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

We previously showed that a purE mutant (delta purE201) of Brucella melitensis 16M is attenuated for growth in cultured human monocytes (E. S. Drazek, H. H. Houng, R. M. Crawford, T. L. Hadfield, D. L. Hoover, and R. L. Warren, Infect. Immun. 63:3297-3301, 1995). To determine if this strain is attenuated in animals, we compared the growth of the delta purE201 mutant with that of strain 16M in BALB/c mice. The number of bacteria in the spleen and spleen weight peaked for both strains between 1 and 2 weeks postinfection (p.i.), though the number of delta purE201 cells was significantly less than the number of 16M cells recovered from the spleens of infected mice. During the next 6 weeks, delta purE201 was essentially eliminated from infected mice (three of five mice sterile; < 100 CFU in two of live mice at 8 weeks p.i.), whereas bacteria persisted at a high level in the spleens of 16M-infected mice (about 106 CFU per spleen). The number of bacteria in the livers and lungs of mice infected with either strain paralleled those in the spleen. Mice infected with 16M had a strong inflammatory response, developing dramatic and prolonged splenomegaly (five to eight times normal spleen weight) and producing serum interleukin-6. In contrast, mice infected with delta purE201 developed only mild, transient splenomegaly at 1 week p.i. and produced no interleukin-6 in their serum. We further characterized the host response to infection by measuring changes in immune spleen cell populations by flow cytometry. CD4- and CD8-positive lymphocytes declined by I week in both experimental groups, while MAC-1-positive cells increased. T-cell subpopulations remained low or declined further, and MAC-1 cells increased to three times normal levels during 8 weeks of infection with 16M but returned to normal by 4 weeks after infection with delta purE201. These results document infectivity and attenuation of delta purE201 and suggest that it should be further evaluated as a potential vaccine.
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PMID:Deletion of purE attenuates Brucella melitensis infection in mice. 867 25

Fas is a 45-kDa membrane protein that transduces an apoptotic signal. The mouse lymphoproliferation (lpr) mutation is a leaky mutation of Fas. In this study, we examined lymphocyte development in Fas-null mice generated by gene targeting. The Fas-/- mice progressively accumulated abnormal T cells (Thy1+, B220+, CD4-, and CD8-) and developed lymphadenopathy and splenomegaly, which were much more accelerated and pronounced than those in lpr mice. In addition, the Fas-null mice showed lymphocytosis, accompanied by lymphocytic infiltration in the lungs and liver. The number of apparently normal B cells also increased, and large amounts of immunoglobulins, including anti-DNA antibodies, were produced. Thymic clonal deletion, assessed by deletion of T cells reactive to mouse endogenous superantigens, was apparently normal in the Fas-/- mice, whereas the peripheral clonal deletion of mature T cells against a bacterial superantigen was impaired. These results suggested that Fas plays a decisive role in peripheral clonal deletion but not in negative selection in the thymus.
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PMID:Enhanced and accelerated lymphoproliferation in Fas-null mice. 870 Aug 97

In the majority of clonal expansions of CD3+ large granular lymphocytes (LGL), referred to as T-LGL leukemia, patients have a chronic disease, often manifested by severe neutropenia, rheumatoid arthritis, and mild to moderate splenomegaly. The characteristic leukemic phenotype is CD3+, CD8+, CD16+, CD57+ and CD56-. Here we report an unusual case of T-LGL (CD3cyt+, CD3surface-, CD16+, CD56-) with clinicopathological features (acute presentation, large tumor mass, and systemic illness with highLGL counts at diagnosis) similar to those described for patients with CD3-natural killer (NK)-LGL leukemia. Two distinct stages of maturation arrest were observed: in the lymph node abnormal cells were CD4+, CD8+ whereas the majority of circulating leukemic cells expressed only CD8. TCR gamma (TCR gamma) gene configuration demonstrated that these originated from the same T cell clone, suggesting a maturation process between the two populations, or preferential passage of CD8 single positive cells into the blood.
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PMID:Aggressive acute CD3+, CD56- T cell large granular lymphocyte leukemia with two stages of maturation arrest. 875 72

Graft-versus-host disease (GVHD) is known to cause profound dysregulation of the immune system, although its effector mechanisms are not fully understood. In this study, we investigated what factors influenced the development of GVHD. BALB/c nude mice (H-2d) injected with MHC-disparate B6(H-2b) spleen cells exhibited transient GVHD such as hunched back, diarrhea, loss of body weight and splenomegaly. No animals died during the period of observation. BALB/c nude mice produced alloantibodies to the donor cells. The injection of the serum from GVHD nude mice into naive nude mice can protect from GVHD. Donor derived H-2b+ cells were recognized in the recipient lymph nodes and skin. Prevention of GVHD was achieved by the pretreatment of spleen cells with anti-Thy-1.2 antibody or anti-CD4 antibody and complement, while it was not done by the pretreatment of spleen cells with anti-CD8 antibody and complement. These data demonstrate that Thy-1.2+ CD4+ CD8- lymphocytes are important effector cells and alloantibodies to the donor cells prevent GVHD in this model.
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PMID:Studies on transient graft-versus-host disease in BALB/c nude mice injected with allogeneic C57BL/6 splenocytes. 886 71

The efficacy and toxicity of ribavirin (25 or 125 mg/kg/day), 2',3'-dideoxyinosine (ddI) (200 mg/kg/day) and a combination of both drugs at these doses given for 6 weeks were investigated in the murine acquired immunodeficiency syndrome model. Our results showed a significant protection against splenomegaly, lymphadenopathy and hypergammaglobulinemia in mice treated with ribavirin at 25 mg/kg/day alone or in combination with ddI at 200 mg/kg/day. A good synergistic effect was observed with the drug combination, whereas ddI alone (200 mg/kg/day) did not give any protection. Ribavirin/ddI combination protected against the loss of CD8 T cells in spleen and restored the capacity of splenocytes to proliferate after activation with a mitogenic agent. Moreover, the drug combination resulted in a protection of the spleen and cervical lymph node architectures and a regression of germinal centers. Hematotoxicity appeared at a dose of 125 mg/kg of ribavirin alone and increased when used concomitantly with ddI. In conclusion, ribavirin and ddI at low doses are synergistic and effective in the murine acquired immunodeficiency disease model, but at high doses they are toxic.
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PMID:Ribavirin potentiates the efficacy and toxicity of 2',3'- dideoxyinosine in the murine acquired immunodeficiency syndrome model. 893 Feb 11

Programmed cell death (or apoptosis) is a physiological process essential to the normal development and homeostatic maintenance of the immune system. The Fas/Apo-1 receptor plays a crucial role in the regulation of apoptosis, as demonstrated by lymphoproliferation in MRL-lpr/lpr mice and by the recently described autoimmune lymphoproliferative syndrome (ALPS) in humans, both of which are due to mutations in the Fas gene. We describe a novel family with ALPS in which three affected siblings carry two distinct missense mutations on both the Fas gene alleles and show lack of Fas-induced apoptosis. The children share common clinical features including splenomegaly and lymphadenopathy, but only one developed severe autoimmune manifestations. In all three siblings, we demonstrated the presence of anergic CD3+CD4-CD8- (double negative, [DN]) T cells; moreover, a chronic lymphocyte activation was found, as demonstrated by the presence of high levels of HLA-DR expression on peripheral CD3+ cells and by the presence of high levels of serum activation markers such as soluble interleukin-2 receptor (slL-2R) and soluble CD30 (sCD30).
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PMID:Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. 902 21

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 (CD95) is a transmembrane molecule that induces programmed cell death (PCD) of lymphocytes. We examined its function in children with chronic thrombocytopenia, serum autoantibodies, and lymphadenopathy and/or splenomegaly. We found that T-cell lines from six of seven patients with this autoimmune/lymphoproliferative disease (ALD) were relatively resistant to PCD induced by monoclonal antibodies to Fas. By contrast, Fas function was normal in control patients with typical chronic idiopathic thrombocytopenic purpura (ITP) without lymphadenopathy. The defect was not due to decreased Fas expression, nor to over-production of soluble forms of Fas. Moreover, it specifically involved the Fas system because PCD was induced in the normal way by methylprednisolone. Complementary DNA sequencing of the Fas gene did not identify any causal mutation in patients with ALD. This distinguished them from patients with the human autoimmune lymphoproliferative syndrome (ALPS), who carry mutations of the Fas gene. Moreover, patients with ALD did not show the peripheral expansion of CD4/CD8 double-negative T cells that characterizes the ALPS phenotype. Fas signaling involves activation of a sphingomyelinase-catalyzing production of ceramide. We found that ceramide-induced PCD was defective in patients with ALD and not in patients with typical chronic ITP. These data suggest that the ALD patient defect involves the Fas signaling pathway downstream from the sphingomyelinase and that Fas gene mutations and double-negative T-cell expansion are not the only signs of a defective Fas system.
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PMID:Deficiency of the Fas apoptosis pathway without Fas gene mutations in pediatric patients with autoimmunity/lymphoproliferation. 910 7

We report the clinical, ultrastructural, immunophenotypic and virological features of nine cases of a rare type of mature T cell disorder formerly designated Sezary cell leukaemia. All patients presented with lymphocytosis ranging from 12.7 to 133 x 10(9)/l, bone marrow infiltration, splenomegaly and lymphadenopathy. Skin involvement was absent at presentation but developed as a terminal event in two patients, one of whom showed a pattern of dermal infiltration different from that characteristic of Sezary syndrome. Cells from eight cases bore a mature T cell phenotype and electronmicroscopy revealed lymphocytes with cerebriform nuclei resembling Sezary cells. All cases except one were HTLV-I negative. Patients were treated with various chemotherapy regimens but with poor outcome, the median survival being 13 months. Laboratory and clinical data suggest great similarity between Sezary cell leukaemia and T prolymphocytic leukaemia (T-PLL), namely coexpression of CD4 and CD8 (3/9 cases), identical chromosomal abnormalities in the three cases studied (isochromosome 8q plus inversion 14 or t(X;14)(q28;q11)) and a remarkable sensitivity to CAMPATH-1H (complete remission of 21 months' duration in one patient), suggesting that this entity could be considered a variant form of T-PLL. The alternative diagnosis of adult T cell leukaemia/lymphoma could not be excluded in one patient in whom positive HTLV-I serology was documented.
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PMID:Sezary cell leukaemia: a distinct T cell disorder or a variant form of T prolymphocytic leukaemia? 920 83

We describe the clinical and laboratory features of an unusual case with Sezary cell-like leukemia. Clinical manifestations were: anemia (Hb 9.4 g/dl), severe thrombocytopenia (5 x 10(9)/l), lymphocytosis (43 x 10(9)/l) and splenomegaly. There was no lymphadenopathy, hepatomegaly or skin lesions. Bone marrow trephine showed diffuse infiltration by atypical lymphoid cells. By ultrastructural analysis the cells were small to medium-size lymphocytes with nuclear features identical to Sezary cells. Immunophenotyping showed that most peripheral blood mononuclear cells were negative with B lymphoid, myeloid, and stem cell-associated markers and were also negative with most T lymphoid markers (CD2, CD4, membrane/cytoplasmic CD3, CD5 and CD8). However, they were positive with CD38 (70%), CD7 (25%) and TIA-2 (25%). Molecular analysis showed a clonal rearrangement of the TCR beta and gamma chain genes. The patient was initially treated with vincristine, doxorubicin and asparaginase and then with six cycles of CHOP, achieving a complete remission and remaining free of disease 22 months from diagnosis. Aberrant immunophenotypes are not frequent in primary T cell leukemias. This is the first case of a rare type of T cell neoplasm, Sezary cell-like leukemia, in which cells lacked most of the T cell-associated antigens.
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PMID:Sezary cell-like leukemia with atypical immunophenotype. 926 98


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