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)

Two female patients of 54 and 48 years, respectively, with pancytopenia and splenomegaly of probable immune origin are reported. The first presented anemic syndrome and fever, and the second bleeding. In both cases large sized splenomegaly was found on physical examination. Serologic and immunologic studies excluded chronic infection or systemic autoimmune disease. Bone marrow biopsy showed hematopoietic hyperplasia with lymphoid nodules and reticulin fibrosis. Treatment with glucocorticoids and splenectomy was performed in one case and only glucocorticoids were administered in the other case with the cytopenias disappearing and the bone marrow becoming normocellular. Reactive follicular hyperplasia was observed in the white pulp of the spleen in one of the patients, as were abundant macrophagic activity in the red pulp, and myeloid metaplasia. The patients remain asymptomatic at 4 and 12 years of follow up. The origin of the process was attributed probably to an immune etiology and differential diagnosis with idiopathic myelofibrosis and non tropical idiopathic splenomegaly must be considered.
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PMID:[Splenomegalic pancytopenia of probable immune origin: cure after treatment with glucocorticoids]. 866 77

Fas is a cell-surface protein belonging to the tumor necrosis factor (TNF) receptor family, whereas the Fas ligand (FasL) is a member of the TNF family. FasL binds to Fas, which results in target cell apoptosis. A family of cysteine proteases is sequentially activated to proceed the Fas-induced apoptosis, whereas Bcl-2 inhibits the process. FasL is expressed in activated T cells and natural killer (NK) cells, and works as an effector of these cytotoxic cells to remove the cells infected by virus, or cancer cells. The Fas system is also involved in peripheral clonal deletion, and/or the activation-induced suicide of T cells to down-regulate the immune reaction. Mouse mutations of lymphoproliferation (lpr) and generalized lymphoproliferative disease (gld), which cause lymphadenopathy and splenomegaly, and accelerate autoimmune disease, are loss-of-function mutations in the Fas and FasL genes, respectively. Moreover, the Fas-null mice established by gene targeting showed hyperplasia in the liver, suggesting that the Fas system is involved in turn-over of senescent hepatocytes.
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PMID:A death factor--the other side of the coin. 895 Apr 63

Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked over accumulation of mature lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS) in humans. To define the clinical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively evaluated with routine clinical studies, lymphocyte phenotyping, genotyping, and in vitro assays for lymphocyte apoptosis. Individual patients were followed up for 3 months to 6 years. ALPS was identified in 9 unrelated children as manifested by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD4- CD8- T cells that express the alpha/beta T-cell receptor (TCR). All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Fas-mediated lymphocyte apoptosis, but clinical features of ALPS were not present in the vast majority of these individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of lymphocyte apoptosis are associated with abnormal lymphoproliferation and autoimmunity. These findings provide evidence that apoptosis of activated lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans. Fas gene mutations account for impaired lymphocyte apoptosis in only a subset of patients with ALPS.
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PMID:Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. 902 57

Fas is a member of the TNF receptor family. Binding of Fas ligand to Fas induces apoptosis in Fas-bearing cells. Fas is expressed in various cells, including thymocytes, peripheral T cells, and activated B cells. The mouse lpr mutation is a loss of function mutation of Fas. MRL-lpr/lpr mice develop lymphadenopathy and splenomegaly, and produce multiple autoantibodies, which results in autoimmune disease. In this report, we describe the establishment of a line of Fas transgenic MRL-lpr mice in which mouse Fas cDNA was expressed using the T cell-specific murine lck promoter. The transgenic mice expressed functional Fas in thymocytes and peripheral T cells, but not in B cells. The transgenic mice did not accumulate abnormal T cells (Thy-1+ B220+), but still accumulated B cells (Thy-1- B220+); they produced a large quantity of Igs (IgG1 and IgG2a), including anti-DNA Abs, and developed glomerulonephritis. These results suggest that autoreactive or activated B cells must be killed through Fas expressed in the B cells by the Fas ligand expressed in activated T cells.
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PMID:Transgenic expression of Fas in T cells blocks lymphoproliferation but not autoimmune disease in MRL-lpr mice. 955 84

It is known that lpr mice develop systemic lymphadenopathy and lupus erythematosus-like autoimmune disease that are associated with the accumulation of CD4- CD8- (double-negative; DN) CD3+ B220+ abnormal T cells as well as normal mature CD4+ or CD8+ single-positive (SP) CD3+ T cells. In order to clarify the role of B cells in the lymphoproliferation and autoimmunity of lpr mice, we created B-cell-deficient C57BL/6 (B6) lpr mice (B6lpr/lpr microMT/microMT) by crossing B6lpr/lpr mice with B6 microMT/microMT mice in which the B-cell development was arrested at pre-B stage owing to a targeted disruption of the immunoglobulin mu heavy-chain gene locus. In the B-cell-deficient B6-lpr mice, both lymphadenopathy and splenomegaly were markedly suppressed. Although the accumulation of both CD3+ B220- SP normal T cells and CD3+ B220+ DN abnormal T cells was inhibited in the B-cell-deficient lpr mice, the decrease in numbers of CD3+ B220- SP normal T cells occurred more strikingly than that of the CD3+ B220+ DN abnormal T cells. Glomerulonephritis did not develop in the B-cell-deficient lpr mice over 40 weeks. The present results indicate that the B cells thus play a crucial role in the extensive proliferation of normal CD3+ B220- mature SP T cells rather than the accumulation of abnormal DN T cells.
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PMID:Proliferation of CD3+ B220- single-positive normal T cells was suppressed in B-cell-deficient lpr mice. 961 74

Lyn and Btk play a critical role in B cell development and intracellular signaling. Lyn-deficient mice exhibit splenomegaly, elevated serum levels of IgM, production of autoantibody and glomerulonephritis with age. On the other hand, xid mice, which carry a point mutation in the btk gene, show a decrease in numbers of peripheral mature B cells, reduced serum levels of IgM and IgG3, disappearance of CD5+ B-1 cells, and low proliferative response to anti-IgM or LPS stimulation in vitro. In order to investigate the interaction between Lyn and Btk during B cell development, we established lyn-deficient xid mice. Lyn-deficient xid mice exhibited greatly reduced numbers of peripheral mature B cells, disappearance of CD5+ B-1 cells, markedly reduced serum levels of IgM and IgG3, low proliferative response to anti-IgM or lipopolysaccharide stimulation and no evidence for autoimmune disease. In addition, splenomegaly in lyn-deficient mice, which was mainly due to the accumulation of Mac-1+, cytoplasmic IgM+ lymphoblast-like cells, was also diminished in lyn-deficient xid mice. Thus, immunological abnormalities found in lyn-deficient mice were strongly affected by the absence of Btk. The present results suggest that the autoimmune symptoms in lyn-deficient mice may be caused by not only the abnormal response of B-2 cells but also that of B-1 cells, and that the interaction between Lyn and Btk is partly in tandem at the signaling pathway in B cells.
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PMID:Abrogation of autoimmune disease in Lyn-deficient mice by the mutation of the Btk gene. 962 May 99

BXSB mice spontaneously develop a lupus-like syndrome that is accelerated by the Yaa gene (Y-linked autoimmune accelerator). We studied the phenotype of disease in (B10 x BXSB)F1 and (BXSB x (B10 x BXSB)F1) backcross mice and genotyped 224 backcross animals to allow a microsatellite-based genome-wide linkage analysis to be conducted. In the backcross population, three intervals on chromosome 1 showed significant linkage to disease, suggesting that multiple loci contribute to the production of autoimmune disease. D1Mit5 at 32.8 cM was linked to development of nephritis (chi(2) = 15.68, p = 7.5 x 10(-5)), as was D1Mit12 at 63.1 cM (chi(2) = 20.17, p = 7.1 x 10(-6)). D1Mit403 at 100 cM was linked to anti-dsDNA Ab production (chi(2) = 17.28, p = 3.2 x 10(-5)). Suggestive linkages to antinuclear Abs and nephritis were identified on chromosome 3, to splenomegaly on chromosome 4, and to anti-ssDNA Ab production on chromosome 10. Chromosome 4 and the telomeric region of chromosome 1 have previously been linked to disease in other mouse models of systemic lupus erythematosus; however, the centromeric regions of chromosome 1 and chromosomes 3 and 10 are unique to BXSB. This implies that, though some loci may be common to a number of mouse models of lupus, different clusters of disease genes confer disease susceptibility in different strains of mice.
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PMID:Multiple lupus susceptibility loci map to chromosome 1 in BXSB mice. 974 33

MRL-lpr/lpr mice have a Fas receptor mutation that leads to abnormalities of apoptosis, lymphoproliferation, and a lupus-like autoimmune disease associated with the production of autoantibodies. Other than Fas pathway defects, little is known about molecular abnormalities that predispose to autoimmunity. Protein kinase CK2 (also termed casein kinase II), a serine-threonine protein kinase whose targets include many critical regulators of cellular growth, is highly expressed in a lymphoproliferative disease of cattle and in many human cancers. Overexpression of the CK2alpha catalytic subunit in lymphocytes of transgenic mice leads to T cell lymphoma. We hypothesized that CK2 dysregulation and Fas mutation might cooperatively augment lymphocyte proliferation and transformation. We find that in MRL-lpr/lpr mice bearing the CK2alpha transgene, the lymphoproliferative process is dramatically exacerbated, as these mice develop massive splenomegaly and lymphadenopathy by 12 wk of age in association with increased autoantibody production and accelerated renal disease. The lymphoid organs are filled with the unusual B220+CD4-CD8- T cells typically seen in MRL-lpr/lpr mice, not the B220-CD4+CD8+ or B220-CD4-CD8+ T cells typically seen in CK2a transgenic lymphomas. The T cells do not fulfill the criteria for transformation, as they are polyclonal and not transplantable or immortal in cell culture. Thus, although the lpr lymphoproliferative and autoimmune syndrome is potentiated by the presence of the CK2a transgene, this combination of apoptotic and proliferative abnormalities appears to be insufficient to transform lymphoid cells.
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PMID:Acceleration of lpr lymphoproliferative and autoimmune disease by transgenic protein kinase CK2 alpha. 982 Apr 86

In lpr mice the insertion of an early transposable element (ETn) into intron 2 of the Fas gene, which mediates apoptosis, causes the development of massive lymphadenopathy, splenomegaly and autoimmune disease. In the present study we investigated the influence of this mutation on ovarian development of lpr mice. By means of in situ hybridisation, the expression of Fas mRNA was detected at the same levels in the ovarian cells of MRL/MpJ-lpr/lpr (MRL/lpr) mice as in those of MRL/MpJ-(+)/+ (MRL/+) mice. However, indirect immunofluorescence (IIF) staining with anti-Fas monoclonal antibody (mAb) on the membrane of follicle and egg of MRL/lpr mice was significantly weaker than that of MRL/+ mice. Furthermore, the expression level of Fas protein at the 45 kDa band from ovarian cell lysates of MRL/lpr mice was much lower than that of MRL/+ mice. The co-incubation of Spodoptera frugiperda (Sf9)-Fas lig- and (L) cells with eggs of MRL/+ mice resulted in apoptosis of eggs, as detected by the terminal deoxynucleotide transferase mediated dUPT-nick end labelled (TUNEL) method. In contrast the co-incubation of Sf9-FasL cells with eggs of MRL/lpr mice did not generate apoptosis in eggs. Following intraperitoneal administration of anti-Fas mAb into both types of mice, most oocytes, a proportion of granulosa cells in the ovary and hepatocytes in liver of MRL/+ mice were positively stained by the TUNEL method, corresponding to the appearance of DNA fragmented ladders by DNA fragmentation assay, while negative signals were obtained in those cells of MRL/lpr mice. As the mice aged, the ovarian size of MRL/lpr mice was found to be much larger than that of MRL/+ mice due to the increased number of ovarian follicles. Therefore, the ovarian adenopathy in MRL/lpr mice was strongly suggested to be caused by the dysfunction of Fas antigen in the ovary.
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PMID:Aberrant expression and dysfunction of Fas antigen in MRL/MpJ-lpr/lpr murine ovary. 992 47

Chronic urticaria is a common clinical disorder that is idiopathic in over 75% of cases. Less commonly, urticaria may be the presenting manifestation of an allergic or infectious disease, endocrinopathy, inherited syndrome, or autoimmune disorder. Rarely, urticaria may be a sign of underlying malignancy, including leukemia. C.C. is a 48-year-old white female who was referred for evaluation of recurrent urticaria for 3 years. The pruritic, erythematous wheals were pinpoint, and appeared to be precipitated by heat, stress, and effort. Prick tests were negative except to D. pteronyssinus. CBCs over the past 5 years revealed WBCs of 2,300-5,000 cells/mm3. Skin biopsy revealed interstitial edema with infiltration of eosinophils and mast cells consistent with urticaria. The impression was probable cholinergic urticaria, for which hydroxyzine was prescribed with fair symptomatic control. One year later, she presented with bright red blood per rectum. Repeat physical examination revealed lymphadenopathy and splenomegaly. Subsequent laboratory studies showed pancytopenia. Endoscopy was normal except for small, nonbleeding hemorrhoids. Bone marrow biopsy revealed histologic evidence of hair, cell leukemia that was treated with 2-chlorodeoxyadenosine. Upon initiation of chemotherapy her pruritus and urticaria subsided. Recent CBC revealed Hgb 9.2 g/dL, platelets 290,000 cells/mm3, and WBC 4,100 cells/mm3. Peripheral blood smear showed no hairy cells.
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PMID:Chronic urticaria as a presenting sign of hairy cell leukemia. 1007 10


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