Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with familial and acquired forms. The familial form is associated with mutations in the perforin gene and both forms are associated with severe defects in lymphocyte cytotoxic function. We examined perforin-deficient mice as a model of HLH in order to gain insight into this poorly understood disorder. While these mice do not spontaneously develop HLH-like symptoms, we found that they manifest all of the features of HLH after infection with lymphocytic choriomeningitic virus (LCMV). Following LCMV infection, perforin-deficient mice develop fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevation of multiple serum cytokine levels, and hemophagocytosis is evident in many tissues. Investigation into how this phenotype develops has revealed that CD8+ T cells, but not natural killer (NK) cells, are necessary for the development of this disorder. Cytokine neutralization studies have revealed that interferon gamma (IFNgamma) is uniquely essential as well. Finally, the excessive amount of IFNgamma seen in affected mice appears to be driven by increased antigen presentation to CD8+ T cells. These studies provide insight into the pathophysiology of HLH, and provide new targets for specific therapeutic intervention in this fatal disorder.
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PMID:An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. 1506 16

Social disruption (SDR) is an effective model of social stress associated with an enhanced inflammatory reactivity of the immune system. The aim of the present study was to further describe SDR effects on cytokine production by spleen cells, testing selectively monocyte and T cell functions as a result of this stressor. For this purpose, splenocytes from control mice (C) and mice socially stressed for 7 days (SDR) were cultured in the presence of lipopolysaccharide (LPS) or concanavalin A (Con A). Splenocyte proliferation, cytokine production and sensitivity of spleen cells to corticosterone were assessed in vitro. The humoral response to keyhole limpet hemocyanin (KLH) immunization was assessed. SDR induced splenomegaly and enhanced splenocyte basal proliferation. The pro-inflammatory influence of SDR was confirmed by an increased release of interleukin-6 (IL-6) by LPS-stimulated cultures and by a reduced sensitivity of spleen cells to the anti-inflammatory effect of corticosterone. The mechanism increasing cytokine production in response to LPS was cytokine specific, since among inflammatory cytokines, IL-6 but not interferon-gamma (IFN-gamma) was enhanced by stress. In stressed mice, the increase in IL-6 and IFN-gamma and the decrease in IL-10 release in Con A-stimulated cultures indicate that SDR did not modify the Th1/Th2 cytokine balance but globally activated T cells. Plasma anti-KLH antibody levels were similar in both groups. Wounded and non-wounded mice presented similar responses to stress. This study shows that social disruption stress enhances the reactivity of cells from both the acquired and innate immune systems.
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PMID:Cytokine production by spleen cells after social defeat in mice: activation of T cells and reduced inhibition by glucocorticoids. 1520 33

Induction of heme oxygenase-1 (HO-1) is protective in tissue injury in models of allograft rejection and vascular inflammation through either prevention of oxidative damage or via immunomodulatory effects. To examine the specific role of HO-1 in modulating the immune response, we examined the differences in immune phenotype between HO-1 knockout (HO-1(-/-)) and wild-type (HO-1(+/+)) mice. Consistent with previous findings, marked splenomegaly and fibrosis were observed in HO-1(-/-) mice. The lymph nodes of HO-1-deficient mice demonstrated a relative paucity of CD3- and B220-positive cells, but no such abnormalities were observed in the thymus. Flow cytometric analysis of isolated splenocytes demonstrated no differences in the proportions of T lymphocytes, B lymphocytes or monocytes/macrophages between the HO-1(-/-) and HO-1(+/+) mice. Significantly higher baseline serum IgM levels were observed in HO-1(-/-) versus HO-1(+/+) mice. Under mitogen stimulation with either lipopolysaccharide or anti-CD3/anti-CD28, HO-1(-/-) splenocytes secreted disproportionately higher levels of pro-inflammatory Th1 cytokines as compared to those from HO-1(+/+) mice. These findings demonstrate significant differences in the immune phenotype between the HO-1(-/-) and the HO-1(+/+) mice. The absence of HO-1 correlates with a Th1-weighted shift in cytokine responses suggesting a general pro-inflammatory tendency associated with HO-1 deficiency.
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PMID:Heme oxygenase-1 modulates early inflammatory responses: evidence from the heme oxygenase-1-deficient mouse. 1533 27

We report a case of Epstein-Barr virus-associated aggressive natural killer cell leukemia/lymphoma with giant splenomegaly in which splenectomy resulted in progression of apoptosis and hemophagocytosis. The serum level of ferritin, triglycerides, interferon-gamma (IFN-gamma), interleukin 10 (IL-10), and soluble Fas ligand (sFasL) increased markedly, and liver damage progressed after splenectomy. The number of apoptotic cells in peripheral blood smears increased following splenectomy. In the present case, splenectomy caused disruption of the cytokine network, resulting in apoptosis of blood cells and hepatocytes, as well as phagocytosis.
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PMID:Marked elevation of soluble fas ligand and cytokine secretion after splenectomy in aggressive natural killer cell leukemia/lymphoma. 1551 19

A 54-year-old man with chronic idiopathic myelofibrosis (CIMF) underwent RIST. His clinical course had been uneventful until day 60, when splenomegaly reappeared. Hepatic dysfunction developed on day 75. Recipient-type hematopoiesis increased to 51% on day 90. After rapid tapering of cyclosporin, serum levels of AST and ALP normalized in parallel with recovery of complete chimerism on day 134. Yet, jaundice progressed. He died of liver failure on day 176. Postmortem examination revealed neither GVHD nor VOD. Graft rejection following RIST for CIMF may lead to fatal hepatic damage through extramedullary hematopoiesis in the liver or cytokine-mediated immune dysregulations.
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PMID:Fatal hepatic failure associated with graft rejection following reduced-intensity stem-cell transplantation for chronic idiopathic myelofibrosis (CIMF). 1562 70

The interleukin-6 (IL-6) cytokine family plays an important role in regulating cellular responses during hematopoiesis. We report here that mice homozygous for a knock-in mutation in the IL-6 cytokine family receptor signaling subunit glycoprotein (gp) 130 (gp130(Y757F/Y757F)) that leads to gp130-dependent signal transducers and activators of transcription (STAT) 1/3 hyperactivation develop a broad spectrum of hematopoietic abnormalities, including splenomegaly, lymphadenopathy, and thrombocytosis. To determine whether STAT3 hyperactivation was responsible for the perturbed hematopoiesis in gp130(Y757F/Y757F) mice, we generated gp130(Y757F/Y757F) mice on a Stat3 heterozygous (Stat3(+/-)) background to specifically reduce gp130-dependent activation of STAT3, but not STAT1. Normal hematopoiesis was observed in gp130(Y757F/Y757F):Stat3(+/-) bone marrow and spleen, with no evidence of the splenomegaly and thrombocytosis displayed by gp130(Y757F/Y757F) mice. The perturbed cellular composition of thymus and lymph nodes in gp130(Y757F/Y757F) mice was also alleviated in gp130(Y757F/Y757F): Stat3(+/-) mice. Furthermore, we show that hematopoietic cells from gp130(Y757F/Y757F) mice exhibited increased survival and proliferation in response to IL-6 family cytokines. Collectively, these data provide genetic evidence that gp130-dependent STAT3 hyperactivation during hematopoiesis has pathological consequences affecting multiple organs, and therefore identify the threshold of STAT3 signaling elicited by IL-6 family cytokines as a critical determinant for hematopoietic homeostasis.
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PMID:The threshold of gp130-dependent STAT3 signaling is critical for normal regulation of hematopoiesis. 1565 55

Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines. Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.
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PMID:A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. 1579 61

Osteopontin is a cytokine essential for initiation of Th1 immune reaction. We established transgenic mice expressing osteopontin in hepatocyte, in which liver necrosis with lymphocyte infiltration developed gradually from 12 weeks of age with up-regulated osteopontin levels in the circulation, suggesting that extrahepatic manifestations might also occur as a result of excessive Th1 immune reaction. We examined histological and immunohistochemical features of various organs in these mice. Splenomegaly and enlargement of lymph nodes around the liver and intestine became apparent with marked infiltration of small lymphocytes in the transgenic mice later than 24 weeks of age. Immunostaining revealed that lymphocytes in the spleen and lymph nodes were positive for either CD3 or CD20, suggesting that the infiltrating lymphocytes were both B and T cells. Similar lymphocyte infiltration was found in the lung, kidney and submandibular gland. Alveolar septa became hypertrophic with lymphocyte infiltration, and the lung showed the appearance of interstitial pneumonia. These lesions are similar to extrahepatic manifestations in chronic hepatitis C patients, suggesting that augmented Th1 immune reaction to hepatitis C virus (HCV) proteins or the proteins with molecular mimicry of HCV may be a contributing factor for the formation of the pathological state not only in the liver but also in various organs under chronic infection of hepatitis C virus.
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PMID:Extrahepatic manifestations in transgenic mice of osteopontin in hepatocytes-A clue to advent of pathological state in various organs of chronic hepatitis C patients. 1585 88

The balance between pro- and anti-inflammatory cytokines modulates inflammation. Intracellular inhibitors of signaling, in turn, contribute to the negative regulation of cytokines. One of these inhibitors is suppressor of cytokine signaling-1 (SOCS-1). Socs1(-/-) mice die by 3 weeks of age with inflammation and fatty necrosis of the liver. Here, cre/loxP deletion of Socs1 was used to investigate the contribution of specific cells/tissues to inflammatory disease. Mice with SOCS-1 deficiency in myeloid and lymphoid cells, but not lymphoid alone, became ill at 50 to 250 days of age. These mice developed splenomegaly and T-cell/macrophage infiltration of many organs, including liver, lung, pancreas, and muscle. There were also abnormally high levels of the proinflammatory cytokines interferon gamma (IFN-gamma), tumor necrosis factor (TNF), and interleukin-12 (IL-12), and activated T cells circulating in these mice. Socs1(null) T cells were found to be hypersensitive to multiple cytokines, including IL-1, IL-2, and IL-12, resulting in IFN-gamma production without requiring T-cell receptor (TCR) ligation. Additionally, Socs1(null) macrophages produced excessive amounts of IL-12 and TNF in response to other cytokines, including IFN-gamma. A dysregulated cytokine network between T cells and macrophages is thus associated with this inflammatory disease. These findings indicate that SOCS-1 is critical in both T cells and macrophages for preventing uncontrolled inflammation.
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PMID:Suppressor of cytokine signaling-1 in T cells and macrophages is critical for preventing lethal inflammation. 1589 15

In this study, we demonstrated that Uncaria tomentosa extract (UTE) protects mice from a lethal dose of Listeria monocytogenes when administered prophylactically at 50, 100, 150 and 200 mg/kg for 7 days, with survival rates up to 35%. These doses also prevented the myelosuppression and the splenomegaly caused by a sublethal infection with L. monocytogenes, due to increased numbers of granulocyte-macrophage progenitors (CFU-GM) in the bone marrow. Non-infected mice treated with 100 mg/kg UTE also presented higher numbers of CFU-GM in the bone marrow than the controls. Investigation of the production of colony-stimulating factors revealed increased colony-stimulating activity (CSA) in the serum of normal and infected mice pre-treated with UTE. Moreover, stimulation of myelopoiesis and CSA occurred in a dose-dependent manner, a plateaux being reached with the dose of 100 mg/kg. Further studies to investigate the levels of factors such as IL-1 and IL-6 were undertaken. We observed increases in the levels of IL-1 and IL-6 in mice infected with L. monocytogenes and treated with 100 mg/kg of UTE. White blood cells (WBC) and differential counting were also performed, and our results demonstrated no significant changes in these data, when infected mice were pre-treated with 100 mg/kg of UTE. All together, our results suggest that UTE indirectly modulates immune activity and probably disengages Listeria-induced supression of these responses by inducing a higher reserve of myeloid progenitors in the bone marrow in consequence of biologically active cytokine release (CSFs, IL-1 and IL-6).
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PMID:Uncaria tomentosa extract increases the number of myeloid progenitor cells in the bone marrow of mice infected with Listeria monocytogenes. 1591 28


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