Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

beta 2-Microglobulin-deficient (beta 2m-) mice generate a CD4+ major histocompatibility complex class II-restricted cytotoxic T-lymphocyte (CTL) response following infection with lymphocytic choriomeningitis (LCM) virus (LCMV). We have determined the cytotoxic mechanism used by these CD4+ CTLs and have examined the role of this cytotoxic activity in pathogenesis of LCM disease in beta 2m- mice. Lysis of LCMV-infected target cells by CTLs from beta 2m- mice is inhibited by addition of soluble Fas-Ig fusion proteins or by pretreatment of the CTLs with the protein synthesis inhibitor emetine. In addition, LCMV-infected cell lines that are resistant to anti-Fas-induced apoptosis are refractory to lysis by these virus-specific CD4+ CTLs. These data indicate that LCMV-specific CD4+ CTLs from beta 2m- mice use a Fas-dependent lytic mechanism. Intracranial (i.c.) infection of beta 2m- mice with LCMV results in loss of body weight. Fas-deficient beta 2m- Jpr mice develop a similar wasting disease following i.c. infection. This suggests that Fas-dependent cytotoxicity is not required for LCMV-induced weight loss. A potential mediator of this chronic wasting disease is tumor necrosis factor (TNF)-alpha, which is produced by LCMV-specific CD4+ CTLs. In contrast to LCMV-induced weight loss, lethal LCM disease in beta 2m- mice is dependent on Fas-mediated cytotoxicity. Transfer of immune splenocytes from LCMV-infected beta 2m- mice into irradiated infected beta 2m- mice results in death of recipient animals. In contrast, transfer of these splenocytes into irradiated infected beta 2m- Jpr mice does not cause death. Thus a role for CD4+ T-cell-mediated cytotoxicity in virus-induced immunopathology has now been demonstrated.
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PMID:Fas-dependent CD4+ cytotoxic T-cell-mediated pathogenesis during virus infection. 896 23

In 1970 at the University of Texas MD Anderson Hospital, Houston TX, we attended a patient with malignant lymphoma and "lymphosarcoma cell leukaemia". The malignant cells were large with fine granular cytoplasm. The patient was febrile without positive cultures and exhibited wasting resembling "graft-vs-host" disease. Both his lymphoma cells collected from the blood, and his serum, exerted strong cytotoxicity toward a battery of human tumour cell lines established in culture. We reported him as the first case of a new entity; "cytotoxic lymphoma". Later, elsewhere, natural killer (NK) cells were characterized, and cases of malignant lymphomas arising from large granular lymphocytes were described, as those of NK cells. Malignant NK cells constitutively express Fas ligand (L), both membrane-bound (m) and soluble (s). Upon binding FasL Fas receptor (R)-positive hosts cells succumb to apoptotic death. Patients with FasL-producer lymphoma cells suffer from anaemia, neutropenia, hepatotoxicity and autoimmunity. The FasL-->FasR system regulates normal lymphocyte homeostasis. This system is used by the placental trophoblast against maternal lymphocytes; by transplants against host lymphocytes; and by donor lymphocytes exerting graft-vs-host-reaction. In tumour immunology, FasR+ tumour cells can be killed by FasL+ lymphocytes and, vice versa, FasL+ tumour cells can induce apoptotic death of FasR+ host lymphocytes ("counterattack on lymphocytes"). Some tumour cells co-express FasL, FasR and bcl-2 and not only escape programmed cell death but also utilize the FasL-->FasR system as an autocrine growth loop ("counterattack on apoptosis").
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PMID:Malignant lymphoma arising from natural killer cells: report of the first case in 1970 and newer developments in the FasL-->FasR system. 946 34

Lethally irradiated mice reconstituted with histocompatible stem cells from Fas-deficient MRL/lpr mice develop a wasting syndrome reminiscent of chronic graft-versus-host disease. However, reconstitution with double Fas-/Fas ligand (FasL)-deficient stem cells does not result in wasting disease, demonstrating that FasL expression is an important component of the effector mechanisms leading to this syndrome. In the absence of wasting disease double-deficient T cells can induce wild-type B cells to make autoantibodies. These data indicate that autoantibody production is regulated by FasL-expressing T cells, and that Fas-sufficient wild-type B cells differ from Fas-deficient Ipr cells only with regard to their sensitivity to FasL.
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PMID:Double mutant MRL-lpr/lpr-gld/gld cells fail to trigger lpr-graft-versus-host disease in syngeneic wild-type recipient mice, but can induce wild-type B cells to make autoantibody. 1089 16

Redox mechanims play important roles in replication of human immunodeficiency virus type 1 (HIV-1) and cellular susceptibility to apoptosis signals. Viral replication and accelerated turnover of CD4+ T cells occur throughout a prolonged asymptomatic phase in patients infected by HIV-1. Disease development is associated with steady loss of CD4+ T cells by apoptosis, increased rate of opportunistic infections and lymphoproliferative diseases, disruption of energy metabolism, and generalized wasting. Such pathological states are preceded by: (i) depletion of intracellular antioxidants, glutathione (GSH) and thioredoxin (TRX), (ii) increased reactive oxygen species (ROS) production, and (iii) changes in mitochondrial transmembrane potential (deltapsi(m)). Disruption of deltapsi(m) appears to be the point of no return in the effector phase of apoptosis. Viral proteins Tat, Nef, Vpr, protease, and gp120, have been implicated in initiation and/or intensification of oxidative stress and disruption of deltapsi(m). Redox-sensitive transcription factors, NF-kappaB, AP-1, and p53, support expression of viral genes and proinflammatory lymphokines. ROS regulate apoptosis signaling through Fas, tumor necrosis factor (TNF), and related cell death receptors, as well as the T-cell receptor. Oxidative stress in HIV-infected donors is accompanied by increased glucose utilization both on the cellular and organismal levels. Generation of GSH and TRX from their corresponding oxidized forms is dependent on NADPH provided through the pentose phosphate pathway of glucose metabolism. This article seeks to delineate the genetic and metabolic bases of HIV-induced oxidative stress. Such understanding should lead to development of effective antioxidant therapies in HIV disease.
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PMID:Genetic and metabolic control of the mitochondrial transmembrane potential and reactive oxygen intermediate production in HIV disease. 1122 68

Fas/Fas ligand (FasL) interaction has been implicated in the pathogenesis of various diseases. To clarify the involvement of Fas/FasL in the pathogenesis of intestinal inflammation, we investigated the preventive and therapeutic effects of neutralizing anti-FasL monoclonal antibody (MAb) on the development of chronic colitis induced by adaptive transfer of CD4+CD45RBhigh T cells to SCID mice. Administration of anti-FasL MAb from 1 day after T cell transfer (prevention study) resulted in a significant improvement of clinical manifestations such as wasting and diarrhea. However, histological examination showed that mucosal inflammation in the colon, such as infiltration of T cells and macrophages, was not improved by the anti-FasL MAb treatment. In vitro studies showed that anti-FasL MAb did not inhibit IFN-gamma production by anti-CD3/CD28-stimulated lamina propria CD4+ T cells but suppressed TNF-alpha and IL-1beta production by lamina propria mononuclear cells. Therapeutic administration of anti-FasL MAb from 3 wk after T cell transfer also improved ongoing wasting disease but not intestinal inflammation. These results suggest that the Fas/FasL interaction plays a critical role in regulating systemic wasting disease but not local intestinal inflammation.
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PMID:Ameliorating effect of anti-Fas ligand MAb on wasting disease in murine model of chronic colitis. 1296 29

Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor superfamily member 6b (TNFRSF6B), was recently identified as a novel biomarker for predicting progression of kidney diseases with potential immune modulation. The purpose of this review is to discuss the current evidence related to DcR3 in kidney diseases and to compare the differences between human and animal studies both in vivo and in vitro. High serum DcR3 predicts the occurrence of peritonitis in patients receiving chronic peritoneal dialysis and is positively correlated with inflammatory markers such as interleukin-6, high-sensitivity C-reactive protein, and adhesion molecules in patients on maintenance hemodialysis (HD). Higher serum DcR3 levels not only independently predict cardiovascular and all-cause mortality in HD patients but also identify older adults on HD at risk of protein-energy wasting in combination with a low geriatric nutritional risk index. Recently, renal tubular epithelial cells (RTECs) expressing DcR3 have also been used to predict progression of chronic kidney disease. Expression of DcR3 was correlated with a 2-fold increase in serum creatinine or failure of kidney allograft. DcR3 could protect renal myofibroblasts against Fas-induced apoptosis and subsequently lead to renal fibrosis. Locally expressed DcR3 in the RTECs may suppress the FasL-Fas-mediated apoptosis of T cells, resulting in an accumulation of allo-reactive T cells. In addition to traditional biological functions, recombinant DcR3.Fc and cytomegalovirus promoter-driven human DcR3 plasmid are able to modulate the activation and differentiation of dendritic cells and macrophages via "non-decoy" action. Both progressive IgA nephropathy and autoimmune crescentic glomerulonephritis in mice can be suppressed after hydrodynamics-based gene delivery of DcR3 plasmid. DcR3-mediated effects in vitro could be surveyed via over-expressing DcR3 or addition of recombinant DcR3.Fc, and CD68-driven DcR3 transgenic mice are suitable for investigating systemic effect in vivo. Inhibition of DcR3 expression in human may be a promising approach for pathomechanism.
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PMID:Role of prognostic biomarker decoy receptor 3 and immunomodulation in kidney diseases. 3135 60