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

Juvenile chronic myelogenous leukemia (JCML) is a rare pediatric malignancy characterized by marked hepatosplenomegaly, leukocytosis with prominent monocytosis, elevated fetal hemoglobin, no Philadelphia chromosome, and generally a poor prognosis. In vitro, JCML peripheral blood granulocyte-macrophage progenitors (granulocyte-macrophage colony-forming units, CFU-GM) demonstrate the unique characteristic of "spontaneous" proliferation at very low cell densities in the absence of exogenous growth factors. The "spontaneous" CFU-GM proliferation can be abolished by prior adherent cell (monocyte) depletion, suggesting a paracrine mode of cellular proliferation. Although previous studies using a [3H]thymidine ([3H]TdR) incorporation assay suggested an important role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in JCML, many non-growth factor-related reasons for [3H]TdR incorporation and the relatively low level of inhibition of [3H]TdR uptake left those conclusions open to question. Therefore, we performed clonal CFU-GM assays, which more specifically reflect cytokine effects on CFU-GM, using JCML peripheral blood mononuclear cells (PBMNC) and neutralizing antibodies against GM-CSF, granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating (M-CSF), interleukin 3 (IL-3), interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), interleukin 4 (IL-4), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF alpha), and interferon gamma (IFN gamma). Cultures containing anti-GM-CSF alone inhibited "spontaneous" JCML CFU-GM by 87% +/- 9% (mean +/- standard error of the mean [SEM]). No other anti-cytokine antibody produced a significant inhibition of CFU-GM growth. Various combinations of antibodies, excluding anti-GM-CSF, failed to demonstrate any synergistic inhibitory effects upon CFU-GM. Because this apparent paracrine cellular stimulation could be due to excessive cytokine production, by monocytes or other accessory cells, we examined cytokine levels in conditioned media from various JCML cell populations using enzyme-linked immunosorbent assays (ELISAs). Monocytes from only a minority of JCML patients produced higher than normal quantities of GM-CSF, G-CSF, IL-1 beta, IL-6, and/or TNF alpha, but no obvious pattern could be discerned. Further, only 7 of 15 JCML monocyte-conditioned media (MCM) had elevated GM-CSF, and 6 of 15 JCML patients had normal levels of all nine cytokines tested. The monocyte depletion experiments and the inhibition experiments with anti-cytokine antibodies taken together demonstrate clearly that the "spontaneous" growth of JCML CFU-GM in vitro critically depends on at least one monocyte-derived growth factor, GM-CSF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of monocyte-derived hemopoietic growth factors in the regulation of myeloproliferation in juvenile chronic myelogenous leukemia. 191 2

The familial form of hemophagocytic lymphohistiocytosis (HLH) is an inherited disease with disturbed immunomodulation and characterized by fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, and coagulopathy, i.e., findings which are similar to many of the reported biological effects of the inflammatory cytokines. Due to the previously shown hypercytokinemia in active HLH with elevated levels of interleukin (IL)-6, tumor necrosis factor-alpha, and interferon-gamma, it has been suggested that cytokine dysregulation may be of pathophysiological importance. Here we have assayed the serum levels of the members of the IL-1 ligand family, the two agonists IL-1 alpha and IL-1 beta and the antagonist IL-1 receptor antagonist (IL-1ra), in nine children with HLH and cerebrospinal fluid (CSF) specimens from four children. Serum IL-1ra was elevated in all patients with active disease to a degree which correlated well with disease activity. Furthermore, the levels decreased day by day during treatment of a patient who suffered a relapse. Moreover, high levels of IL-1ra were also detected in CSF during active disease. However, IL-1 beta levels were all within normal limits and circulating IL-1 alpha levels were normal in all but two patients.
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PMID:Elevated circulating levels of interleukin-1 receptor antagonist but not IL-1 agonists in hemophagocytic lymphohistiocytosis. 861 86

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

Gaucher's disease is characterized by hepatosplenomegaly, bone-marrow infiltration, osteonecrosis and bone thinning, associated with the presence of pathological macrophages that contain undegraded glycosphingolipids. To investigate the possible role of cytokines in the systemic and local manifestations of established Gaucher's disease, interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF alpha) and interleukin-10 (IL-10) were measured in freshly-separated serum. Samples from eight male and 14 female patients with type 1 Gaucher's disease were compared with sera from 22 healthy age- and sex-matched controls. Concentrations of IL-6 and IL-10 were significantly elevated in sera from patients with Gaucher's disease (11.9 +/- 1.8 (SEM) pg/ml and 5.4 +/- 0.5 (SEM) pg/ml, respectively) compared with those of controls (4.1 +/- 0.9 (SEM) and 0.8 +/- 0.3 (SEM) pg/ml, p < 0.0001). No significant differences in concentrations of TNF alpha or IL-1 beta were identified. IL-6 has been implicated in the development of localized osteolysis in multiple myeloma and in the development of post-menopausal osteoporosis. High concentrations of IL-6 in the serum of patients with Gaucher's disease may thus reflect the development of the bone lesions commonly associated with this disorder. Since IL-6 and IL-10 are important regulators of lymphocyte growth and differentiation, and IL-6 concentrations were significantly raised in patients with oligo- or polyclonal increases in serum immunoglobulins, enhanced release of these cytokines from pathological macrophages provides a pathological link between Gaucher's disease and associated lympho-proliferative disorders.
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PMID:Pro-inflammatory cytokines and the pathogenesis of Gaucher's disease: increased release of interleukin-6 and interleukin-10. 909 85