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Germinal centers in the spleens of neonates and stillbirths.

Sections of spleens from 235 stillbirths and 227 babies who died between the ages of 1 and 35 days were examined. None of the stillbirths showed any germinal centres, neither did the spleens of any of the babies who died between the ages of 1 and 14 days. From the age of 15 days onwards, the germinal centres started to appear in varying numbers. The appearance of germinal centres in the spleen is further delayed in infants born before 37 wk gestation. Germinal centres in the spleen in neonates do not appear to be related to the presence of inflammatory changes elsewhere in the infant.

Age Factors

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

Electrophysiologic evaluations of thymectomy in myasthenia gravis. Preliminary findings.

Electric testing was performed in 106 myasthenia gravis patients before and after transcervical thymectomy. Twenty-nine were followed for 3 to 24 months. Results were correlated with thymic pathology, duration of disease, age at operation, and follow-up clinical status. Electric improvement was significantly greater in patients without thymic germinal centers or with only rare to occasional germinal centers, in patients operated on within 1 year after onset of symptoms, and in patients under age 30. Electric improvement immediately after thymectomy heralded later clinical improvement in those patients without germinal centers or with rare to occasional germinal centers. Electric-clinical correlations were excellent in patients with longer follow-up. Serial electric testing provides an objective evaluation of the patients' clinical status post-thymectomy.

Adult

Thymic hyperplasia and neoplasia: a review of current concepts.

Although the term thymic hyperplasia is used most commonly to indicate the occurrence of germinal centers in the thymus, cognizance must be taken of the fact that such centers may occur in apparently normal thymuses in both children and adults. A concept of thymic compartmentalization is proposed with origin of germinal centers in the perivascular space (extraparenchymal compartment) of the thymus. These germinal centers contain a high percentage of B lymphocytes in contrast to the true thymic parenchyma. Although the significance of germinal centers in the thymus parenchyma. Although the significance of germinal centers in the thymus in myasthenia gravis remains controversial, removal of nonneoplastic thymus in this condition is of proven therapeutic value. A variety of neoplasms originating in the thymus have previously been lumped together under the single term "thymoma." It is apparent, however, that thymoma, thymic carcinoid, various lymphomas, and germ cell tumors that arise in the thymus differ not only pathologically but also in their clinical behavior. Thymoma is regarded as an epithelial neoplasm and ultrastucturally is characterized by many desmosomes and tonofilaments. The lymphocytes do not behave in a malignant manner, and lymphomas of the thymus should be sharply separated from true thymoma. Poorly differentiated thymic carcinoma and histiocytic lymphoma may be distinguishable only by the electron microscopic demonstration of desmosomes and filaments in the thymic carcinoma. The evidence that Hodgkin's disease of the thymus ("granulomatous thymoma") is not a variant of thymoma appears overwhelming. Lymphoblastic lymphoma of the thymus is a distinctive neoplasm that is especially prevalent in teenage males. High levels of terminal transferase characterize the lymphoblasts and there is a striking tendency for leukemia to occur. Thymic carcinoid is usually nonfunctional, although one-third of the reported cases are associated with Cushing's syndrome. On light microscopy a ribbon pattern and punctate necroses are characteristic of thymic carcinoids. Electron microscopic demonstration of many dense core granules is invaluable in establishing this diagnosis. An important clue to the diagnosis of thymic seminoma (a neoplasm that shows the same radiosensitivity as its testicular counterpart) is the frequent presence of epithelioid and giant cell granulomas and germinal centers. Separation of the various thymic neoplasms described not only is justifiable on pathologic grounds but is often essential for appropriate patient investigation and treatment.

Adolescent

Qualitative and quantitative morphologic study of Peyer's patches of the mouse after neonatal thymectomy and hydrocortisone injection.

Peyer's patches in normal adult mice, neonatally thymectomized mice and mice injected with hydrocortisone were studied qualitatively and quantitatively by light microscopy. The patch was divided into germinal center, follicular area, parafollicular area and dome area. In normal mice, the volumetric ratio of the germinal center to the entire patch was 30.9%; that of the follicular area, 33.3%; that of the parafollicular area, 27.7%; and that of the dome area, 8.2%. Thymus-dependent small lymphocytes were 40% of small lymphocytes in the patch. Out of the total thymus-dependent small lymphocytes in the patch, 13% were included in the germinal center; 19%, in the follicular area; 62%, in the parafollicular area; and 6%, in the dome area. Hydrocortisone-sensitive small lymphocytes were 65% of the total small lymphocytes in the patch, the germinal center contained 9%; the follicular area, 84%; the parafollicular area, 2%; and the dome area, 5%. The epithelium over the dome area was invaded by numerous small lymphocytes. Forty-eight percent of lymphocytes within the epithelium over the dome were thymus-dependent and 67% were hydrocortisone-sensitive. It is concluded that Peyer's patch may be considered as a peripheral lymphatic tissue, functionally as well as morphologically.

Animals

Correlation between immunohistochemical localization of carcinoembryonic antigen (CEA) and histological estimation of carcinomas, normal mucosae and lymph nodes of the digestive tract in humans.

The localization of the carcinoembryonic antigen (CEA) in carcinomas and mucosae of the digestive tract in humans and in mesenteric lymph nodes was studied by indirect immunofluorescence. In colonic and gastric adenocarcinomas, CEA had typical centroglandular localization. Cytoplasmic localization of the CEA was seen in invasive cancer cells having lost their glandular organization. CEA was also present in colonic and gastric mucosae surrounding the tumor. In gastric mucosa obtained at autopsy from subjects with nonneoplastic diseases, CEA was found only in glands having undergone intestinal metaplasia. In lymph nodes of cancer patients CEA was always present in metastatic cells and in germinal centers. Characteristic localization of CEA in germinal centers of metastatic and nonmetastatic lymph nodes could suggest the presence of CEA-anti-CEA immune complexes.

Adenocarcinoma

Peyer's patches, gut IgA plasma cells and thymic function: study in nude mice bearing thymic grafts.

Nude mice have poorly developed Peyer's patches with very small or no germinal centers and little lymphoid cell proliferation, and a marked decrease in the number of gut-IgA plasma cells. Thymus grafts, which restore the T lymphocyte population of their lymphoid organs to nearly normal levels, lead to a considerable development of the Peyer's patches and of their germinal centers, assocaited with a considerable increase in gut IgA plasma cells, and in the serum IgA level. These findings are consistent with the postulated relationship between the Peyer's patches germinal center cells and the gut IgA plasma cells, and might help to explain the association of thymic defects, low serum IgA, and lack of intestinal IgA plasma cells observed in some immunodeficiency syndromes of man. Nude mice also have marked decrease in the number of lymphocytes present within the intestinal epithelium. These intraepithelial lymphocytes lymphocytes, which have been shown to be of T nature, are restored to normal numbers after thymus grafting.

Animals

Transcervical thymectomy with the aid of mediastinoscopy for myasthenia gravis: eight years' experience.

Fifty-eight patients with myasthenia gravis, including 12 children, underwent thymectomy. Eleven of them (19%) had total stable remission and 42 (72%) showed clinical improvement and were able to reduce their anticholinesterase medication. These two groups combined comprised 53 patients (91%). There was no operative or postoperative mortality. Histopathological examination of the resected thymuses revealed a tumor (benign thymoma) in 4 patients (7%), thymitis in 36(62%), and no pathological changes in 18(31%). Patients with few or no germinal centers tended to achieve remission more rapidly than those with numerous germinal centers.

Adolescent

Transformation of nodular lymphoma to an immunoblastic IgM-producing tumor.

Two cases of nodular lymphocytic lymphoma that transformed into leukemic processes with IgM-kappa-type monoclonal proteins are reported. The transformations occurred 21 and 34 months after the diagnosis of lymphoma and were associated with rapid deterioration of the patients' conditions. The leukemic phase was characterized by plasmacytic and immunoblastic appearing lymphoid cells in the peripheral blood and marrow. Such transformation, though rare, is not unexpected in view of the currently postulated origin of nodular lymphomas in germinal center cells and of immunoglobulin-producing tumors in cells derived from germinal center cells.

Adult

Spontaneous remission of myasthenia gravis in patients with thymoma.

In 42 cases of myasthenia gravis with thymoma, the tumor was removed surgically. In four of these cases, myasthenic symptoms had remitted before operation. However, in two of these four cases, myasthenic symptoms returned after operation, despite apparently total thymectomy. In two of the four cases that remitted before operation, the thymus was found to be highly involuted, without germinal centers; in another case, the thymus was found to be moderately involuted, and germinal centers were found. In the nonrelapsing cases, only the tumor itself was removed, with residual thymic tissue being left behind. The thymoma in all cases consisted of polygonal epithelial cells and lymphocytes.

Adult

Histological and autoradiographical findings in the immunologically stimulated spleen.

In order to estimate the role of a possible immunological coeffect on the splenic cellular proliferation during wound healing after mechanical or thermal lesions of internal organs, light microscopical and autoradiographical investigations with tritiated thymidine were performed on spleens of non-germfree rats, immunized by a single injection of sheep erythrocytes. Two days after an initial dissociation of preexisting germinal centers in the spleen a steep rise of the percentages of labeled cells in newly formed germinal centers occurs with a maximum on the fifth day. In the marginal zone an increased cell proliferation (mostly large lymphoid blasts) starts at 12 hours. In the lymphatic mantle zone a marked increase of labeled basophilic blasts (immunoblasts) can be observed with a maximum on the second day. The values are higher in the perifollicular B cell region than in the periarteriolar T cell region. In the red pulp of the spleen the highest percentages of labeled cells occur five days after the antigen injection. These findings in the spleen after a strong antigenic stimulation are characteristic for an immunological reaction of anamnestic type. In comparison with investigations of the spleen after cryolesions in internal organs such studies may be particularly helpful in judging the proportion of an unknown immunological reaction in the spleen after such an operation, which by tissue necroses and cellular destruction may have caused denaturation of self components.

Animals

Lymphopenia and lymph node histology following repetitive extracorporeal irradiation of blood in normal and thymectomized calves.

Repetitive extracorporeal irradiation of the circulating blood (RECIB) in normal or thymectomized calves and RECIB plus Imuran were used for comparative studies on the depletion of blood and lymph node lymphocytes. Elimination of the easily mobilizable pool of lymphocytes was almost complete within approximately 6 days after commencing RECIB and was reflected by a reduction of approximately 50% in the numbers of paracortical lymphocytes. Blood lymphocyte counts were reduced to approximately 1/3 to 1/4 of the pre-irradiation values. Thymectomized calves had lower pre-irradiation blood lymphocyte counts than non-operated controls, however, the reduction in the number of blood lymphocytes was proportionally similar. Continuation of RECIB beyond one week did not result in a further depletion of blood lymphocytes. The lymphocyte counts in the follicular cortex and in the medulla of lymph nodes were not significantly changed by the various procedures. RECIB of 8-16 days duration did not alter the number of germinal centers in non-thymectomized calves, however, in thymectomized animals treated with Recib, the number of germinal centers was reduced.

Animals

The organization of lymphoid tissue in relation to function.

Organized lymphoid tissue is found in the thymus, spleen, lymph nodes; lining the respiratory and alimentary tracts; and also occurring at sites of chronic inflammation. Apart from the thymus which is involved in the regulation of T-cell function, the other tissues are organized into T-cell and B-cell areas. Lymphocytes in T-cell areas respond by proliferation in cell-mediated immunity and by the production of suppressor cells and helper for antibody formation. B-cell areas are involved in the humoral antibody response. B-cells are segregated into lymph follicles where they form germinal centers and are found at the corticomedullary junction where they differentiate into plasma cells. The role of lymph follicles in becoming germinal centers is poorly understood, but these areas are known to be the site of antigen trapping in primed animals. The particular function of the spleen as a localized area of lymphoid tissue along the course of the blood vascular system is discussed, particularly with respect to its ability to respond to soluble antigen released from sites of localized antigen deposition such as tumors.

Antibody Formation