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)

Secreted growth factors are integral components of the bone marrow (BM) niche and can regulate survival, proliferation, and differentiation of committed hematopoietic stem cells (HSCs). However, downstream genes activated in HSCs by early-acting cytokines are not well characterized. To better define intracellular cytokine signaling in HSC function, we have analyzed mice lacking expression of both signal transducer and activator of transcription 5a (STAT5a) and STAT5b (STAT5ab(-/-)). These studies specifically avoided possible autoimmune and/or splenomegaly disease-mediated indirect effects on HSC function by using 2 independent approaches: (1) by crossing onto the C57Bl/6 RAG2(-/-) background, and (2) by generation of wild-type chimeric mice reconstituted with transplanted STAT5ab(-/-) BM cells. These experiments demonstrated that STAT5-deficient HSCs have cell autonomous defects in competitive long-term repopulating activity. Furthermore, in the chimeric mice, injected wild-type BM cells showed a progressive multilineage competitive repopulating advantage in vivo, demonstrating that steady-state hematopoiesis was also highly STAT5-dependent. Consistent with the in vivo repopulating deficiency, when Sca-1(+)c-kit(+)lin(-) (KLS) cells were isolated and stimulated with growth factors in vitro, up to a 13-fold reduced expansion of total nucleated cells was observed in response to cocktails containing interleukin 3 (IL-3), IL-6, stem cell factor (SCF), Flt3 ligand, and thrombopoietin. Notably, a 10-fold reduction in expansion was observed with IL-3 and SCF. However, STAT5 activation was not required for regeneration of the KLS pool in vivo following transplant or for secondary repopulating ability. These studies support a major role for STAT5 activation as a cellular determinant of cytokine-mediated HSC repopulating potential but not self-renewal capacity.
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PMID:Cell intrinsic defects in cytokine responsiveness of STAT5-deficient hematopoietic stem cells. 1239 7

Several studies suggest an implication of transforming growth factor-beta1 (TGF-beta1) in the promotion of myelofibrosis associated with hematopoietic malignancies, but the involvement of this cytokine is not fully investigated. To test directly the impact of TGF-beta1 in the pathogenesis of myelofibrosis, bone marrow stem cells from homozygous TGF-beta1 null (TGF-beta1(-/-)) and wild-type (WT) littermates were infected with a retrovirus encoding the murine thrombopoietin (TPO) protein and engrafted into lethally irradiated wild-type hosts for long-term reconstitution. Over the 4 months of follow-up, TPO levels in plasma were markedly elevated in both groups of mice, and animals typically developed a myeloproliferative syndrome characterized by thrombocytosis, leukocytosis, splenomegaly, increased numbers of progenitors in blood, and extramedullary hematopoiesis. Severe fibrosis was observed in spleen and marrow from all the mice engrafted with WT cells. In contrast, none of the mice repopulated with TGF-beta1(-/-) cells (chimerism > 70%) showed deposition of reticulin fibers at any time during the follow-up. In accordance with the development of fibrosis, latent TGF-beta1 levels in plasma and extracellular fluid of the spleen from mice engrafted with WT cells were increased 6-fold and 4-fold, respectively, over levels found in normal hosts, whereas no increase over baseline levels could be demonstrated in animals undergoing transplantation with TGF-beta1(-/-) cells. These data provide evidence that TGF-beta1 produced by hematopoietic cells is pivotal for the pathogenesis of myelofibrosis that develops in mice with TPO overexpression.
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PMID:Prominent role of TGF-beta 1 in thrombopoietin-induced myelofibrosis in mice. 1239 81

Hairy-cell leukaemia is an indolent lymphoproliferative malignancy characterized by infiltration of the bone marrow, liver, spleen, and occasionally lymph nodes with a malignant B cell with hair-like cytoplasmic projections. This involvement leads to splenomegaly with secondary consumption of red cells, platelets and neutrophils as well as other complications of an enlarged spleen, including infarction-or-rarely rupture. The common haematological complications of anaemia, neutropenia and thrombocytopenia are due not only to the enlarged spleen but probably also to hairy cells in the bone marrow inducing cytokine-mediated suppression of haematopoiesis. Hepatic involvement, although frequent, only occasionally leads to liver dysfunction. Infections are a major cause of morbidity and mortality in patients with hairy-cell leukaemia, presumably owing to neutropenia and monocytopenia in these patients. The infections seen may be due to unusual pathogens, including Mycobacterium and Listeria. Autoimmune disease, including polyarthitis and vasculitis, occurs frequently and does not correlate with the severity of the disease. Other rare complications include bone involvement, meningitis and ascites. A wide range of secondary malignancies have been reported in patients with hairy-cell leukaemia, but it is still unclear whether the incidence is increased and whether they are related to the disease or treatment.
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PMID:Clinical manifestations and infectious complications of hairy-cell leukaemia. 1267 Apr 63

There is great potential for novel vaccines based on recombinant proteins and synthetic peptides. Unfortunately these antigens often lack the immunogenicity of whole, killed pathogens used in traditional vaccines. Thus there is strong interest in the identification of immunological adjuvants with low reactogenicity, but high potency, to enhance immune responses and realize the potential of these new vaccine strategies. CD40 antibodies have been shown to have adjuvant effects when administered at very high doses. These large doses are impractical and induce a cascade of cytokine release giving rise to septic shock-like symptoms, as well as splenomegaly and polyclonal antibody production. We show here that a very small amount of CD40 antibody can exhibit potent adjuvant effects when attached to soluble antigen. The lack of detectable systemic effects indicates that this method may be a powerful and practical means of enhancing the efficacy of recombinant vaccines.
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PMID:A potent adjuvant effect of CD40 antibody attached to antigen. 1270 21

The hemophagocytic syndrome (HPS) is an uncommon, often misdiagnosed life-threatening disorder of immune regulation, characterized by a widespread proliferation and multisystemic infiltration of non-malignant histiocytes that undergo uncontrolled hemophagocytosis in bone marrow and/or reticulo-endothelial system. The HPS immune dysfunction consists in a low or absent cytotoxic T and natural killercell activity and in hyperactivation of T lymphocytes and macrophages, with consequent proinflammatory cytokine storm. Clinically, HPS is characterized by high fever, lymphadenopathies, hepato-splenomegaly, liver dysfunction, (pan)cytopenia, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, as well as coagulopathy and neurological manifestations in many cases. A hereditary/primary variant (familial hemophagocytic lymphohistiocytosis) and an acquired/secondary form (reactive HPS) are known. This latter may occur in several disorders, including infections, immunodeficiency states, malignancies, lymphoproliferative and autoimmune diseases. Without treatment, HPS fatally has an unfavourable prognosis. Recently, outcome improvements have been reported, due to better therapeutic strategies. The clinical and pathological features of this syndrome are reviewed.
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PMID:[The hemophagocytic syndrome (macrophage activation syndrome)]. 1271 99

Retinoic acids, a group of natural and synthetic vitamin A derivatives, have potent antiproliferative and anti-inflammatory properties. Recently, retinoic acids were reported to inhibit Th1 cytokine production. We investigated the effects of retinoic acid on lupus nephritis in a model of NZB/NZW F(1) (NZB/W F(1)) mice. Three-month-old NZB/W F(1) mice were separated into two groups: one treated with all-trans-retinoic acid (ATRA; 0.5 mg i.p., three times weekly for 7 mo) and one with saline as a control. Compared with controls, ATRA-treated mice survived longer and exhibited a significant reduction of proteinuria, renal pathological findings including glomerular IgG deposits, and serum anti-DNA Abs. Splenomegaly was less marked in the treated mice than in controls. Transcripts encoding IFN-gamma, IL-2, and IL-10 in splenic CD4(+) T cells were significantly reduced in treated mice compared with controls. We conclude that treatment with ATRA in SLE-prone NZB/W F(1) mice significantly alleviates autoimmune renal disorder and prolongs survival; this may thus represent a novel approach to the treatment of patients with lupus nephritis.
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PMID:Retinoic acid reduces autoimmune renal injury and increases survival in NZB/W F1 mice. 1275 64

CD1d-restricted NKT cells are a novel T cell lineage with unusual features. They co-express some NK cell receptors and recognize glycolipid antigens through an invariant T cell receptor (TCR) in the context of CD1d molecules. Upon activation through the TCR, NKT cells produce large amounts of IFN-gamma and IL-4. It has been proposed that rapid cytokine output by activated NKT cells may induce bystander activation of other lymphoid lineages. The impact of CD1d-restricted NKT cell activation in the induction of B cell-mediated immune responses to infection is still unclear. We show here that CD1-restricted NKT cells contribute to malarial splenomegaly associated with expansion of the splenic B cell pool and enhance parasite-specific antibody formation in response to Plasmodium berghei infection. The increased B cell-mediated response correlates with the ability of NKT cells to promote Th2 immune responses. Additionally, antibody responses against the glycosylphosphatidylinositol (GPI)-anchored protein merozoite surface protein 1 (MSP-1) were found to be significantly lower in CD1(-/-) mice compared to wild-type animals. P. berghei-infected MHC class II (MHCII)(-/-) mice also generated antibodies against MSP-1, suggesting that antibody production against GPI-anchored antigens in response to malaria infection can arise from both MHCII-dependent and independent pathways.
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PMID:CD1d-restricted NKT cells contribute to malarial splenomegaly and enhance parasite-specific antibody responses. 1293 35

We report on a German couple found dead at home 7 days after returning from Burkina Faso. Postmortem evaluation revealed Plasmodium falciparum infection with a parasitemia of approximately 80% in both cases. No pathological findings of the organs were present at autopsy except moderate splenomegaly in both cases and myocarditis in one case. Typical findings of fatal malaria like petechial hemorrhages of the brain or other organs, or sequestration of parasitized erythrocytes in venules and capillaries were absent. Lack of sequestration with excessive hyperparasitemia leading to systemic hypoxemia and host cytokine release may have contributed to the rapid fatal course in these nonimmune patients.
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PMID:Fatal malaria in a German couple returning from Burkina Faso. 1456 54

The autoimmune/lymphoproliferative syndrome (ALPS) displays defective function of Fas, autoimmunities, lymphadenopathy/splenomegaly, and expansion of CD4/CD8 double-negative (DN) T cells. Dianzani autoimmune/lymphoproliferative disease (DALD) is an ALPS variant lacking DN cells. Both forms have been ascribed to inherited mutations hitting the Fas system but other factors may be involved. A pilot cDNA array analysis on a DALD patient detected overexpression of the cytokine osteopontin (OPN). This observation was confirmed by enzyme-linked immunosorbent assay (ELISA) detection of higher OPN serum levels in DALD patients (n = 25) than in controls (n = 50). Analysis of the OPN cDNA identified 4 polymorphisms forming 3 haplotypes (A, B, and C). Their overall distribution and genotypic combinations were different in patients (N = 26) and controls (N = 158) (P <.01). Subjects carrying haplotype B and/or C had an 8-fold higher risk of developing DALD than haplotype A homozygotes. Several data suggest that these haplotypes influence OPN levels: (1) in DALD families, high levels cosegregated with haplotype B or C; (2) in healthy controls, haplotype B or C carriers displayed higher levels than haplotype A homozygotes; and (3) in AB and AC heterozygotes, mRNA for haplotype B or C was more abundant than that for haplotype A. In vitro, exogenous OPN decreased activation-induced T-cell death, which suggests that high OPN levels are involved in the apoptosis defect.
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PMID:High levels of osteopontin associated with polymorphisms in its gene are a risk factor for development of autoimmunity/lymphoproliferation. 1459 38

An IL-2-expressing, attenuated strain of Salmonella typhimurium (strain GIDIL2) was previously shown to survive poorly and to have lower immunogenicity in susceptible mice than its parental, non-cytokine-expressing strain (designated BRD509). In the present study, we compared the immune responses induced by both bacterial strains in inherently Salmonella-resistant C3H/HeN mice. Analysis of the bacterial loads in the peritoneum and spleen revealed that colony-forming units (CFUs) of GIDIL2 were consistently lower than the corresponding BRD509 CFUs. As early as 48 h after inoculation, there were 60-fold lower CFUs of GIDIL2 than BRD509 organisms in the peritoneal cavity. Similarly, the differences in splenic CFUs of GIDIL2 were 20- to 50-fold lower than those of BRD509 over a period of 3-21 days post-injection. This rapid rate of clearance of the GIDIL2 organisms correlated with significantly decreased infection-induced splenomegaly and nitric oxide production by spleen cells. However, despite the poor survival of GIDIL2 organisms in vivo, they could activate peritoneal NK cells efficiently. As early as 48 h after immunization, equivalent levels of NK-mediated cellular cytotoxicity were induced by BRD509 and GIDIL2 strains. Direct evidence for priming of the immune response was shown by demonstrating increased production of IFN-gamma in a recall response by spleen memory T cells obtained 3 weeks after immunization. Finally, mice inoculated with a single dose of either BRD509 or GIDIL2 organisms were fully protected against a challenge of >100-fold the LD50 dose of virulent Salmonella. Taken together, our data demonstrate that despite their rapid clearance from the reticuloendothelial system, IL-2-expressing Salmonella are immunogenic and fully capable of affording excellent protection against virulent challenge in Salmonella-resistant C3H/HeN mice.
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PMID:Poor survival but high immunogenicity of IL-2-expressing Salmonella typhimurium in inherently resistant mice. 1505 Sep 62


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