Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019214 (hepatosplenomegaly)
 4,408 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 28-year-old male was admitted to our hospital because of hepatosplenomegaly and granular lymphocytosis. His peripheral leukocyte count was 3,000/microliters with 43% of granular lymphocytes (GL). These GLs were immunologically phenotyped as CD2+CD3-CD4-CD8-CD16+CD56+HLA-DR+ and were found that TcR genes coding beta and gamma chains were not rearranged. Chromosomal analysis of his GLs stimulated with IL-2 showed 47 XY, +8. This patient was diagnosed as a granular lymphocyte leukemia of natural killer cell type. Blood chemistry showed elevation of serum GOT, GPT and LDH values. The fever persisted until administration of prednisolone was initiated. But 40 days after, high fever appeared again and the liver and spleen were extremely enlarged. Combined chemotherapy was then started but resulted in no effects. He died of hepatic failure on the 77th day from admission. 47 XY, +8, that has been reported in acute non-lymphocytic leukemia and myelodysplastic syndrome, may be related to the pathogenesis in some cases of granular lymphocyte leukemia.
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PMID:[Granular lymphocyte leukemia of natural killer cell type; association with 47 XY, +8 by interleukin 2 (IL-2)-stimulated chromosomal analysis]. 225 62

An 18-year-old man was admitted to our hospital because of 39 degrees C fever for over one month, marked hepatosplenomegaly, and pancytopenia. Malignant histiocytosis, malignant lymphoma, or hemophagocytic syndrome were ruled out by bone marrow aspiration and liver biopsy. A diagnosis of chronic EB virus infection was made according to his characteristic clinical features, abnormally high titiers of anti-EBV antibodies (VCA-IgG x 2560, EA-IgG x 1280), and the detection of EBV genome in the peripheral blood mononuclear cells by polymerase chain reaction. He also manifested granular lymphocyte proliferative disorder (GLPD). The phenotype of the proliferating granular lymphocytes was CD2 (+), CD3 (-), CD56 (+), and IL-2R beta (+), showing the NK lineage of these cells. Chromosomal abnormality of the cells cultured for a short time with IL-2 and a monoclonal junctional DNA structure of EB virus terminal repeat analyzed by the Southern blotting provided definitive evidence for the monoclonal expansion of the granular lymphocytes. These findings indicate a causative role of EV virus in NK-GLPD or NK-leukemia.
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PMID:[Chronic active EB virus infection accompanied by monoclonal proliferation of granular lymphocytes]. 778 25

Autoimmune lymphoproliferative syndrome (ALPS) is marked by massive lymphadenopathy, hepatosplenomegaly, autoimmunity and the presence of increased numbers of circulating and tissue TCR-alpha beta, CD4- CD8- T cells. The underlying defect is that of decreased T cell and B cell apoptosis, due in most, but not all, cases to heterozygous mutations of the Fas gene and corresponding defective Fas signaling function. Here we measure in vivo and in vitro cytokine secretion in ALPS to shed light on the relation of apoptosis defects to the development of autoimmunity. In in vivo studies, ALPS patients manifested greatly increased circulating levels of IL-10 (> 100-fold), compared with both healthy individuals and various disease controls; in contrast, their levels of IL-1 beta, IL-4, and IFN-gamma were normal and their levels of IL-2 and TNF-alpha were marginally increased. In parallel in vitro studies, ALPS patients CD4+ DR+ T cells stimulated either with anti-CD3/CD28 or anti-CD2/CD28 produced increased amounts of IL-4 and IL-5 (10 to 20-fold) and decreased amounts of IFN-gamma (4-fold) as compared with those of control CD4+ DR+ T cells. In contrast, ALPS patients' CD4-/CD8- T cells produced very low amounts of cytokines. Finally, ALPS patients' peripheral monocytes/macrophages produced decreased amounts of IL-12 (30-fold) and increased amounts of IL-10 (5-fold). In conclusion, ALPS is marked by the presence of DR+ T cells that exhibit a skewed Th2 cytokine response upon various forms of stimulation. This cytokine response, in the presence of increased circulating IL-10 levels, is likely to define the cytokine milieu that accounts for the humoral autoimmune features of ALPS and, perhaps, of other humoral autoimmune states.
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PMID:Characteristic T helper 2 T cell cytokine abnormalities in autoimmune lymphoproliferative syndrome, a syndrome marked by defective apoptosis and humoral autoimmunity. 902 33

Omenn's syndrome (OS) is characterized by erythrodermia, hepatosplenomegaly, lymphadenopathy, hypereosinophilia and elevated IgE levels associated with increased susceptibility to severe infections. Peripheral blood T cells, though usually present in normal number, show an activated phenotype (including an increased expression of CD95/Fas), a Th2 pattern of cytokine secretion and defective proliferative response to mitogens. In this report, we demonstrate that T cells from patients with OS undergo an excessive cell death in vitro resulting from two mechanisms. First, a substantial number of peripheral blood lymphocytes from OS patients die in unstimulated cultures (p = 0.009 vs. healthy controls). This spontaneous apoptosis is associated with reduced expression of bcl-2 gene product (p < 0.05) and can be prevented by addition of interleukin (IL)-2 (which also prevents down-modulation of bcl-2), while is independent from CD95 signaling. Second, lymphocytes from OS patients are highly susceptible to activation-induced cell death (AICD) induced with mitogens. This mechanism is largely independent from IL-2, while it can be significantly inhibited blocking CD95 with an IgG2b monoclonal antibody (mAb). The dependence of AICD from signals transduced via CD95 was confirmed showing that cross-linking CD95 with an IgM mAb induces a higher cell death in purified CD4+ CD45R0+ cells from OS patients than in controls (comparable for CD95 expression). Both mechanisms of cell death observed in this study result from lymphocyte hyperactivation occurring in vivo in these patients and may contribute to functional T cell defects of OS.
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PMID:In vitro cell death of activated lymphocytes in Omenn's syndrome. 939 97

Malignant histiocytosis (MH)-like B-cell lymphoma (BCL) is a neoplastic proliferation of large B cells clinically characterized by fever, hepatosplenomegaly, haemophagocytosis and abnormal laboratory data, without lymphadenopathy or skin lesions. Interestingly, most cases have been reported in Asian patients, and it is unclear whether MH-like BCL is biologically distinct from conventional large B-cell lymphomas. We report five Japanese patients with MH-like BCL. Biopsied specimens of bone marrow, liver and/or spleen showed infiltration of neoplastic B cells accompanied by haemophagocytosing histiocytes. Lymphoma cells were positive for CD19, CD20 and HLA-DR surface antigens, and negative for CD5 and CD10. In four cases elevated serum levels of interleukin (IL)-6 and the soluble IL-2 receptor isoform were noted, but not IL-1beta, IL-2 or tumour necrosis factor-alpha. Autopsies of two cases were pathologically diagnosed as intravascular lymphomatosis (IVL). Based on these observations, the current and nine previous cases reported as MH-like BCL in Japan were re-evaluated. They appear to form a peculiar variant of IVL, characterized by bone marrow involvement at presentation, haemophagocytic syndrome, and a rapidly aggressive clinical course, but rarely neurological complications or skin lesions. This variant may merit separate consideration because of the problems posed in the initial diagnosis and therapeutic approaches.
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PMID:Malignant histiocytosis-like B-cell lymphoma, a distinct pathologic variant of intravascular lymphomatosis: a report of five cases and review of the literature. 940 Oct 80

The occurrence of sarcoidosis in combination with common variable immunodeficiency (CVID) has been described in a small number of patients. In these patients, sarcoidosis consisted of lymphadenopathy, mild to moderate pulmonary involvement and hepatosplenomegaly. However, severe and rapidly progressive pulmonary fibrosis in combination with a severe defect of the cellular and humoral immune system has not been described yet. In our patient, defects of the T and B cell system resulted in severe immunodeficiency. The defect of the humoral immune system was characterized by the impairment of specific antibody production in vivo. In addition, hypogammaglobulinemia with missing IgA and IgE along with a marked defect in IgM and IgG production was noted. There was a progressively reduced lymphocyte proliferation in response to T cell mitogens, while proliferation after specific IL-2 stimulation was normal. A Th1 lymphocyte-subset-like profile might thus play a role in the pathogenesis and might form the connecting link between sarcoidosis and CVID. This is the report of a so far new and unique combination of severe immunodeficiency and sarcoidosis also associated with a congenital dysmorphia consisting of a palatal cleft. The findings of the 40 patients with CVID and sarcoidosis reported so far are discussed in order to point out the typical features of patients with this uncommon syndrome.
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PMID:Sarcoidosis and common variable immunodeficiency. A case of a malignant course of sarcoidosis in conjunction with severe impairment of the cellular and humoral immune system. 1085 23

Intracardial inoculation of BALB/c mice with Leishmania donovani amastigotes induced progressive visceral leishmaniasis (VL) with increasing splenic parasite load when followed upto 4-month postinfection period. In contrast, the liver parasite load reached maximum around 2-month postinfection period following which it started declining. The infection pattern differed somewhat from the earlier reports on mouse model of VL induced by intravenous inoculation of parasites with respect to the duration as well as magnitude of parasite burden in the organs (liver and spleen) and associated hepatosplenomegaly. Immunosuppression in mice with progressive VL was manifested in the form of impairment of proliferative response of the splenic mononuclear cells (SPMC) to in vitro stimulation with leishmanial antigen or the mitogen concanavalin A (ConA), although ConA stimulated cells were found to be capable of IL-2 and IFN-gamma synthesis. Differential expression of activating (IL-2, IFN-gamma and TNF-alpha) as well as deactivating (IL-4 and TGF-beta) cytokines was demonstrable in the spleen and liver of animals during the course of infection. Further, the synthesis of inducible nitric oxide synthase (iNOS) enzyme increased considerably in the liver as well as in the spleen of 4-month infected animal with parallel increase in the transcripts of the iNOS activating cytokines IFN-gamma and TNF-alpha. The temporal variation in the organ specific immune response could be related to the differential control of parasite burden in the liver and spleen of the infected host.
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PMID:Infection pattern and immune response in the spleen and liver of BALB/c mice intracardially infected with Leishmania donovani amastigotes. 1264 14

Visceral leishmaniasis (VL) produced in BALB/c mice through intracardial administration of Leishmania donovani amastigotes was accompanied by hepatosplenomegaly with high organ parasite load and lymphadenopathy when followed up to 4-months or so. To elucidate the mechanism of immunosuppression associated with VL, we report here progressive impairment of the proliferative response of lymph node cells (lymphocytes) from infected animals (I-LNC) to in vitro stimulation with the combination of phorbol 12-myristate 13-acetate (PMA) and ionomycin (Io) that could be related to the downregulation of PKC and MAP kinase (ERK 1/2) activation process. Further, pretreatment of I-LNC with the protein phosphatase inhibitor okadaic acid (OA), but not with calyculin A or sodium orthovanadate, significantly restored their proliferative response as well as PMA-induced activation of PKC. A population of LNC (primarily T-lymphocytes) from chronically infected animals was shown to undergo apoptosis, the number of which increased considerably following PMA+ Io stimulation. The apoptotic pathway, which was followed through binding of cells to Annexin V, activation of caspase-3 and fragmentation of DNA, involved destabilization of mitochondria, probably as a result of downregulation of PKC and Bcl-2. Interestingly, prior incubation of I-LNC with OA reversed the state of cell cycle arrest (anergy) and apoptosis through progression of cells from G0/G1 to S and G2/M phases with transcriptional activation of IL-2 and IL-2R genes. Our results suggest that the cellular (immune) dysfunction in VL could be attributed to dephosphorylation of key molecules in the T-lymphocyte signaling pathway by Ser/Thr phosphatase leading to their inactivation.
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PMID:Lymph node cells from BALB/c mice with chronic visceral leishmaniasis exhibiting cellular anergy and apoptosis: involvement of Ser/Thr phosphatase. 1701 55

Familial hemophagocytic lymphohistiocytosis (FHL) is typically an early onset, fatal disease characterized by a sepsislike illness with cytopenia, hepatosplenomegaly, and deficient lymphocyte cytotoxicity. Disease-causing mutations have been identified in genes encoding perforin (PRF1/FHL2), Munc13-4 (UNC13D/FHL3), and syntaxin-11 (STX11/FHL4). In contrast to mutations leading to loss of perforin and Munc13-4 function, it is unclear how syntaxin-11 loss-of-function mutations contribute to disease. We show here that freshly isolated, resting natural killer (NK) cells and CD8(+) T cells express syntaxin-11. In infants, NK cells are the predominant perforin-containing cell type. NK cells from FHL4 patients fail to degranulate when encountering susceptible target cells. Unexpectedly, IL-2 stimulation partially restores degranulation and cytotoxicity by NK cells, which could explain the less severe disease progression observed in FHL4 patients, compared with FHL2 and FHL3 patients. Since the effector T-cell compartment is still immature in infants, our data suggest that the observed defect in NK-cell degranulation may contribute to the pathophysiology of FHL, that evaluation of NK-cell degranulation in suspected FHL patients may facilitate diagnosis, and that these new insights may offer novel therapeutic possibilities.
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PMID:Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients. 1752 86

We present a 68-year-old man suffering from transverse myelopathy since May 2010. The spinal cord MRI showed a T2- hyperintense lesion invading the Th5 level spinal cord. Although the patient transiently responded to steroid-pulse therapy, his neurological symptoms degenerated three months after wards. On admission, he had an apparent hepatosplenomegaly, but no lymphadenopathy. A laboratory examination revealed bicytopenia and increased levels ofLDH and soluble IL-2 receptors. Histological analysis ofa skin biopsy specimen demonstrated proliferation of large atypical lymphoid cells positive for CD20 and CD79a in the small capillaries, leading to our diagnosis of intravascular large B-cell lymphoma(IVLBCL). Thus, the patient's progressive myelopathy was probably caused by IVLBCL invasion. The patient responded well to Rituximab-combined CHOP therapy(R-CHOP), and his neurological symptoms improved immediately. A spinal cord MRI showed the disappearance of the abnormal signal after two courses of R -CHOP. IVLBCL often presents with neurological manifestations, including transverse myelopathy.
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PMID:[A case of intravascular large B-cell lymphoma associated with transverse myelopathy]. 2208 4


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