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)

Serum neopterin levels were analysed in 43 patients with primary hypogammaglobulinaemia (25 common variable immunodeficiency (CVI), 12 congenital hypogammaglobulinaemia (CH), six X-linked hypogammaglobulinaemia (XLH)), and in 33 healthy controls. The neopterin values were correlated to lymphocyte subset counts in peripheral blood, lymphocyte mitogen responses and clinical and histological manifestations in the study group. Serum neopterin levels were significantly elevated in all subgroups of patients and particularly in the CVI groups where the highest concentrations were found (P less than 0.001, CVI versus controls). Furthermore, in CVI and CH patients elevated neopterin levels were strongly correlated to decreased number of CD4+ lymphocytes (rs = -0.61, P less than 0.005 and rs = -0.83, P less than 0.001, respectively). In the CVI group high neopterin levels were also significantly correlated to low number of circulatory B (CD19+) lymphocytes (rs = -0.58, P less than 0.05). Both patients with moderately and those with severely depressed lymphocyte mitogen responses had significantly higher neopterin levels than those with normal responses. In addition, high neopterin levels were significantly associated with the occurrence of splenomegaly and nodular intestinal lymphoid hyperplasia. The immunological findings were consistently observed in longitudinal testing, and appeared to be characteristic for the individual patient. High serum neopterin levels are thought to be a marker for hyperactivity in monocytes/macrophages, and dysfunction of these cells may therefore be associated with fundamental immune pathology in some subgroups of primary hypogammaglobulinaemia.
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PMID:Raised serum neopterin levels in patients with primary hypogammaglobulinaemia; correlation to other immunological parameters and to clinical and histological features. 163 65

Serum immunoreactive interleukin (IL-)1 alpha, IL-4, IL-6 and tumor necrosis factor (TNF) alpha were measured in 42 patients with primary hypogammaglobulinemia (25 common variable immunodeficiency (CVI), 10 congenital hypogammaglobulinemia (CH), 7 X-linked agammaglobulinemia (XLA), and in 21 healthy controls. The cytokine levels were correlated to other immunological parameters including serum levels of neopterin and soluble CD8 (sCD8) antigen. IL-6 was detectable in 48% and IL-4 in 36% of the CVI patients, but in none of the controls. Seventy-five percent of the CVI patients with elevated IL-4 levels had detectable IL-6. In contrast, no patients in the XLA group and only three CH patients had detectable IL-4 or IL-6 levels. TNF alpha and IL-1 alpha were detected in only a few serum samples with no significant differences between patients and controls. In the CVI group elevated IL-6 levels were significantly associated to reduced numbers of CD4+ and CD19+ lymphocytes, elevated levels of neopterin and sCD8 antigen, and occurrence of splenomegaly and bronchiectasis. The raised IL-6 levels were confirmed in longitudinal testing, probably reflecting a characteristic immunological dysregulation in these patients. Cytokine alterations may play a role in the pathogenesis of the immunodeficiency and for the clinical manifestations in CVI patients. Alternatively, elevated cytokine levels may be only a marker of chronic immune activation, particularly in monocytes, possibly delineating a distinct subgroup of patients within the heterogeneous CVI group.
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PMID:Elevated serum levels of interleukin-4 and interleukin-6 in patients with common variable immunodeficiency (CVI) are associated with chronic immune activation and low numbers of CD4+ lymphocytes. 790 14

Monocyte and macrophage dysfunction may be important for both immunopathogenesis and clinical manifestations in subgroups of patients with primary hypogammaglobulinaemia. In the present study we examined the ability to generate reactive oxygen species (ROS) in isolated monocytes from these patients by two different methods: superoxide dismutase (SOD) inhibitable cytochrome c reduction by O2- and nitroblue tetrazolium (NBT) reduction. Monocyte from patients with common variable immunodeficiency (CVI) demonstrated significantly enhanced ROS generation both unstimulated and stimulated (unopsonized zymosan and phorbol myristate acetate (PMA)). The enhanced oxidative burst response in CVI patients was found both with and without serum containing medium. Furthermore, serum from CVI patients did significantly enhance the oxidative burst response in monocytes from healthy blood donors compared with the effect of control serum. The enhanced ROS generation in CVI patients was significantly correlated with elevated serum levels of neopterin, reduced numbers of CD4+ lymphocytes in peripheral blood and occurrence of splenomegaly. In contrast to the CVI group, monocytes from patients with X-linked agammaglobulinaemia (XLA) did not show enhanced ROS generation. The increased oxidative burst response in monocytes from CVI patients most probably reflects in vivo activation of these cells. Our observations indicate the presence of a subgroup of CVI patients characterized by chronic immune activation particularly of monocytes. The enhanced ROS generation might be involved in immunopathogenesis (e.g. T cell dysfunction) and in the pathogenesis of clinical manifestations (e.g. malignancies and autoimmune disorders) in these patients.
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PMID:Enhanced generation of reactive oxygen species in monocytes from patients with common variable immunodeficiency. 805 Jan 70

A 16-year old woman with LGL leukemia developed peripheral neuropathy. She showed virus-associated hemophagocytic syndrome (VAHS)-like signs including high fever, liver dysfunction, huge splenomegaly, hepatomegaly and pancytopenia. The presence of chronic active EB virus infection was proved by marked high titers for IgG and IgA antibodies to the Epstein-Barr viral capsid and early antigens and low titers of antibody to Epstein-Barr nuclear antigens. She showed dysesthesia and paresthesia of bilateral lower extremities with marked swelling and tenderness, and later developed muscular weakness and atrophy with areflexia of lower extremities. Findings of the central nervous system dysfunction were not observed except for the acceleration of jaw jerk. Pleocytosis and increased protein levels in the cerebrospinal fluid were found. Pulse therapy of methyl-prednisolone and high dose intravenous immunoglobulin therapy (20 g/day for 3 days) were effective for neurological findings. The increased neopterin in the cerebrospinal fluid suggested that peripheral neuropathy was caused by activated macrophages.
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PMID:[Peripheral neuropathy in large granular lymphocytic leukemia]. 821 4

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by defective immunoglobulin production and high frequency of bacterial infections, autoimmunity and manifestations of chronic inflammation. Abnormalities of CD4+CD25high forkhead box P3 (FoxP3)+ regulatory T cells (Treg) have been associated with autoimmune and inflammatory disorders, and we hypothesized that CVID might be characterized by Treg abnormalities. CD3+ cells from patients and controls were analysed for the expression of FoxP3 mRNA by real time reverse transcription-polymerase chain reaction (RT-PCR). Peripheral blood mononuclear cells from CVID patients and controls were stained for Treg markers, analysed by flow cytometry and compared to clinical characteristics. The main findings were: (i) CVID patients had significantly decreased expression of FoxP3 mRNA and decreased proportions of CD4+CD25highFoxP3+ cells compared to controls; (ii) CVID patients with splenomegaly had even lower proportions of Treg compared to other patients and controls; (iii) serum levels of the inflammatory marker neopterin were correlated negatively with the proportions of Treg within the CVID population, while there was no significant association with bronchiectasis. We have demonstrated decreased proportions of Treg in CVID patients, particularly in those with signs of chronic inflammation. Decreased proportions of TReg are suggested to be pathogenetically important in autoimmunity, and our results suggest that TReg may have a similar role in CVID.
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PMID:Low numbers of regulatory T cells in common variable immunodeficiency: association with chronic inflammation in vivo. 1730 2

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by defective immunoglobulin production and high frequency of bacterial infections, autoimmunity and manifestations of chronic inflammation. The urokinase plasminogen activator (uPA), its cell bound and soluble receptor (uPAR, suPAR) have complex biological functions involving innate immune defense mechanisms and regulation of inflammation. Based on this dual role, we hypothesized that the uPA system could be affected in CVID, and examined expression of components of the uPA system in subgroups of CVID. All CVID-patients had increased plasma levels of suPAR with particularly high levels in those with splenomegaly and thrombocytopenia. Plasma uPA levels were also raised in these patients, and both suPAR and uPA levels correlated with the monocyte activation marker neopterin. Monocytes from CVID patients had increased expression of uPAR. We show an increased activation of the uPA system possibly contributing to the inflammatory phenotype seen in subgroups of CVID patients.
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PMID:Enhanced levels of urokinase plasminogen activator and its soluble receptor in common variable immunodeficiency. 1923 8

The objective of this study was to characterize the rhesus macaque (RM) as a model for inhalational brucellosis in support of the U.S. Food and Drug Administration's (FDA) Animal Rule. The pathophysiology of chronic Brucella melitensis aerosol infection was monitored in two phases that each occurred over an 8-week time period; dose escalation (8 RMs; targeted doses of 5.0E+03, 5.0E+04, or 5.0E+05 CFU/animal or the unchallenged control) and natural history (12 RMs; targeted dose of 2.50E+05 CFU/animal or the unchallenged control). RMs given an aerosol challenge with B. melitensis developed undulating fevers (6/6 phase I; 8/9 phase II), positive enriched blood cultures (5/10; phase II), and bacterial burdens in tissues starting 14 to 21 days postchallenge (6/6 phase I; 10/10 phase II). In addition, 80% (8/10; phase II) of infected RMs seroconverted 14 to 21 days postchallenge. RMs developed elevations in certain liver enzymes and had an increased inflammatory response by 3 weeks postchallenge as shown by increases in C-reactive protein (6/8) and neopterin (4/8), which correlated with the onset of a fever. As early as 14 days postchallenge, positive liver biopsy specimens were detected (2/8), and ultrasound imaging showed the development of splenomegaly. Finally, histopathologic examination found lesions attributed to Brucella infection in the liver, kidney, lung, and/or spleen of all animals. The disease progression observed with the RMs in this study is analogous to human brucellosis pathophysiology. Thus, the results from this study support the use of the RM as an animal model for inhalational brucellosis to evaluate the efficacy of novel vaccines and therapeutics against B. melitensis.
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PMID:Pathophysiology of the rhesus macaque model for inhalational brucellosis. 2206 15