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LYVE-1, a receptor molecule for hyaluronan, is expressed in the lymphatic endothelium, blood sinus endothelium, and certain macrophage lineages. The present immunohistochemical study revealed a broader distribution of LYVE-1 in vascular endothelial cells of the murine lung, adrenal gland, and heart as well as the liver and spleen. In addition, sinus reticular cells-including sinuslining cells-in the medulla of the lymph node also intensely expressed LYVE-1. Ultrastructurally, immuno-gold particles for LYVE-1 were localized on the entire length of plasma membrane in all cell types. Most of these LYVE-1-expressing cells had previously been classified as the reticuloendothelial system (RES) specialized for eliminating foreign particles. An LPS stimulation decreased the LYVE-1 expression in macrophages but elevated the expression at mRNA and protein levels in the liver and lung, major organs for the elimination of blood-born waste substances. LYVE-1-expressing endothelial cells in these organs participated in the endocytosis of exogenous particles, and the uptake ability was conspicuously enhanced by the LPS challenge. Although the expression of the degrading enzyme, hyaluronidase, was generally low in the LYVE-1-expressing cells, they were topographically associated with a dense distribution of macrophages possessing hyaluronidase activities in each tissue. These findings suggest that the LYVE-1-expressing cells might be involved in the uptake of hyaluronan and other waste products as well as foreign particles circulating in the blood and lymph while participating in the subsequent degradation in relay with adjacent macrophage populations.

Magnetic nanoparticles can be used for numerous in vitro and in vivo applications. However, since uptake by the reticuloendothelial system represents an obstacle for the achievement of nanoparticle diagnostic and therapeutic goals, the aim of the present study was to evaluate the uptake of dimercaptosuccinic acid coated magnetic nanoparticles by reticuloendothelial system phagocytic cells present in lymph nodes, spleen, and liver tissue and how the presence of these particles could have an impact on the morphology of these organs in capuchin monkeys (Sapajus spp.). Animals were intravenously injected with dimercaptosuccinic acid coated magnetic nanoparticles and euthanized 12 hours and 90 days post-injection. Organs were processed by transmission electron microscopy and histological techniques. Samples of spleen and lymph nodes showed no morphological changes. Nevertheless, liver samples collected 90 days post-administration showed slight morphological alteration in space of Disse. Moreover, morphometrical analysis of hepatic mitochondria was performed, suggesting a clear positive correlation between mitochondrial area and dimercaptosuccinic acid coated magnetic nanoparticles administration time. The present results are directly relevant to current safety considerations in clinical diagnostic and therapeutic uses of magnetic nanoparticles.

The vascular endothelia express a variety of structural and biological phenotypes. We used an intravital injection method of plant derived lectins (Lycopersicon esculentum lectin (LEL), Ricinus communis Agglutinin-I (RCA-I), Ulex europaeus Agglutinin-I (UEA-I) and Concanavalin A (ConA)) to elucidate the morphology and function of the sinusoidal endothelium of the liver and bone marrow. All four lectins stained the sinusoidal endothelia of the liver and bone marrow in a patchy granular pattern which differed from the uniform and smooth staining pattern of non-sinusoidal vessels in other organs. By transmission electron microscopy, the granular pattern was identified as internalization of these lectins and subsequent accumulation within the endothelial cells, suggesting their active endocytosis. The endocytosis of these lectins emphasizes the fact that sinusoidal endothelial cells of the liver and bone marrow belong to the reticuloendothelial system (RES), a cell system characterized by internalization of foreign material. We introduce this intravital lectin injection as a useful technique to discriminate sinusoidal endothelial of the liver and bone marrow from other vascular endothelia.

By injecting lithium carmine (Lit-car) into living animals, Ribbert (1904) and Kiyono (1914) showed that specific staining occurred in some cells in various organs. Kiyono termed those cells "histiocytes" which consisted of free amoeboid cells and cells of reticulo-endothelium. Aschoff (1924) introduced the concept 'reticulo-endothelial system (RES)' for the collection of cells having in common the property of vital staining. Van Furth (1972) proposed the term "mononuclear phagocyte system (MPS)" advocated that RES be replaced by MPS. As a consequence we presently suffer from a "reticulo-endothelial confusion", based on the delusion that cells other than macrophages are not members of the RES. The point that most clearly illustrates this is the fact that the Lit-car-laden cells in the body are named macrophages in modern textbooks of histology. To clarify the confusion, we re-examined the vital staining at light and electron microscopic levels and analyzed the scavenger cells using biochemical methods. Injected Lit-car was actively endocytosed by sinusoidal endothelial cells in the liver and reticular cells in the sinus of lymph nodes. Of note, uptake of the dye was comparatively much lower in macrophages/monocytes. Our findings indicate the existence of scavenger endothelial cells and reticular cells in blood and lymphatic circulations respectively. We name these two systems "the scavenger RES" collectively.

Mammalian thymic histogenesis can be morphologically divided into three consecutive stages: a) epithelial, b) lymphopoietic or lympho-epithelial, and 3) differentiated cellular microenvironmental, with formation of Hassall's bodies (HBs). Immunomorphological changes characteristic of human thymic involution begin during or soon after the first year after birth, and continue progressively throughout the entire life span. The 3% to 5% annual reduction in the number of cells of the human thymic microenvironment continues until middle age, when it slows down to less than 1% per year. According to the extrapolation of these results, total loss of thymic reticulo-epithelial (RE) tissue and the associated thymocytes should occur at the age of 120 years in humans. The marked reduction of the thymic cellular microenvironment is a well- controlled physiological process and is presumably under both local and global regulation by the cells of the RE meshwork and by the neuroendocrine axis, respectively. In humans, the age related decline of facteur thymique serique (FTS) levels in blood begins after 20 years of age and FTS completely disappears between the 5th and 6th decade of life. In contrast, serum levels of thymosin-alpha 1 and thymopoietin seem to decline earlier, starting as early as 10 years of age. The influences of a variety of other hormones on the involution of the thymus have also been characterized: testosterone, estrogen, and hydrocortisone treatment results in marked involution, cortisone and progesterone administration have a slight to moderate effect while use of desoxycorticosterone has no effect. The experimental administration of thyroxin yielded dose dependent results: low doses resulted in thymic hypertrophy, higher doses produced a slight hypertrophy, while the highest employed doses caused thymic atrophy. The atrophy was of apicnotic type, very different from that detected after treatment with corticoid hormones. Thymus transplantation experiments indicate that age-related, physiological thymic involution has been genetically preprogrammed. Grafting of the thymus from one week old C3H leukemic strain mice into 6 month old hosts resulted in changes in thymic weight and involution patterns that were synchronous in all recipients, in direct correlation with the glands in the donor, but not in the host. These data strongly suggest that the stimulus for thymus cell proliferation and differentiation is genetically determined within the organ implant. Since the thymus is the primary T-lymphopoietic organ during mammalian ontogenesis, its age-related involution with typical immunomorphological alterations can be held responsible only for the decline in antigen-specific T lymphocyte immune functions. Thymic involution and diminished T lymphocyte proliferation can be partially restored by thymic tissue transplantation or use of thymic hormones. The only partial reconstitution of CD4+ T helper lymphocyte subset after antineoplastic chemotherapy and bone marrow transplantation represents a significant, therapy complicating, clinical problem. After high-dose chemotherapy, restoration of thymus dependent CD4+ T lymphocyte genesis was reported only in children. Our radiation, stem cell transplantation, and hormone treatment experiments in animals strongly suggest age and time dependent regeneration of the cytoarchitecture of the thymic cellular microenvironment, as well as intrathymic lymphopoiesis. The human body's zinc pool undergoes progressive reduction, resulting in low zinc plasma levels and a negative crude zinc balance in older rodents, as well as humans. Previous research suggests that the diminished bioavailability of zinc in older mammals may represent one of the major factors for the involution of the thymus and consequent cellular immunological dysfunction. In PBMCs, zinc induces several cytokines, predominantly IL-1, IL-6 and TNF-alpha, and therefore, has an immense immunoregulative capacity. (ABSTRACT TRUNCATED)

Background: Head-kidney, considered the major fish lympho-haemopoietic tissue, consists of cells of the different haemopoietic series supported by a network of stromal cells whose morphofunctional properties have not been established. We report the ultrastructure and cytochemical features of the reticulo-endothelial stroma of the head-kidney from the seawater teleost gilthead seabream (Sparus aurata L.)., Methods: Samples of head-kidney were processed for electron microscopic study. Some of the samples were incubated for acid and alkaline phosphatase, peroxidase, glucose-6-phosphatase, or ATPase., Results: The reticulo-endothelial stroma of gilthead seabream head-kidney consists of sinusoidal cells (endothelial and adventitial cells) and reticular cells (macrophage-type reticulum and fibroblast-like reticular cells). Transcytosis vesicles and rounded medium electron-dense granules were observed in the cytoplasm of the endothelial cells. The adventitial cells partially covered the outside surface of the endothelial cells and were joined by desmosomes. The macrophage-type reticulum cells were characterized by their cytoplasmic processes and acid phosphatase positive lysosomes. The fibroblast-like reticular cells were joined by desmosomes and formed an extensive network between the haemopoietic parenchyma. They were peroxidase negative and acid and alkaline phosphatase, glucose-6-phosphatase, beta-glucuronidase, and ATPase positive., Conclusions: The ultrastructural and cytochemical features of the reticulo-endothelial stroma of the gilthead seabream head-kidney are similar to those of mammalian bone marrow, suggesting phylogenetic analogies between both tissues.

The morphology of reticular cells of the sheathed arteries, in the red pulp of pig spleen, was studied by using transmission electron microscopy; and their histochemical reactivity with periodic acid-thiocarbohydrazide-silver proteinate (PA-TCH-SP). The phagocytic ability was evaluated by injecting colloidal carbon into the splenic artery. Reticular cells of the sheathed arteries were classified as type I and type II cells. Type I cells have a nucleus with scanty chromatin, and the cytoplasm reacts positively to PA-TCH-SP. The PA-TCH-SP-positive granules are considered to be subunits of beta-glycogen particles based on their morphological features. Type II cells have a nucleus with abundant chromatin and are not stained by PA-TCH-SP. Both types of reticular cells are connected with reticular fibers. Results of the colloidal carbon injection showed that type I reticular cells did not ingest carbon particles during the time frame of the experiment, whereas type II reticular cells are phagocytic and ingested carbon.

The reticular framework and reticular fibers in the thymus, cervical lymph node, spleen and bone marrow of Wistar rats were studied by transmission electron microscopy and morphometrical method. The reticular framework was usually observed in these organs as a common structure that consisted mainly of the slender cytoplasmic processes of the fibroblastic reticular cells interconnected with tight junction. Ultrastructurally, the reticular fibers were a mixture of collagen fibrils and amorphous materials, and were almost completely ensheathed by the cytoplasm of fibroblastic reticular cells. Such characteristic structure of the reticular fibers was found not only in the thymus, lymph node and spleen, but also in the bone marrow where it has not been clearly demonstrated previously. Morphometrical analysis revealed that the content of collagen fibrils in the reticular fiber in the lymphoid tissues (the thymus, lymph node and splenic white pulp) was much greater than that in the hematopoietic tissues (the bone marrow and splenic red pulp). Based on these evidences, it was reasonably considered that the reticular framework and reticular fiber ensheathed by the cytoplasm of the fibroblastic reticular cells were the most representative common structure in the reticuloendothelial system (RES) and played some important roles in the functions of RES.

In the lymph nodes of adult rats reticular fibers are known to be covered by the processes of reticular cells. This study aims to visualize the sequence of the envelopment of reticular fibers by reticular cells during development. Rat popliteal lymph nodes of one to twenty-three days after birth were examined by electron microscopy. At the earliest stages, collagenous protofibrils were found in the intercellular space between studded mesenchymal cells. The protofibrils clustered around the plasma membrane of immature reticular cells and then became arranged into microfibrils of 30-40 nm in diameter. Bundles of the fibrils which might be called reticular fibers were surrounded by processes of more than one reticular cell. Then the reticular fiber came to be enclosed by the cytoplasmic process of a single reticular cell. Finally at 16-23 days after birth, the reticular fiber was completely ensheathed by the thick cytoplasmic process of a single reticular cell closed with a junctional complex. Throughout these periods, basal lamina-like materials existed between the reticular fiber and cytoplasmic process. Clumps of fibrils were rarely in contact with leukocytes, including lymphocytes. Immature elastic fibers appeared among collagenous fibrils of the reticular fiber when the fiber came to be enclosed by processes of some reticular cells. It was shown that the enclosure of the reticular fiber by the reticular cell did not result from physical pressure due to the increase of the number of lymphocytes, but the reticular cell actively enclosed the reticular fiber.(ABSTRACT TRUNCATED AT 250 WORDS)

A structural analysis of cells that contained the interferon-alpha-induced lupus inclusions (LI) was performed using a high-voltage electron microscope to determine the exact cellular location of LI and their association with normal cell organelles. LI were induced in the human B lymphoblastoid cell line, Daudi, by culturing with the pure recombinant human leukocyte interferon, IFLrA. Just prior to harvesting, a portion of the cells was treated with monensin to selectively swell the Golgi apparatus, and thereby simplify their identification using the electron microscope. Organellar associations between LI and the outer nuclear envelope and Golgi apparatus were identified in stereopairs of 1-micron sections prepared from both cells that were not treated with monensin and those that were treated with monensin. Serial 0.25-micron sections of the monensin-treated cells were prepared, and seven arbitrarily chosen cells were examined. Each of these cells contained a single LI, and it formed throughout an endoplasmic-reticulum region that made contact with both the outer nuclear envelope and the Golgi vesicles. Reconstruction of a cell by computer from the digitized negatives of serial sections clearly illustrated these relationships. This study reports the first determination of the association between LI and the Golgi apparatus. It also identifies the presence of only one LI in every cell, and the routine association of the LI with both the outer nuclear envelope and the Golgi apparatus. The unique cell location of LI formation suggests their functioning in membrane biogenesis, the trafficking of proteins to the plasma membrane or to cytoplasmic vesicles, or the processing of proteins for secretion.

Serological studies conducted on sera from a group of 31 male SLE patients revealed a 32% prevalence of 7S IgM and a 9.7% prevalence of IgA deficiency. Previous reports using similar methods indicated a higher (43-50%) prevalence of 7S IgM than was found in studies involving predominantly females with SLE (15-18%), and an overall prevalence of IgA deficiency ranging from 0.95% to 4.6%. Males resembled females in the prevalence of Fc-receptor specific reticuloendothelial system dysfunction, correlating with levels of circulating immune complex-like material and disease activity.

The REp cells of the bursa follicle medulla of chicken were isolated in vitro. Culture of the REp cells was maintained over a period of 10 days and the cells were observed at 3 and 10 days by means of transmission electron microscopy (TEM) and immunofluorescence. The use of an anticytokeratin monoclonal antibody confirmed their epithelial nature. TEM observations showed the presence of desmosomes and tonofilaments, which are characteristic of epithelial cells. Furthermore, to some extent the cells regenerated in vitro the network they form in vivo. Though the growth rate becomes slower with time, the features of the REp cells do not significantly change.

The Hermansky-Pudlak syndrome is an autosomal recessive disorder consisting of the triad of albinism, a bleeding diathesis, and ceroid deposition within the reticuloendothelial system. In this study of a patient with Hermansky-Pudlak syndrome, we demonstrate the presence of ceroid within dermal macrophages. Electron microscopic studies suggest that melanosomes may be a substrate for the formation of ceroid in the skin. A review of the clinical and pathophysiologic features of this disorder is presented.

It has long been recognized that synovial intimal cells are phagocytic and that they are capable of picking up colloidal or particulate material injected into the circulation. Hence they have been described as the "articular territory of the reticuloendothelial system." Ultrastructural studies have added a wealth new knowledge and details about the remarkable endocytotic powers of synovial cells. It has been shown that they can endocytose not only small particulate substances like colloidal iron, colloidal gold, and thorotrast but also relatively large objects like masses of fibrin and entire erythrocytes. Controversy has arisen as to whether it is the Type A or Type B cell that is the main scavenger of the joint. Evidence will be presented to show that this is a somewhat fictitious controversy and that these are not distinct and different races of cells with different functions but merely cells whose differences in morphology reflects the function they are performing at a given moment.

The ultrastructure of eleven thymomas with lymphocytic predominance, one "epitheloid" cell thymoma and two normal human thymuses is described with special reference to "Emperipolesis". All patients have had myasthenia gravis. The normal human thymus consists of three parts: outer cortex, inner cortex, and medulla. The outer cortex contains mainly lymphoblasts and Metcalf's macrophages within the so-called "Clark-packet's". The inner cortex consists mainly lymphocytes and interdigitating reticulum cells, and the medulla of epithelial cells, lymphocytes and Hassall's corpuscles. In all cases of lympho-epithelial thymoma and in normal human thymuses there are enormous interdigitations between epithelial (tumor) cells, lymphocytes and macrophages. The "epitheloid" cell thymomas also show findings which suggest an epithelial cell interaction. We have not found intact lymphocytes inside the cytoplasm of normal and/or tumor epithelial cells, macrophages or interdigitating reticulum cells. The intracellular existence of intact lymphocytes has been termed "Emperipolesis" by Humble, Jayne, and Pulvertaft, meaning "internal wandering". These investigations indicate that "Emperipolesis" is not an adequate term for cellular interaction in normal human thymuses and thymomas. A false impression of intraepithelial location of thymic lymphocytes is created by two-dimensional sections of complex thymic structure. These ultrastructural studies revealed damage to lymphocytes only in macrophages with lymphocytolysis within these cells and accumulation of numerous heterophagic vacuoles containing fragments of lymphocytic debris within them.

A 9-year-old horse had numerous firm, painless nodules of the skin and subcutis. Moderately vascular granulation tissue with numerous uni- or multinuclear reticuloendothelial cells was in the nodules and the regional lymph nodes but not in the viscera. By using special stains and electron microscopy, widespread amyloid deposits, mainly in the cytoplasm of reticuloendothelial cells, were identified. Amyloid was probably produced within the reticuloendothelial cells, then expelled from the dying cell and deposited in the intercellular space.

The ultrastructural characteristics of the fibroblastic reticulum cell (FRC) in human reactive lymph nodes, which were studied electron microscopically, indicate a myofibroblastic cell with unique properties. Its contractile element is probably useful in controlling the volume of the lymph node and possibly in the movement of antigens and antibodies. The FRC may also play a role in other immunologic functions and seems to be preponderant in some lymphomas.

Using a panel of monoclonal antibodies and antisera in situ, the authors have defined subsets of human dendritic cells and macrophages that exhibit specific morphologic and microenvironmental characteristics. All subsets contained cells that reacted with antibodies directed against HLA-A,B,C, HLA-Dr, leukocyte common, Leu-M3, and Leu-3(T4) antigens. R4/23 and anti-S100 defined three major subsets. R4/23+, S100- cells constituted the B-cell-related follicular dendritic cells, which were identified only within the germinal center/mantle microenvironment of lymphoid follicles. R4/23-, S100+ cells constituted the T-cell-related dendritic cell subset. Anti-Leu-6(T6) further subdivided this group into Leu-6(T6)- interdigitating cells within the T-cell microenvironments of lymphoid organs and Leu-6(T6)+ Langerhans cells found predominantly in epithelial microenvironments, especially the skin. R4/23-, S100- cells constituted the nondendritic tissue macrophage subset which was widely distributed, primarily outside of dendritic-cell microenvironments. These data indicate that although dendritic cells and macrophages share several common antigenic features, morphologically and microenvironmentally distinct subsets express distinct immunologic phenotypes. Such data may provide insight into the ontogeny and function of these subsets and constitute a basis for the comparison of normal dendritic cells and macrophages to various histiocytic proliferative disorders.

The reticulo-epithelial (RE) cells of the thymus are presumably playing a crucial role in the differentiation of the T lineage lymphoid cells, but how this happens is still a matter for speculation. This paper describes a method for rapid preparation of thymic RE cells with as little damage as possible, their culture, and the analysis of their membrane antigens and of other cytological properties. The cultured cells are pleiomorphic, but at least two types can be distinguished, one being round and very villous, the other one being flat and very cystic. Thymus RE cells have species specific surface antigens and large amounts of H-2 antigen. The possible presence of theta antigen is unclear. Most cells have no detectable Tla antigen. In vitro, they show some uptake of normal mouse serum immunoglobulins. RE cells show a surface migration of ligand-bound membrane antigen; such a capping is much slower than for lymphocytes, and is inhibited by 10 mM NaN3; The drug also causes the apparition of long microprojections (or retraction fibres) on the villous RE cell type, as is also caused by a slight fixation with formalin. Type C virus particles are found in RE cells from AKR mice as young as 1 day.

The effect of highly purified leukocytosis (lymphocytosis)-promoting factor (LPF) of Bordetella pertussis on physical lymphocyte and reticuloepithelial (RE) cell association was studied in an in vitro thymus model. First, a simplified in vitro system to assess the lympho-RE-cell association was developed. A completely confluent layer of thymic RE cells was formed by cultivating trypsinized thymus cell suspensions from 2- to 7-day-old mice. When thymic lymphoid cells were seeded on this cell layer and cultivated overnight, a significant proportion of them were found underneath the RE cell layer. This physical lympho-RE-cell association was quantitated by counting the lymphoid cells underneath the RE cell layers. Second, the effect of LPF on this physical lympho-RE-cell association phenomenon was investigated. Addition of LPF to the culture markedly inhibited the formation of the lympho-RE-cell complex; that is, it inhibited the infiltration of lymphoid cells under the RE cell layer. LPF rendered a nearly maximal level of inhibitory effect at a dose of 0.1 ng/ml. Furthermore, LPF enhanced the liberation of lymphoid cells from preformed lympho-RE-cell complexes. On the other hand, LPF had no direct cytotoxic effect on lymphoid cells at doses below 1 microgram/ml. In order to investigate whether LPF produced the effect by acting on lymphoid cells, RE cells, or both, the following experiments were performed. When lymphoid cells were pretreated with LPF and added to normal RE cell layers, the lympho-RE-cell association was maximally inhibited above the dose of 1 ng/ml. Treatment of these LPF-treated lymphoid cells with anti-LPF antibodies failed to abrogate the effect of LPF. When RE cell layers were similarly pretreated with LPF and were cultivated with normal lymphoid cells, however, much higher doses of LPF, above 100 ng/ml, were required for maximal inhibition. Furthermore, treatment of these LPF-treated RE cells with anti-LPF antibodies abrogated the effect of LPF. Therefore, the apparent effect of LPF on RE cells was considered to be due to the carry-over by RE cells of LPF, which should directly act on lymphoid cells at extremely low doses. On the basis of these results, it was concluded that LPF acted directly on lymphoid cells without mediation of RE cells. These in vitro results appear to parallel the effects of LPF in vivo, where it induces a depletion of cells in the thymus. The model may be useful to study this phenomenon and the concomitant accumulation of blood lymphocytes.

A single dose of 8-16 mg of carbon C11/1431a was injected intravenously into rats, guinea-pigs, mice, goats and two pigs. Examination with the naked eye, dissecting microscope, light microscope and electron microscope of tissues from these animals sacrificed minutes, hours, weeks and up to 23 months after the injection revealed phogocytosis of most of the infected carbon by the professional phagocytes of the reticuloendothelial system (RES). However, in the non-RES sites carbon was trapped in significant amounts in the endothelial cells, the interendothelial spaces, pericytes and perivascular macrophages of the subepithelial capillaries and venules in the anterior nasal mucosa. The catchment area often showed partially fenestrated capillaries and redundant porous basement membrane around the venules. The leakage of carbon through these vessels was through these vessels was thought to be caused partly by the unusual porosity of the vascular walls and partly due to vascular stasis induced by constant loss of heat to the inspired air stream in post-natal life. The importance of these findings in the predilective localization of several granulomatous diseases and various forms of vasculitis in the nasal mucosa id discussed.

The electron microscopic examination of various organs and tumours of different species proved that the ultrastructural equivalent of reticulin fibres is not a uniform substance. Reticulin fibres are either basement membranes or an amorphous mass which appears as argyrophil fibres under the light microscope. Microfibrils may in some cases produce an argyrophilic reticulum. The claimed identity of reticulin and collagen can partly be explained by the chemical similarity of collagen and basement membranes. It seems possible, moreover, that the amorphous mass and microfibrils, which may be an ultrastructural substrate of reticulin, are composed of a material essentially similar to that of collagen.

Confusion regarding microcirculatory pathways in normal human spleen has arisen due to extrapolation from pathological material and from other mammalian spleens, not to mention difficulties in tracing intricate three-dimensional routes from the study of thin sections or cut surfaces of tissue. We examined microcirculatory pathways in normal human spleens freshly obtained from organ transplant donors. A modified corrosion casting procedure was used to obtain an open view of vessels and their connections. Our results demonstrate: 1) "arteriolar-capillary bundles" within lymphatic nodules and extensive branching of arterioles in the marginal zone (MZ); 2) the marginal sinus around lymphatic nodules; 3) the peri-marginal cavernous sinus (PMCS) outside the MZ or immediately adjacent to the nodule itself; the PMCS receives flow via ellipsoid sheaths and MZ, or directly from arterial capillaries, and drains into venous sinuses; 4) fast pathways for flow into venous sinuses via ellipsoid sheaths; 5) arterial capillary terminations in the reticular meshwork of the red pulp or MZ ("open" circulation); direct connections to venous sinuses also occur ("closed" circulation), although rarely; and 6) numerous open-ended venous sinuses in the MZ, allowing a large proportion of the splenic inflow to bypass the red cell filtration sites in the reticular meshwork and at venous sinus walls.

Firstly, the author has investigated how low-dose heparin had influence on reticuloendothelial system of the normal Wistar rats. Secondly, the effect of the low-dose heparin therapy on E. coli endotoxin shock was investigated as to the ultrastructural changes of the liver and spleen of rats. Activation of the phagocytosis which was substantiated by increased uptake of the carbon was observed in heparin administered rats. In this group, abundant development of intra-cellular organellae was noted in the cytoplasm of the hepatic Kupffer cells, macrophages and reticulum cells of the spleen. The E.coli endotoxin administration resulted in formation of micro-thrombi in sinusoidal spaces of the liver at 4 hours after administration. The Kupffer cells also involved in striking disintegration and necrosis. Similarly the sinusoidal lining cells were denudated with disintegration and necrosis. The above-mentioned changes persisted for long term, while the changes less in heparin administered group. The active phagocytic process was discernible in the latter group. Cellular preservation was also excellent in the spleen. The mortality was lower in initial heparin-treated group in comparison with that of untreated control group.

Neither the concept of the Reticulo-Endothelial-System (RES) Aschoff's (1924) nor that of the Reticulo-Histiocyte-System (RHS) provides a satisfactory framework into which the present knowledge of the phagocytic mononuclear cells can be fitted. Current knowledge concerning morphology, histochemistry (peroxydase and esterase activity), immunology (specific surface antigens, receptors on the cell membranes), function (immune phagocytosis, pinocytosis), kinetics (3H-thymidine labelling) and culture makes it possible to place all highly phagocytic mononuclear cells and their precursors in one system, which is called the Mononuclear-Phagocytic-System (MPS) (Langevoort, Cohn, Hirsch, Humphrey, Spector, van Furth, 1969). Kinetic studies with labelled cells have shown, that mononuclear phagocytes originate from precursor cells in the bone marrow (stem cell leads to monoblasts leads to promonocytes), than are circulating in the peripheral blood as monocytes and are transformed to tissue macrophages entering tissues. The MPS comprises following cells in following organs: connective tissue (histiocytes resp. macrophages); liver (Kupffer-cells); lung (alveolar macrophages); lymph nodes (free and fixed macrophages); bone marrow (macrophages); serous cavities (pleural and peritoneal macrophages); bone tissue (osteoclasts?); nervous system (microglial cells) (SEE Table 1). The reticular cells, endothelial cells and fibroblasts (fibrocytes) can therefore not be included in the MPS. Besides differences in morphology, histochemistry and function, they derive from mesenchymal cells and not from the bone marrow as the MPS. The present investigation demonstrates the structure and significance of the MPS in various kinds of chronic-specific and non-specific rhinosinusitis. On semithin sections two kinds of macrophages can be distinguished light-microscopically: 1. Larger macrophages with many phagosomes (storage cells) (Fig. 1A), which can exhibit sometimes a ring-shape on sections embracing greater parts of the interstitium (Fig. 1B). Such forms are mainly found in chronic (maxillary) sinusitis and are interpretated as "scavenger" macrophages. 2. The second type consists of smaller macrophages with extremely ruffling of the cell surface, which is interpretated as an expression of highly (specific?) stimulated states. These later macrophages can be seen mainly in edematous nasal polyps, which might be caused by allergic reactions of the anaphylactic type. The fine structure of the phagocytes is to some extent dependent on the actual development and functional state: there are "immature" macrophages, which are practically indistinguishable from blood monocytes (Fig. 2A); some of them can be stimulated and can therefore show many surface foldings and projections (Fig. 2B). The "mature" macrophage shows a well developed Golgi-area and many secondary lysosomes (Fig. 3). The storage type of the macrophages, which can predominate in some cases of chronic maxillary sinusitis, is characterized by many electron-lucent vacuoles (Fig. 4)...

Reticular cells in the rat spleen were studied with the electron microscope. Besides well developed cisterns of the granular endoplasmic reticulum and the Golgi complex like in fibroblasts, the reticular cells contain small bundles of microfilaments, dense bodies and hemidesmosomes as in the smooth muscle cell. Based on these cytological characteristics, it is suggested that the reticular cells are fibro-muscular in nature, and they may play roles in fibrogenesis as well as in regulation of the blood flow by their contraction in the splenic reticular tissue.

38 patients with congestive cardiomyopathy of apparantly primary origin had a myocardial biopsy. The histology of the fragment of myocardium was studied both by light microscopy and electron microscopy. The results were compared with those from 3 "control" cases and with 16 cases of congestive asystole secondary to a known cause. The non-specific patternss which were observed were of 3 types: patterns of degeneration, pattern of hypertrophy, and interstitial fibrosis. Chronic alcholism had no modifying effect on the ultrastructure. Finally, the group in which the morphology was altered had a higher mortality, but the prognostic significance of the degree of severity of the morphological change must be treated with caution in each individual case.

In traumatic brain lesions microglia cells are often plastered on the outer surface of capillaries. Basement membranes delimit these juxtacepillary cells from pericytes and endothelial cells. In altered nervous tissue many stages in the activation of pericytes may be seen at the same time. It is clearly demonstrable that these pericytes attack the basement membrane vigorously from inside. After penetration of the basement membrane these cells propel themselves between the perivascular feet processes of astrocytes and squeeze between the intracellular gaps, becoming surrounded by the cell processes of the neruopil. The observations suggest that in reactive stages in microglia cells may, at least in part, originate from the perivascular mesenchymal tissue.

A study was done to find out whether apotransferrin receptors are involved in the release of iron from reticuloendothelial cells. To this end, human macrophages which had been obtained by culturing blood monocytes for 7 days were incubated with either diferric or apotransferrin at the physiological pH of 7.4 or at an acidic pH (6.0). While specific diferric transferrin receptors (Kd 1.3 X 10(-8) M) were demonstrated at pH 7.4, no apotransferrin receptors were found. In contrast, both diferric receptors (Kd 2.1 X 10(-8) M) and apotransferrin receptors (Kd 6.8 X 10(-9) M) were found at pH 6.0. The findings of specific apotransferrin binding at acidic pH fits in with the current understanding of iron uptake by cells, in which the iron-transferrin complex is endocytosed and the iron is released at acidic pH. The present results suggest that the apotransferrin remains attached to its receptor in the endocytosed vesicle at this acidic pH but that it becomes detached at the cell surface where the pH is neutral. No evidence was found to indicate that iron is transported out of macrophages via apotransferrin receptors at the physiological pH.

The mathematical study using the Wicksell transformation of the size distribution of the mononuclear alveolar cells has shown two different populations among the alveolar macrophages obtained from 4 adult men. These two types of cells could be also found out and described by electron microscopy. The large cells (14 microns in diameter) looked like the "alveolar macrophage ", with many phagolysosomes. The small cells (7 microns in diameter), less numerous (1/3 of the whole population) resembled monocytes. These data in man are compared to those found in rabbits and the role ot two kinds of cells is discussed.

The splenic response in lethal 17XL Plasmodium yoelii murine malaria is vigorous, displaying marked phagocytosis, erythropoiesis, lymphopoiesis, plasmacytopoiesis, and, from day 3 of infection, increasing levels of parasitized erythrocytes. There is also a pronounced response of newly characterized fibroblastic stromal cells which branch and fuse with one another, forming extensive, complex, irregular, syncytial membranous sheets which provide a variety of barriers. Hence, I term these barrier cells (BC), and their fusion results in barrier-forming complexes (BFC). BC form adherent surfaces, trapping parasitized erythrocytes and monocytes-macrophages, facilitating phagocytosis. They envelop single plasma cells, erythrocytes, erythroblasts, lymphocytes, reticulocytes, monocytes-macrophages, or clusters of them. They surround blood vessels, forming blood-spleen barriers. They are insinuated into the circumferential reticulum at the periphery of white pulp, isolating white pulp. They form channels in red pulp, directing blood flow. They are associated with collagen. There appear to be several sources of BC. They may originate by activation of established reticular cells which form the filtration beds, by activation of reticular cells covering the pulp surface of capsule and trabeculae, and as a major source in this malaria, from circulating progenitors entering the splenic pulp from the vasculature. In non-lethal malaria, these barrier systems protect splenic reticulocytes from parasitization. In the lethal 17XL malaria they do not, and there follows a considerable increase in parasitization in the spleen with a corresponding increase in active macrophages. Large-scale parasitization and parasite recycling through the great stores of splenic reticulocytes in the lethal malaria, and the failure of parasitization of these splenic reticulocytes reserves on the non-lethal malaria, suggests that the actions of the spleen aggravate the lethal malaria and ameliorate the non-lethal. This is supported by the finding that non-lethal malaria is aggravated and lethal malaria ameliorated by splenectomy.

Electronmicroscopic and cytochemical studies were performed to localize interdigitating reticulum cells (IDC) in the popliteal lymph node of the rat. The morphological features of the IDC of the rat correspond to those described for other species, but also show similarities to normal macrophages in the rat. This is considered to be an argument in favour of the common origin of IDC's and macrophages. Ultrahistochemical studies with horseradish peroxidase (HRP) reveal no phagocytotic capacity of IDC's. After perfusion fixation containing ruthenium red (RR) the surface coat stains heavily: RR is also found deep in the membrane invaginations of the IDC, indicating the presence of polyanionic sialoglycoproteins. The post-capillary-venules (PVC) are very permeable to both HRP and RR. The phosphotungstic acid-chromic acid stain (PTA-CrA) also reveals glycoproteins in the surface coat; these glycoproteins are susceptible to alpha-neuraminidase, whereas glycoproteins in the Golgi complexes, lysosomes and in the vesicular complexes of IDC are not. The glycoproteins of the latter are susceptible to 0.1 N NaOH. These findings indicate that IDC produce different kinds of glycoprotein, one of which may be secreted and act as a factor for stimulating peripheral T-lymphocytes. Intimate contact between IDC's and PCV's could be observed. It is therefore conceivable that IDC's play an important role in the homing of T-lymphocytes.

The ultrastructural study of the growth cartilage of pycnodysostosis reveals the presence of abnormal inclusions in the majority of the chondrocytes. The inclusions are single membrane bound and contain granular material and lamellar irregularly interwoven structures which at very high magnification appear to be made up of dense parallel bands. These vacuoles displace adjacent structures and some of them appear to be closely related to the Golgi apparatus. In addition, appearances are sometimes seen which suggest the expulsion of the vacuoles into the cell capsules. The abnormal chondrocyte inclusions are visible by optic microscopy and stained with Nile blue on frozen section. Thus, histochemical and ultrastructural characteristics suggest a lipid (probably phospholipid) content. Many authors have already stressed the role of lipids in the process of calcification. The abnormalities described might bear some relation to the densification of the skeleton seen in pycnodysostosis.

The tissue distribution of lipid microspheres (LMs), drug carriers for targeting therapy of anti-inflammatory drugs, was morphologically studied by electron microscope. In areas of inflammation in rats and mice, LMs were taken up by macrophages and accumulated around endothelial cells of blood vessels, and were observed to penetrate to the outer layer of blood vessels. LMs were also observed in reticuloendothelial cells such as Kupffer cells and splenic macrophages. Furthermore, the uptake of LMs by polymorphonucleocytes (PMNs) in areas of inflammation was enhanced 2-3 fold when LMs were coated with homogeneous IgG. These findings are in agreement with the tissue distribution results previously reported by the authors in studies using radioisotope-labelled LMs. The present and previous reports indicate that LMs could be used as a novel drug carrier, similarly to liposomes, in a drug delivery system specific for areas of inflammation and reticuloendothelial systems.

The development of the thymus was studied with histological, transmission electron microscopic (TEM) and histochemical methods in 100 dog fetuses (beagle), between day 19 of gestation and day 21 after birth. Thymus development could be divided in three stages: 1/Formation of epithelial palisades; 2/Initiation of lymphopoiesis; 3/Differentiation of the medulla and Hassall's bodies (HB). The epithelial anlagen were seen at day 23 of gestation showing the characteristic palisade structure of the endodermally derived epithelium. Ten days later the beginning of lymphoiesis and the reticularization of the epithelial cells could be seen. The first HB could be found at day 38 when cortical-medullary differentiation is recognized. The histochemical observation demonstrated a rich content of PAS positive coarse granules in the cytoplasm of reticulo-epithelial (RE) cells. On the other hand, the HB showed a diffuse PAS positive reaction. The ultrastructural investigations demonstrated the presence of desmosomes connecting RE cells to one another. Desmosomes were not found between RE and lymphocytes. The growth of the developing thymus into the mesenchymal matrix resulted in the lobulation of the organ by connective tissue cells and fibers. The first mast cells were seen at day 35 of gestation, most abundantly in the interlobular connective tissue (ICT) although a few were present in the cortex and somewhat more in the medulla, near the HB. At the end of development small groups of neutrophil cell precursors appeared in the ICT and the cortex. Cysts were not present up to day 21 after birth.

After an uneventful psychomotor development, a Jordanian boy developed increasing blindness, deafness, myoclonic jerks, tetraspasticity and dementia beginning at the age of 8 months and finally resulting in coma during which he died at the age of 3 years and 4 months. Two of his older siblings had possibly suffered from the same disease, but one of them had died in the Near East without adequate diagnosis. Autopsy revealed infantile neuronal ceroid-lipofuscinosis (NCL). Lipopigments showing typical autofluorescence and PAS staining granules were abundant in the markedly atrophic brain and numerous visceral organs, especially in cells of the reticulo-endothelial system, intestinal tunica propria, the bone marrow and hepatic von Kupffer cells. Ubiquitous accumulation of these NCL-typical lipopigments were found in adventitial mesenchymal cells of small vessels, particularly in lungs, liver and lymphatic organs. Lipopigments had accreted to a lesser degree in podocytes of renal glomerula and Sertoli cells, and in striated muscle fibers only around nuclei. Lymphocytes, smooth muscle cells and stratified epithelial cells did not contain lipopigments. The ultrastructure of the membrane-surrounded osmiophilic cytosomes consisted predominantly of finely granular lipofuscin although short membranous profiles were occasionally embedded within this granular matrix. These morphological findings emphasize the diagnostic importance of lymph node, rectal and bone marrow biopsies and, to a lesser degree, of liver biopsy in infantile neuronal ceroid-lipofuscinosis. The nosology of infantile NCL, independent of the ethnic background, was further clarified by our studies on ultrastructure and visceral distribution of these lipopigments. Morphological damage to parenchymal cells of visceral organs, contrary to the widespread loss of cortical neurons in the brain could not be demonstrated.

The morphology and interactions of lymphoreticular cells in cultures of human tumour tissue was studied by transmission and surface scanning electron microscopy. Macrophages are very common in non-lymphoid neoplasms and vary considerably in shape and surface morphology, with features of mature stimulated cells. Lymphocytes adhere to macrophages more often than to tumour cells. Close contact between macrophages and tumour cells also occurs, but there is no evidence that the infiltrating macrophages or lymphocytes have an overt cytotoxic effect under these cultural conditions. A variety of interactions are seen in cultures of Hodgkin's lymphoma, lymphosarcoma and reticulum cell sarcoma. The only cultural characteristics that may be specific for lymphoma tissue are large intravacuolar collections of lymphocytes within macrophages or giant cells and the rare close spatial relationship between lymphocytes and degenerate macrophages, the latter particularly in Hodgkin's lymphoma. These observations demonstrate the disturbed cellular interrelationships that exist in lymphoma tissue.