UMLS:C0038002 - FACTA Search

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Query: UMLS:C0038002 (splenomegaly)
9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hairy cell leukemia (HCL), a rare haematological disorder of B-cell origin, mainly presents with bone marrow infiltration, haematopoietic insufficiency, and splenomegaly. In some cases, osteolytic lesions can be observed. Many of these clinical features, especially haematopoietic insufficiency and osteolytic lesions are likely to be caused by soluble factors, such as cytokines. There is evidence that these factors are produced by the malignant hairy cells themselves, suggesting a paracrine pathway. The importance of autocrine as well as paracrine growth loops in growth regulation of HCL-cells is supported by a series of excellent studies, performed within the last few years. It could be clearly shown that cytokines are involved in this autocrine and paracrine regulatory process. The most important cytokines which should be mentioned in this respect are tumor necrosis factor alpha, (TNF alpha). Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-6 (IL-6) and B-cell-growth factor (BCGF). The role of other factors such as viruses and oncogenes remains rather unclear. Nevertheless, recent data suggest that the c-fms, which encodes for the macrophage colony stimulating factor (M-CSF) may be involved in the pathophysiological control of HCL growth. In this review, we summarise the important data and studies performed recently which shed light on the complex network of autocrine and paracrine growth regulation of HCL.
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PMID:Autocrine and paracrine regulation of neoplastic cell growth in hairy cell leukemia. 754 30

We have previously shown chronic immune activation and enhanced generation of reactive oxygen species in common variable immunodeficiency (CVI). In the present study, we examined levels of glutathione, the dominant intracellular thiol, that play an important protective role against oxidative and inflammatory stress in plasma and in monocytes and lymphocyte subsets in 20 CVI patients and in 16 healthy controls. CD4+ lymphocytes from CVI patients had significantly lower levels of both total and reduced glutathione as well as a lower ratio of reduced to total glutathione compared with healthy controls. This decrease in glutathione levels in CD4+ lymphocytes was most pronounced in the CD45RA+ subset. Plasma levels of total glutathione were also significantly decreased in CVI. In contrast, monocytes from CVI patients exhibited increased levels of both total and reduced glutathione compared with blood donor monocytes. CVI patients had significantly raised serum levels of tumor necrosis factor alpha (TNF alpha) and TNF alpha concentration was strongly associated with glutathione depletion in CD4+ lymphocytes. Furthermore, the lowest levels of both total and reduced glutathione were found in a subgroup of CVI patients characterized by persistent immune activation in vivo, decreased numbers of CD4+ lymphocytes in peripheral blood, and splenomegaly. Finally, supplementation of cell cultures with glutathione-monoethyl ester did significantly enhance interleukin-2 production from peripheral blood mononuclear cells in CVI patients. These glutathione abnormalities in CVI indicate increased oxidative stress, particularly in CD4+ lymphocytes, and intracellular depletion of reduced glutathione of the demonstrated magnitude may have profound implications for CD4+ lymphocyte function and the immunodeficiency in CVI.
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PMID:Decreased levels of total and reduced glutathione in CD4+ lymphocytes in common variable immunodeficiency are associated with activation of the tumor necrosis factor system: possible immunopathogenic role of oxidative stress. 763 46

We investigated whether gamma interferon (IFN-gamma; a Th1 cytokine), tumor necrosis factor alpha (TNF-alpha), and interleukin-4 (IL-4; a Th2 cytokine) modulate nitric oxide (NO) production in vivo during blood stage infection with Plasmodium chabaudi AS. Treatment of resistant C57BL/6 mice, which resolve infection with P. chabaudi AS and produce increased levels of IFN-gamma, TNF-alpha, and NO early during infection, with anti-IFN- gamma plus anti-TNF-alpha monoclonal antibodies (MAbs) resulted in a reduction of both splenic inducible NO synthase mRNA and serum NO3- levels by 50 and 100%, respectively. Treatment with the anti-TNF-alpha MAb alone reduced only serum NO3- levels by 35%, and treatment with the anti-IFN-gamma MAb alone had no effect on NO production by these mice during infection. Susceptible A/J mice, which succumb to infection with P. chabaudi AS and produce increased levels of IL-4 but low levels of IFN-gamma, TNF-alpha, and NO early during infection, were treated with an anti-IL-4 MAb. The latter treatment had no effect on NO production by this mouse strain during infection. In addition, our results also demonstrate that treatment of resistant C57BL/6 mice with anti-IFN-gamma plus anti-TNF-alpha MAbs affects, in addition to NO production, other traits of resistance to P. chabaudi AS malaria such as the peak level of parasitemia and the development of splenomegaly. Furthermore, the change in spleen weight was shown to be an IFN-gamma-independent effect of TNF-alpha. Treatment of susceptible A/J mice during infection with an anti IL-4 MAb had no effect on these markers of resistance. Thus, these results demonstrate that TNF-alpha and IFN-gamma are critical in the regulation of NO production and other traits of resistance during P. chabaudi AS malaria in C57BL/6 mice. These data also indicate that treatment with an anti-IL-4 antibody alone is not able to induce NO production or confer resistance to A/J mice against P. chabaudi AS malaria.
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PMID:In vivo regulation of nitric oxide production by tumor necrosis factor alpha and gamma interferon, but not by interleukin-4, during blood stage malaria in mice. 855 72

Both interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) are produced early in intracellular bacterial infection. Depletion of either IL-12 or TNF-alpha by a single injection of specific antibody 4 h before the injection of Brucella abortus 19 led to the exacerbation of infection 2 weeks later. Whereas the effect of IL-12 depletion on resistance was persistent and exacerbation was still significant 6 weeks later, the bacterial numbers in mice depleted of TNF-alpha were similar to the bacterial numbers in control infected mice by 6 weeks postinfection. Massive splenomegaly, which is often seen in 2-week Brucella-infected mice, was not observed in IL-12- or TNF-alpha-depleted mice. Both IL-12- and TNF-alpha-depleted mice showed reduced cell accumulation in the spleen compared with the massive cell accumulation in control infected mice. Granuloma formation in livers was much reduced in IL-12-depleted mice but not in TNF-alpha-depleted mice. Gamma interferon (IFN-gamma) production by cells from TNF-alpha-depleted mice was not significantly different from that of cells from control infected mice. In contrast, the production of IFN-gamma by both CD4+ and CD8+ T cells from IL-12-depleted mice was greatly reduced, compared with that from control infected mice. This effect was still observed when the antibody injection was delayed for up to 7 days postinfection, but injections of anti-IL-12 antibody into mice with established Brucella infection had no significant effect on IFN-gamma production by T cells. Taken together, these results suggested that IL-12 contributed to resistance mainly via an IFN-gamma-dependent pathway and had a profound effect on the induction of acquired cellular resistance. In contrast, TNF-alpha was involved in resistance possibly via direct action on effector cells and may not be essential for the induction of acquired cellular resistance.
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PMID:Tumor necrosis factor alpha and interleukin-12 contribute to resistance to the intracellular bacterium Brucella abortus by different mechanisms. 869 8

We investigated the importance of enterococcal aggregation substance (AS) and enterococcal binding substance (EBS) in rabbit models of Enterococcus faecalis cardiac infections. First, American Dutch belted rabbits were injected intraventricularly with 10(8) CFU and observed for 2 days. No clinical signs of illness developed in animals given AS- EBS- organisms, and all survived. All rabbits given AS- EBS+ organisms developed signs of illness, including significant pericardial inflammation, but only one of six died. All animals given AS+ EBS- organisms developed signs of illness, including pericardial inflammation, and survived. All rabbits given AS+ EBS+ organisms developed signs of illness and died. None of the rabbits receiving AS+ EBS+ organisms showed gross pericardial inflammation. The lethality and lack of inflammation are consistent with the presence of a superantigen. Rabbit and human lymphocytes were highly stimulated in vitro by cell extracts, but not cell-free culture fluids, of AS+ EBS+ organisms. In contrast, cell extracts from AS- EBS- organisms weakly stimulated lymphocyte proliferation. Culture fluids from human lymphocytes stimulated with AS+/EBS+ enterococci contained high levels of gamma interferon and tumor necrosis factor alpha (TNF-alpha) and TNF-beta, which is consistent with functional stimulation of T-lymphocyte proliferation and macrophage activation. Subsequent experiments examined the abilities of the same strains to cause endocarditis in a catheterization model. New Zealand White rabbits underwent transaortic catheterization for 2 h, at which time catheters were removed and animals were injected with 2 x 10(9) CFU of test organisms. None of the animals given AS- EBS- organisms developed vegetations or showed autopsy evidence of tissue damage. Rabbits given AS- EBS+ or AS+ EBS- organisms developed small vegetations and had splenomegaly at autopsy. All rabbits given AS+ EBS+ organisms developed large vegetations and had splenomegaly and lung congestion at autopsy. Similar experiments that left catheters in place for 3 days revealed that all rabbits given AS- EBS- or AS+ EBS+ organisms developed vegetations, but animals given AS+ EBS+ organisms had larger vegetations and autopsy evidence of lung congestion. These experiments provide direct evidence that these two cell wall components play an important role in the pathogenesis of endocarditis as well as in conjugative plasmid transfer.
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PMID:Aggregation and binding substances enhance pathogenicity in rabbit models of Enterococcus faecalis endocarditis. 942 61

We demonstrate in this study the cytotoxic effects of inorganic arsenicals, arsenite and arsenate, and organic arsenic compounds, monomethylarsonic acid (MAA), dimethylarsinic acid (DMAA), and trimethylarsine oxide (TMAO), which are metabolites of inorganic arsenicals in human bodies, using murine macrophages in vitro. Inorganic arsenicals, both arsenite and arsenate, are strongly toxic to macrophages, and the concentration that decreased the number of surviving cells to 50% of that in untreated controls (IC50) was 5 or 500 microM, respectively. These inorganic arsenicals mainly caused necrotic cell death with partially apoptotic cell death; about 80% of dead cells were necrotic, and 20% were apoptotic. The inorganic arsenicals also induced marked release of an inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), at cytotoxic doses. This strong cytotoxicity of an inorganic arsenical, arsenite, might be mediated via active oxygen and protease activation because it was inhibited by the addition of some antioxidant reagents, such as superoxide dismutase (SOD), catalase, and GSH, or by a peptide inhibitor of interleukin-1 beta-converting enzyme (ICE). It is likely that these immunotoxic effects of inorganic arsenicals may evoke both immunosuppression and inflammation, and they may be central factors causing carcinogenesis and severe inflammatory responses, such as hepatomegaly and splenomegaly, in chronic arsenicosis patients who daily ingested arsenic-contaminated well water. In contrast, the cytotoxic effects of methylated arsenic compounds were lower than those of inorganic arsenicals. The IC50 value of DMAA was about 5 mM, and MAA and TMAO had no toxicity even at concentrations over 10 mM. Additionally, these methylated chemicals suppressed the TNFalpha release from macrophages. DMAA induced mainly apoptotic cell death in macrophages as indicated by cellular morphological changes, condensed nuclei, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL), and DNA fragmentation. However, the cytotoxicity of DMAA might be induced via a different mechanism from that of inorganic arsenicals because it was not abolished by the additions of SOD, catalase, or ICE inhibitor. Conversely, GSH enhanced the toxicity of DMAA. These data suggest that methylation of inorganic arsenicals in mammals plays an important role in suppression of both severe immunosuppression and inflammatory responses caused by inorganic arsenicals.
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PMID:Inorganic and methylated arsenic compounds induce cell death in murine macrophages via different mechanisms. 954 97

We have shown that Walker 256/S mammary carcinoma caused osteoporosis-like changes in young female rats, accompanied by low serum estradiol and hypercalciuria without changes in the serum levels of calcium, phosphorus, and parathyroid hormone-related peptide. In this study, we investigated the cause of bone loss after Walker 256/S inoculation into female 6-week-old Wistar Imamichi rats, focusing on the sex hormone balance in the host animal. Walker 256/S-bearing rats showed characteristic osteoporosis, with a significant increase in spleen weight and a significant decrease in uterine weight by 14 days after s.c. tumor inoculation. In the in vitro bone marrow culture, mineralized nodule formation ability decreased according to the time after tumor inoculation, and tartrate-resistant acid phosphatase-positive multinucleated cell formation increased at 7 days after tumor inoculation, but it began to decrease at 14 days after tumor inoculation. This indicates that after inoculation with Walker 256/S tumor, the progenitors of osteoblasts and ostroclasts lost their balance in the bone turnover, resulting in bone resorption. On the other hand, Walker 256/S carcinoma expressed luteinizing hormone-releasing hormone (LH-RH) mRNA, and in Walker 256/S-bearing rats, the serum LH-RH level increased significantly from 3 days after tumor inoculation, whereas in the healthy control rats, this level was very low. Consequently, the serum levels of follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone were significantly lower in the tumor-bearing rats than in the healthy control rats. Because the LH-RH gene is located in the long prolactin release-inhibiting factor (PIF) gene and mRNA amplified by reverse transcription-PCR in this study contained whole LH-RH and a part of PIF, the Walker 256/S tumor is thought to express PIF. Indeed, the serum prolactin level decreased in tumor-bearing rats. The serum level of growth hormone, one of the other pituitary hormones, was not changed. Moreover, the level of an osteolytic cytokine, tumor necrosis factor alpha, increased in the serum of Walker 256/S-bearing rats, although this may be a result of the immune response of the host animal to tumor growth as well as an enlarged spleen. In conclusion, the Walker 256/S tumor lowers estrogen secretion through ectopical oversecretion of LH-RH, and then osteolytic cytokines, such as tumor necrosis factor alpha, increase in tumor-bearing rats, escape the control of estrogen, and activate osteoclasts, resulting in bone loss in a short period.
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PMID:Walker 256/S carcinosarcoma causes osteoporosis-like changes through ectopical secretion of luteinizing hormone-releasing hormone. 1009 51

It has previously been reported that inhibition of delayed-type hypersensitivity-mediating functions of T cells during mycobacterial infection in mice is haplotype dependent. In the present study, we show that Mycobacterium bovis BCG infection induced, in susceptible C57BL/6 and BALB/c mice but not in resistant C3H/HeJ and DBA/2 mice, an important splenomegaly. An in vitro defect in T-cell proliferation in response to T-cell receptor (TCR) stimulation with mitogens or anti-CD3 antibodies was associated with enhanced levels of CD4(+) and CD8(+) T-cell apoptosis in susceptible but not in resistant mice 2 weeks after infection. Further investigations of C57BL/6 and C3H/HeJ mice revealed that in vivo splenomegaly was associated with destruction of the lymphoid tissue architecture, liver cellular infiltrates, and increased numbers of apoptotic cells in both spleen and liver tissue sections. Infection of C57BL/6 mice but not of C3H/HeJ mice induced massive production of tumor necrosis factor alpha (TNF-alpha) in serum, as well as an increase in Fas and Fas ligand (FasL) expression in T cells. In vitro addition of neutralizing anti-TNF-alpha antibodies led to a significant reduction in CD3-induced T-cell apoptosis of both CD4(+) and CD8(+) T cells of C57BL/6 mice, while the blockade of Fas-FasL interactions reduced apoptosis only in CD4(+) but not in CD8(+) T cells. Together, these results suggest that TNF-alpha and Fas-FasL interactions play a role in the activation-induced cell death (AICD) process associated with a defect in T-cell proliferation of the susceptible C57BL/6 mice. T-cell death by apoptosis may represent one of the important components of the ineffective immune response against mycobacterium-induced immunopathology in susceptible hosts.
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PMID:Ineffective cellular immune response associated with T-cell apoptosis in susceptible Mycobacterium bovis BCG-infected mice. 1085 44

C3H/HeJ mice have an impaired ability to respond to lipopolysaccharide (LPS) due to a mutation in the gene that encodes Toll-like receptor 4 (TLR4). The effect of TLR4 deficiency on host responses to endodontic infections is unknown. In the present study, we compared periapical bone destruction, sepsis, and inflammatory cytokine production in LPS-hyporesponsive C3H/HeJ and wild-type control C3H/HeOuJ mice. The mandibular first molars of both strains were subjected to pulpal exposure and infection with a mixture of four anaerobic pathogens, Prevotella intermedia, Fusobacterium nucleatum, Streptococcus intermedius, and Peptostreptococcus micros. At sacrifice on day 21, TLR4-deficient C3H/HeJ mice had significantly reduced periapical bone destruction compared to wild-type C3H/HeOuJ mice (P < 0.001). The decreased bone destruction in C3H/HeJ correlated with reduced expression of the bone resorptive cytokines interleukin 1alpha (IL-1alpha) (P < 0.01) and IL-1beta (P < 0.05) as well as the proinflammatory cytokine IL-12 (P < 0.05). No significant differences were seen in the levels of gamma interferon, tumor necrosis factor alpha (TNF-alpha), or IL-10 between the two strains. The expression of IL-1alpha, IL-1beta, TNF-alpha, IL-10, and IL-12 were all significantly reduced in vitro in macrophages from both TLR4-deficient C3H/HeJ and C57BL/10ScNCr strains, compared to wild-type controls. Notably, the responses of TLR4-deficient macrophages to both gram-positive and gram-negative bacteria were similarly reduced. Neither C3H/HeJ nor C3H/HeOuJ mice exhibited orofacial abscess development or infection dissemination as determined by splenomegaly or cachexia. We conclude that intact TLR function mediates increased proinflammatory responses and bone destruction in response to mixed anaerobic infections.
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PMID:Toll-like receptor 4-deficient mice have reduced bone destruction following mixed anaerobic infection. 1089 73

The contribution of granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic and immunoregulatory cytokine, to resistance to blood-stage malaria was investigated by infecting GM-CSF-deficient (knockout [KO]) mice with Plasmodium chabaudi AS. KO mice were more susceptible to infection than wild-type (WT) mice, as evidenced by higher peak parasitemia, recurrent recrudescent parasitemia, and high mortality. P. chabaudi AS-infected KO mice had impaired splenomegaly and lower leukocytosis but equivalent levels of anemia compared to infected WT mice. Both bone marrow and splenic erythropoiesis were normal in infected KO mice. However, granulocyte-macrophage colony formation was significantly decreased in these tissues of uninfected and infected KO mice, and the numbers of macrophages in the spleen and peritoneal cavity were significantly lower than in infected WT mice. Serum levels of gamma interferon (IFN-gamma) were found to be significantly higher in uninfected KO mice, and the level of this cytokine was not increased during infection. In contrast, IFN-gamma levels were significantly above normal levels in infected WT mice. During infection, tumor necrosis factor alpha (TNF-alpha) levels were significantly increased in KO mice and were significantly higher than TNF-alpha levels in infected WT mice. Our results indicate that GM-CSF contributes to resistance to P. chabaudi AS infection and that it is involved in the development of splenomegaly, leukocytosis, and granulocyte-macrophage hematopoiesis. GM-CSF may also regulate IFN-gamma and TNF-alpha production and activity in response to infection. The abnormal responses seen in infected KO mice may be due to the lack of GM-CSF during development, to the lack of GM-CSF in the infected mature mice, or to both.
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PMID:Granulocyte-macrophage colony-stimulating factor-deficient mice have impaired resistance to blood-stage malaria. 1111 98

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