The wall of hepatic sinusoids is a morphological and functional unit made up of four different cell populations, i.e., endothelial cells, Kupffer cells, perisinusoidal stellate cells (fat-storing cells), and lymphocytes including pit cells (liver-associated LGLs).
The core element of this unit is the endothelial lining which provides a bed for other sinusoidal cells. Endothelial cells are highly fenestrated and sieve the fluids exchanged between the sinusoidal lumen and the space of Disse. Presence of numerous receptors on endothelial cells supports the receptor-mediated endocytosis of various substances. Adhesion molecules are expressed on the surface of these cells. Kupffer cells are resident macrophages, and clear endotoxin from the blood stream. When activated, Kupffer cells secrete metabolites of arachidonic acid, TNF, IL-1, IFN, and reactive oxygen products. Stellate cells are located perisinusoidally surrounding the sinusoidal tubes and, on the other hand, send thorn-like microprojections to parenchymal cells. Stellate cells store vitamin A and produce Type I, III and IV collagens and other extracellular matrix. Pit cells are characterized by the presence of dense granules and rod-cored vesicles. After administration of BRMs, number of pit cells increases adhering to the endothelial lining and liver-associated NK activity is augmented. Paracrine and autocrine secretions of mediators and cytokines from sinusoidal cells modulate functions of the sinusoidal wall and parenchymal cells.
Currently the RES is restricted only to the system of macrophages. From the modern concept of sinusoidal cells in the liver, however, phagocytosis is only the trigger for starting the cascade of broad RES functions beyond the single cell line. The liver RES is not only Kupffer cells but the sinusoidal wall itself which provides a microenvironment between the blood stream and parenchymal cells. The RES is specifically organized tissue in the body, as suggested by early investigators.

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In order to elucidate the role of Kupffer cells in granuloma formation in the liver under a severe monocytopenic condition, two monocytopenic mouse models were examined after glucan injection.
In monocytopenic mice induced by administration of strontium-89, hepatic granulomas were formed but smaller, less numerous, and more irregular in shape than those in the control mice. In osteopetrotic (op/op) mice defective in the production of macrophage colony-stimulating factor, differentiation of monocytes into macrophages were completely impaired. Hepatic granulomas were also smaller and less numerous in op/op mice than those in normal littermates. In both mouse models, however, Kupffer cells differentiated into epithelioid cells and multinucleated giant cells in the granuloma. Kupffer cells proliferated in conditions depleted of blood monocytes or with defective transformation of monocytes into macrophages during granuloma formation in both mouse models. These results indicate that Kupffer cells are a distinct population of macrophages possibly derived from granulocyte-macrophage colony-forming cells or earlier progenitors but not from blood monocytes, and participate in glucan-induced granuloma formation without supply of blood monocytes.

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The aim of this paper is to show the relationship between Kupffer cell function and endotoxin in the experimental liver injury and clinical liver disease.
We all have a bacterial flora in our intestine as a source of endotoxin, and once liver injury was occured, in association with the failure of Kupffer cell function of the liver, these endogenous endotoxin will appear in the peripheral circulation.
The results of our clinical study on hepatitis A and alcoholic liver disease, suggest the reticuloendotherial system of the liver markedly damaged and systemic endotoxemia is thought to be responsible for the various clinical manifestations and the excerbation of the course of these disease, and that endotoxin plays an important role in the pathogenesis of liver injury in hepatitis A and alcoholic liver disease.

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Kupffer cells produced cytokines including interleukin 1 (IL1) and tumor necrosis factor (TNF), chemical mediator in cluding platelet activating factor (PAF) and arachidonic acid metabolites including prostaglandins (PGs) and leukotrienes (LTs). When Kupffer cells treated with PGs, production of IL1 and TNF was significantly reduced. But, the production of cytokines increased by Kupffer cells treated with LTs. Furthermore, TNF and IFN-γ increased PGs production by Kupffer cells. But, IFN-α and IFN-β decreased PGs production. These results was suggested that networks in Kupffer cells may be regulated by cytokine cascade and arachidonic acid cascade.

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Allogenic bone marrow transplantation (BMT) has been successfully carried out as the curative treatment for the patients with hematological malignancies as well as aplastic anemia; however, it has been accompanied by several complications. Hepatic graft-versus-host disease (GVHD) is one of the causes of liver dysfunction after BMT. On the other hand, it has been reported that tumor necrosis factor-α (TNFα) plays an essential role in the pathogenesis of the cutaneous and intestinal lesions of acute GVHD. In this paper, we histologically investigated the effect of TNFα on liver damage in a murine bone marrow transplant model. Furthermore, we investigated the effect of spleen cell on hepatic GVHD, since these cells contain abundant T cells and induce severe GVHD. By the injection of spleen cells, the marked T cell infiltration was observed around bile ducts and the dotty, partially focal T cell infiltration was found in the liver parenchyma. In addition to the presence of T cells with hepatocytes, the degenerative change of hepatocyte membranes was found without the contact of T cells by electron microscopy. It might be caused by the effect of TNFα. TNFα can activate and increase macrophages and in turn it induces a variety of cytokines secreted by T cells, macrophages and other cells; therefore, in the case of the injection of TNFα, we could not obtain any similar changes in the liver to that induced by the inoculation of spleen cells.

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The present study was performed to clarify the physicochemical characterization and role of human lymphocytic alkaline phosphatase (ALP). The results obtained were as follows:
1) ALP was extracted from childhood tonsillar tissue and purified by anion exchange chromatography. Lymphocytic ALP was categorized as one of universal type because of the similarity to that of the liver and bone according to the results of inhibition test, electrophoretic analysis and immunohistochemical staining.
2) Enzyme-and immunohistochemical staining revealed that the mantle zone lymphocytes were positive for Type II protein kinase C (PKC) but they were distinctly divided into outer & inner layers, ALP positive and negative, respectively.
3) By immunohistochemical double staining of PKC and Ki-67, it was likely considered that PKC might play an important role for the B-lymphocyte activation from GO to G1 of the cell cycle.
4) The appearance and disappearance of ALP positive lymphocytes were temporarily observed in short term culture for blastoid transformation of the B lymphocytes stimulated by LPS (bacterial lipopolysaccahide).
5) In vitro, ALP was released with an incubation of the lymphocytes with PI-PLC (phosphatidylinositol specific phospholipase C). The evidence suggests that lymphocytic ALP is considered to be phosphatidylinositol anchor.
6) Following after the release of ALP from the lymphocytes, the PKC activity decreased markedly in cytosol fraction, while an increase of PKC activity was observed in a particulate fraction containing cellular membrane.
7) From the present study, it was concluded that diacylglycerol (DG) made by the cleavage of ALP anchor may increase PKC activity, resulting in the occurrence of the activation & differentiation of B lymphocytes.

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It has been reported that human T-cell leukemia virus type I (HTLV-I) is closely associated with the development of adult T-cell leukemia (ATL). Furthermore, it has become to be known that the interleukin-2 (IL-2)/interleukin-2 receptor (IL-2R) system in ATL plays an important role in HTLV-I-related leukemogenesis.
In the study, IL-2 production and IL-2R expression of mononuclear cells (MNCs) in the blood of patients with HTLV-I-related disease were examined by cultivating the MNCs in the presence or absence of phytohemagglutinin (PHA). The sandwich radioimmunoassay method was used for quantitation of IL-2 in the supernatant of the medium, and the direct immunofluorescence method was employed for the detection of IL-2R.
Spontaneous IL-2 production from MNCs was seen in 3 of 8 patients with acute and lymphoma type of ATL, in 6 of 9 with chronic type of ATL, in 6 of 10 with smouldering type of ATL, and in 20 of 32 HTLV-I carriers. However, IL-2 production was not induced by PHA stimulation in 7 of 8 patients with acute and lymphoma type of ATL, in 7 of 9 with chronic type of ATL, in 3 of 10 with smouldering type of ATL, and in 10 of 32 HTLV-I carriers.
IL-2R expression on MNCs from these patients with HTLV-I-related disease increased by the cultivation. However, the rate of increase of the IL-2R expression in the PHA-stimulated group (IL-2R expression after culture/that of fresh cells) decreased in association with the progression of HTLV-I-related disease.
These data revealed that MNCs from not only patients with ATL but also from some HTLV-I carriers showed abnormal IL-2 production and IL-2R expression. In other words, the IL-2/IL-2R system abonormality present in ATL also exists in some HTLV-I carriers. Further study of HTLV-I carriers with this IL-2/IL-2R abnormality is necessary to predict whether ATL develops in the patients.

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We examined the tissue factor (TF) activity in human mononuclear cells (MNCs), human umbilical vein endothelial cells (HUVECs) or HUVECs incubated with the medium from MNCs. The TF activity of HUVEC cultured without stimulation was hardly detected, but that of MNC cultured without it increased until 18 hours. When they were cultured with lipopolysaccharide (LPS) and cytokines, the TF activity was further increased dose-dependently, and reached a maximum within 6-12 hours. The TF activity of MNC cultured with LPS, interleukin-1 (IL-1) and interleukin-6 (IL-6) was significantly increased. That of HUVEC cultured with LPS, IL-1 or tumor necrosis factor (TNF) was markedly increased. Furthermore, TF activity of HUVEC incubated with the medium from MNCs cultured with various cytokines was more increased. Although TF activity of HUVEC or MNC cultured with colony stimulating factor and interferron was hardly increased, that of HUVEC incubated with the medium from MNC cultured with them was markedly increased. The TF activity of HUVEC incubated with the medium from MNCs cultured with LPS was dependent on the cell number of cultured MNC. LPS-stimulated MNC also released TNF and IL-1, and the levels within 12-24 hours. We speculated that MNCs and vascular endothelial cells interacted together and played an important role in hemostasis.

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The seventy-six cases of primary gastric lymphomas have been studied morpholigically, immunohistochemically and genetically. The lymphomas usually showed B-cell phenotype. According to the update Kiel classification 33 were of low-grade malignancy (all B-cell) and 43 were of high-grade malignancy (41 of B-cells and 2 of T-cell). Diffuse, follicular and interfollicular types were categorized by the infiltrating patterns. Specific interfollicular pattern was detected in 14 cases and the cases consisted of various histological groups, including lymphocytic type with monoclonal surface immunoglobulin and clear cell variant, and possessed no bcl-2 gene rearrangement. Bcl-2 gene rearrangement was detected in three of centroblastic type including one with follicular patterns, and one of centroblastic/centrocytic type. The results indicate the presence of follicular center cell origin of the gastric lymphoma.

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The authors report a 71-year-old man with T-cell malignancy presenting with fever, hepatosplenomegaly, pancytopenia and coagulopathy in the absence of lymphadenopathy. Repeated bone marrow examinations revealed decreased hematopoiesis with proliferation of mature histiocytes showing hemophagocytosis and few abnormal cells. His symptoms and laboratory findings transiently improved after high dose methyl-prednisolone therapy. But two weeks later, he suffered from fever and severe diarrhea concomitant with appearance of atypical lymphoid cells in bone marrow and peripheral blood. Immunophenotypic studies of these cells suggested monoclonal proliferation of CD8⁺T-cells. He died of septic shock 3 days after the start of CHOP therapy. At autopsy, the proliferation of erythrophagocytic histiocytes was conspicuous in bone marrow, liver and spleen, but lymphomatous involvement was not seen anywhere.
DNA analysis of lymphoid cells of ante mortem bone marrow revealed rearrangements of T-cell receptor (TcR)β chain and γ chain genes, deletion of TcR δ chain gene and germline configulation in immunoglobulin heavy chain (IgH) gene. These findings suggest that this case presented as hemophagocytic syndrome associated with underlying T-cell malignancy which later manifested.
Reactive hemophagocytic syndrome can be an early and prominent manifestation of T-cell malignancy, and differentiation from other causes of hemophagocytic syndrome can be difficult. The demonstration of TcR gene rearrangements with Southern blot analysis is very useful for the diagnosis of underlying T-cell malignancy which may be difficult with conventional morphological and/or immunophenotypic studies.

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A case of myelodysplastic syndrome (MDS) complicated by malignant lymphoma is reported. The patient was a 68-year-old male who was admitted to hospital with severe anemia and was diagnosed as having MDS on the basis of hematological examinations and the findings of bone marrow biopsy. Treatment with steroid hormones, anabolic hormone preparations, and blood transfusion proved unsuccessful and he died of infection six months later.
At autopsy, the bone marrow was hypoplastic and blast cells showed very poor differentiation, the megakaryocytes were decreased in number, and the erythroblasts had abnormal nuclei. Systemic lymphadenopathy (paratracheal, mesenteric, parapancreatic and paraaortic) was found. Histological examination of the lymph-nodes revealed diffuse proliferation of medium sized lymphocytes which had B cell markers and showed plasmacytoid differentiation.
The starry sky constellation of large mononuclear phagocytes in the lymphoma tissue was quite similar to the histology of Burkitt's lymphoma. There was evidence of generalized cryptococcosis and candidiasis. Malignant lymphoma complicating MDS is very rare, but the exsistence of this case suggests that a clonal abnormality of the pluripotent hematopoietic stem cells occurs in MDS.

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A case of B-cell lymphoma with multiple osteolytic lesions, marked hypercalcemia and paraprotein of IgMκ type, was reported. The patient was a 53-year-old male, who was admitted to our hospital in July, 1988, because of back pain. On physical examination, generalized lymphadenopathy and an abdominal large mass (φ15cm) were observed. Lymph node biopsy revealed diffuse large cell lymphoma (LSG criteria) which was classified as B-cell type. Systemic bone roentrgenological examinations demonstrated multiple lytic lesions, including punched-out lesions, although bone scintigraphy (^99mTc-MDP) was negative. Marked hypercalcemia (15.6mg/dl), elevated level of serum LDH (4070U/1), and IgMκ paraproteinemia were also observed. Atypical large lymphoid cells were seen in bone marrow. Consequently, the clinical stage was determind to be IV (Ann Arbor classification). The patient was treated with elcatonin, dexamethasone, and hydration, and then with CHOP therapy. The serum calcium level returned to normal, and lymphadenopathy and the abdominal mass regressed. However, the lymphoma was reflactory to further treatment and the patient died of septicemia.
In order to investigate osteoclast activating factor (OAF) in this case, parathyroid hormone (PTH), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β were measured. The levels of PTH and TNF-α remained within normal ranges throughout the course. The serum IL-1β level was slightly higher (0.27ng/ml) than normal (<0.2ng/ml) at the initiation of the treatment, and returned to the normal range after CHOP therapy. The serum IL-1β level remained normal, even when the patient developed septicemia. It is suggested that IL-1β plays a role as an OAF in the osteolytic mechanism and hypercalcemia.

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Gandy-Gamna nodules and focal hemosiderin depositions in the spleens obtained from 4 patients with idiopathic portal hypertension (IPH), 5 with liver cirrhosis (LC), and one with extrahepatic portal vein obstruction (EHO) were examined histologically. In all patients except one with IPH, full-scale, large, cross-cut sections stained by the Perls iron reaction were examined. In one patient of each disease group, serial sections were also used for three-dimensional observation. The Gandy-Gamna nodules are caused by hemorrhage and connective tissue proliferation in the periarteriolar lymphocyte sheath (PALS). Hemosiderin deposition extended to the trabecula via the lymphatic flow in the PALS, which is the reverse of that of blood in the arteriole. Although calcium deposition is observed later, it is not considered to be essential to the formation of a Gandy-Gamna nodule. Three-dimensional observation revealed that Gandy-Gamna nodules are not spherical, but spindle-shaped or branched, as a result of their formation along the central arterioles; however, they give the appearance of being two-dimensionally round in a single section.
Gandy-Gamna nodules are concluded to be characteristic of the spleen of patients with portal hypertension. The definition of Gandy-Gamna nodules as nodules composed of proliferating connective tissue and hemosiderin deposition with calcification are not sufficient, and their location and histogenesis are also important considerations in this definition.

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