, and may cause the formation of anti-L-asparaginase antibodies. This study reports observations on the effect of L-asparginase on the 7S gamma-globulin levels and on the behaviour of the germinal centers in spleen and lymph nodes. It has been found that after administration of low or intermediate doses of L-asparginase, a decrease in the size of the follicular marginal zones occurred. This was accompanied by an enlargement of the germinal centers. Furthermore the spleen weight decreased and the concentration of 7S gamma-globulin diminished slightly. In animals given high doses of L-asparaginase, germinal centers were enlarged even more but marginal zones appeared repopulated although not to the degree of the controls. The spleen weight of these enzyme-injected animals reached almost the normal values, while a statistically significant decrease of 7S gamma-globulin concentrations was found.
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Reactive hyperplasia of paracortex and germinal centers of the regional lymph nodes in gastric carcinoma cases as a favorable prognostic indicator.
The prognosis of 141 patients subjected to curative resection for gastric carcinoma was analyzed with special reference to the paracortex, germinal centers and sinus histiocytes in the regional lymph nodes. Five years survival rates of the patients with paracortical and/or germinal center hyperplasia (PH and/or GH) was definitely superior to those without such hyperplasia. This difference was most pronounced in those with moderately advanced stage. The incidence of lymph node metastasis was lower in the patients with PH or GH. The presence of sinus histiocytosis (SH) seemed to be correlated neither with a longer survival nor with lower incidence of lymph node metastasis. No close correlation was found between PH, GH and SH on one hand and histological types of the primary gastric carcinomas on the other. These results suggest that cell mediated and/or humoral immune response may play an important role in host resistance against gastric carcinoma.
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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.
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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).
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Reduction of trapping of aggregated human IgG in germinal centers by mitogens.
The effect of nonspecific mitogens on the trapping of 125I-labeled aggregated human IgG (125I-AHGG) in germinal centers (GC) of mouse spleens has been investigated by both radioactivity uptake and immunofluorescence. Phytohemagglutinin and concanavalin A (Con A) significantly decreased trapping. Lipopolysaccharide produced less inhibition, and pokeweed mitogen had no significant effect. The maximum inhibition occurred with 250--500 mug Con A. This had no effect on 125I-AHGG uptake in liver kidney and blood. No differences were found between i.p. and i.v. routes of Con A injection. The effect of mitogens on the 125I-AHGG trapping in GC is due more likely to modification of the migratory properties of lymphocytes brought about by surface binding, than to their mitogenic properties, since Con A decreased 125I-AHGG localization in thymectomized, x-irradiated and bone marrow-reconstituted animals.
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