Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pediatric autoimmune liver disease is mainly represented by two similar liver disorders: autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), both characterized by hypergammalobulinemia, interface hepatitis and the presence of a wide range of circulating autoantibodies. Although similar features are seen in AIH and inflammatory bowel disease, histological biliary changes are more common in ASC. In addition to their role as diagnostic markers, autoantibodies, such as anti-extractable nuclear antigen (ENA) antibodies and liver kidney microsomal antibody type 1 (LKM1) may be involved directly in inducing aggressive liver diseases. Although the cellular immune response in pediatric autoimmune liver disease has been less intensively investigated than humoral immunity, the importance of antigen specific T cells has been explored. Both alphabeta and gammadelta T cells derived from either peripheral blood and liver biopsies have highly heterogeneous TCR gene usage and cytolytic activity has been demonstrated. There have been attempts to seek triggers of liver autoimmunity and several sequences shared in common between autoantigens and hepatotropic viruses, namely hepatitis B, C and cytomegalovirus have been identified. The presence of cross-reactivity between homologous sequences, especially between HCV and cytochromes, supports the possibility that molecular mimicry plays a role in the induction of autoantibodies and autoreactive cytotoxic T cells.
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PMID:Pediatric autoimmune liver diseases: the molecular basis of humoral and cellular immunity. 1189 84

Natural T (NT) lymphocytes recognize infected cells or microbial compounds without the classical genetic restriction of polymorphic major histocompatibility complex (MHC) molecules. This innate recognition pathway results in a broad and rapid antimicrobial response that may be critical for controlling the spread of intracellular pathogens, requiring the elimination of the infecting agent from both extracellular spaces and host cells. NT cells are mainly composed of alphabeta and gammadelta T lymphocytes that express natural killer (NK) receptors and recognize preferentially various nonpeptidic antigens. Similar to NK cells, NT lymphocytes can 'see' and kill target cells deficient in the expression of one or more MHC class I molecules. NT cells expressing the alphabeta TCR can recognize lipid and lipoglycan antigens presented in the context of nonpolymorphic CD1 molecules, whereas phosphocarbohydrates and akilamines induce constitutive responses in most Vgamma9Vdelta2 NT lymphocytes. The remaining fraction of gammadelta NT cells express the Vdelta1 chain associated with different Vgamma-chains and may directly recognize self-antigens such as MICA, MICB or CD1 molecules. It is possible that NT lymphocytes may play two opposite roles during intracellular infections. First, in the acute phase, they may be critical for the initiation of pathogen elimination. Second, in the chronic phase, NT cells may be dangerous, if their potential autoreactivity is not well controlled. It is conceivable that novel strategies of immune intervention against emerging and re-emerging intracellular pathogens, such as human immundeficiency virus (HIV), hepatitis-C virus (HCV) and Mycobacterium tuberculosis (MTB) may involve the control of NT cell activation/anergy by (nonpeptidic) immunoregulatory drugs.
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PMID:Natural T cell immunity to intracellular pathogens and nonpeptidic immunoregulatory drugs. 1189 39

Previous work has shown that stimulation of APCs via CD40 strongly influences the outcome of a CD8 T cell response. In this study, we examined the effect of CD40 ligation on peripheral tolerance induction of self-reactive CD8 T cells in an adoptive transfer model. Naive CD8 T cells from TCR-transgenic (tg) mice specific for the gp33 epitope of lymphocytic choriomeningitis virus were tolerized when transferred into H8-tg mice expressing the gp33 epitope under the control of a MHC class I promoter. However, if the H8 recipient mice were treated with agonistic anti-CD40 Abs, TCR-tg cells vigorously proliferated, and induced destruction of lymphoid organs and hepatitis. Break of peripheral tolerance induction was B cell independent and did not require CD28/B7 interactions. These findings provide further in vivo evidence for the crucial role of the activation state of the APC in peripheral tolerance induction and suggest the need for caution in systemically activating APC via CD40 ligation in the presence of self-reactive T cells.
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PMID:CD40 ligation in the presence of self-reactive CD8 T cells leads to severe immunopathology. 1199 66

Multiple sclerosis, a chronic inflammatory disease of the CNS, is characterized by immune-mediated demyelination. Many patients have a remitting-relapsing course of disease with exacerbations often following unrelated microbial illnesses. The relationship between the two events remains obscure. One possibility is that T cells specific for the inciting microbial pathogen are able to effect demyelination at a site of ongoing inflammation within the CNS. This possibility was examined in mice infected with mouse hepatitis virus, a well-described model of virus-induced demyelination. Using transgenic TCR/recombination activation gene 2(-/-) mice with only non-mouse hepatitis virus-specific T cells, we show that CD8 T cells are able to cause demyelination in the absence of cognate Ag in the CNS, but only if specifically activated. These findings demonstrate a novel mechanism for immune-mediated neuropathology and show that activated CD8 T cells may serve as important mediators of bystander demyelination during times of infection, including in patients with multiple sclerosis.
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PMID:Bystander CD8 T cell-mediated demyelination after viral infection of the central nervous system. 1213 83

Alfa-Galactosyl Ceramide was isolated from Ocean sponge which has antitumor effect against several tumors in in vivo animal model with no cytotoxicity. KRN7000(KRN) is the most potent alpha-Galactosyl Ceramide modified from the one isolated from Ocean sponge. KRN is also active against metastatic tumors through the activation ofanimal immune system. Research efforts in learning the mechanism of action, we found the important role of dendritic cells(DC) and NKT cells. NKT cells was first characterized in 1988 which is overlap some part with NK cells and T-Cells and majority is different from NK and T. KRN is active through the activation of DC and NKT in giving antigen specific immune stimulation in animal. This antigen specific stimulation is memorized by immune system and can reject second tumor challenge. KRN is not active in nude mice and NKT deficient animal. NKT cells level in blood is lower in patients with autoimmune disease, cancer, HIV positive or aplastic anemia. NKT rapidly releases IL-4 and IFN-gamma at high level when activated. NKT is CD1d and TCR restricted. NKT plays important role in autoimmune disease such as Type 1 Diabetes, Scleroderma and Systemic Lupus Erythematosus, infections such as Mycobacteria, Listeria and Malaria, GVHD control and tumor rejection. NKT acts as double edge sword, aggressive and suppressive ways. KRN can prevent the onset of Type 1 Diabetes, inhibit replication of hepatitis virus B in liver and suppress malaria replication in activating NKT cells. KRN can activate NKT through DC and activated NKT activates NK, T and macrophage. KRN also expands NKT cells and expanded NKT has full function. Although the exact role of DC and NKT is not clear, KRN clinical study results in conjunction with DC and NKT cell activation are expected.
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PMID:Role of NKT cells and alpha-galactosyl ceramide. 1243 Aug 64

Hepatitis-associated aplastic anemia (HAA) is a syndrome of bone marrow failure following an acute attack of seronegative hepatitis. Clinical features and liver histology suggest a central role for an immune-mediated mechanism. To characterize the immune response, we investigated the T-cell repertoire (T-cell receptor [TCR] V(beta) chain subfamily) of intrahepatic lymphocytes in HAA patients by TCR spectratyping. In 6 of 7 HAA liver samples, a broad skewing pattern in the 21 V(beta) subfamilies tested was observed. In total, 62% +/- 18% of HAA spectratypes showed a skewed pattern, similar to 68% +/- 18% skewed spectratype patterns in 3 of 4 patients with confirmed viral hepatitis. Additionally, the T-cell repertoire had similarly low levels of complexity. In the peripheral blood lymphocytes (PBLs) of a separate group of HAA patients prior to treatment, 60% +/- 15% skewed spectratypes were detected, compared with only 18% +/- 8% skewed spectratypes in healthy controls. After successful immunosuppressive treatment, an apparent reversion to a normal T-cell repertoire with a corresponding significant increase in T-cell repertoire complexity was observed in the HAA samples. In conclusion, our data suggest an antigen-driven T-cell expansion in HAA and achievement of a normal T-cell repertoire during recovery from HAA.
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PMID:Analysis of T-cell repertoire in hepatitis-associated aplastic anemia. 1498 56

gammadelta T cells mediate demyelination in athymic (nude) mice infected with the neurotropic coronavirus mouse hepatitis virus strain JHM. Now, we show that these cells also mediate the same process in mice lacking alphabeta T cells (T-cell receptor beta-deficient [TCRbeta(-/-)] mice) and demyelination is gamma interferon (IFN-gamma) dependent. Most strikingly, our results also show a major role for NKG2D, expressed on gammadelta T cells, in the demyelinating process with in vivo blockade of NKG2D interactions resulting in a 60% reduction in demyelination. NKG2D may serve as a primary recognition receptor or as a costimulatory molecule. We show that NKG2D(+) gammadelta T cells in the JHM-infected central nervous system express the adaptor molecule DAP12 and an NKG2D isoform (NKG2D short), both required for NKG2D to serve as a primary receptor. These results are consistent with models in which gammadelta T cells mediate demyelination using the same effector cytokine, IFN-gamma, as CD8 T cells and do so without a requirement for signaling through the TCR.
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PMID:Important roles for gamma interferon and NKG2D in gammadelta T-cell-induced demyelination in T-cell receptor beta-deficient mice infected with a coronavirus. 1601 2

The 77C-->G mutation in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of 77C-->G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, and HIV-1. To investigate the mechanisms by which the variant allele may contribute to disease susceptibility, we compared T cell reactivity in heterozygous carriers of the mutation (healthy individuals and multiple sclerosis patients) and wild-type controls. In vitro-generated T cell lines and freshly isolated CD4+CD45R0+ primed/memory T cells from 77C-->G individuals aberrantly expressed CD45RA isoforms and showed enhanced proliferation and IL-2 production when stimulated with anti-TCR/CD3 mAb or Ag. Mutant T cell lines contained a more active pool of p56lck tyrosine kinase and responded with increased phosphorylation of Zap70 and TCR-zeta and an enhanced Ca2+ flux to TCR/CD3 stimulation. These data suggest that 77C-->G may act as a risk factor for certain diseases by increasing the intensity of TCR signaling.
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PMID:The 77C->G mutation in the human CD45 (PTPRC) gene leads to increased intensity of TCR signaling in T cell lines from healthy individuals and patients with multiple sclerosis. 1639 78

NKT cells are a subset of regulatory lymphocytes characterized by co-expression of the NK cell receptor-CD161 and an invariant TCR-alpha chain (Valpha14-Jalpha28). They are most abundant in the liver, spleen, and bone marrow. NKT lymphocytes have been implicated in the regulation of autoimmune processes in both mice and humans. Activation of NKT lymphocytes leads to rapid amplification of either IFNgamma or IL4, endowing these cells with the capability to mediate both pro-inflammatory and anti-inflammatory immune responses. Activation of this subset of cells is associated with significant liver damage in the Concanavalin A immune mediated hepatitis model. Administration of CD1d ligand has a protective role in collagen-induced arthritis in mice. Disease amelioration was associated with a shift in the immune balance from a pathological Th1 type response towards a protective Th2 type response. In humans, patients with SLE, scleroderma, diabetes, multiple sclerosis, and rheumatoid arthritis have lower numbers of peripheral NKT cells. NKT lymphocytes promote tumor rejection in experimental models of tumor immunotherapy. In contrast, NKT lymphocyte-related anti-tumor activity is associated with pro-inflammatory Th1-type immune responses. NKT cells were shown to have a role in suppression of hepatocellular carcinoma (HCC) via immune regulation towards tumor derived antigens, and adoptive transfer of dendritic cells pulsed ex vivo with the same antigens. NKT lymphocytes are activated by interaction of their TCR with glycolipids presented by CD1d, a nonpolymorphic, MHC class I-like molecule expressed by antigen presenting cells, and also by hepatocytes. Several possible ligands for NKT cells have recently been suggested including CD1d bound Glucocerebroside. Glucocerebroside (GC, beta-glucosylceramide), a naturally occurring glycolipid, is a metabolic intermediate in the anabolic and catabolic pathways of complex glycosphingolipids. Its synthesis from ceramide is catalyzed by the enzyme glucosylceramide synthase. Inherited deficiency of glucocerebrosidase, a lysosomal hydrolase, results in Gaucher's disease. Patients with Gaucher's disease have altered humoral and cellular immune profiles and increased peripheral blood NKT lymphocytes. CD1d-bound glucocerebroside does not activate NKT cells directly, and may inhibit activation of NKT cells by alpha-GalCer. On the other hand, glucosylceramide-synthase deficiency was shown to lead to defective ligand presentation by CD1d, with secondary inhibition of NKT cell activation. Recent studies have suggested that a number of glycolipids, including GC, have an immune modulatory effect in several immune mediated disorders. The ability to alter NKT lymphocyte function in various settings and the potential application of natural glycolipids for treatment are discussed.
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PMID:Glycolipids as immune modulatory tools. 1710 Jun 36

CD137-mediated signals costimulate T cells and protect them from activation-induced apoptosis; they induce curative antitumor immunity and enhance antiviral immune responses in mice. In contrast, anti-CD137 agonistic mAbs can suppress T-dependent humoral immunity and reverse the course of established autoimmune disease. These results have provided a rationale for assessing the therapeutic potential of CD137 ligands in human clinical trials. In this study, we report that a single 200-mug injection of anti-CD137 given to otherwise naive BALB/c or C57BL/6 mice led to the development of a series of immunological anomalies. These included splenomegaly, lymphadenopathy, hepatomegaly, multifocal hepatitis, anemia, altered trafficking of B cells and CD8 T cells, loss of NK cells, and a 10-fold increase in bone marrow (BM) cells bearing the phenotype of hemopoietic stem cells. These events were dependent on CD8 T cells, TNF-alpha, IFN-gamma, and type I IFNs. BM cells up-regulated Fas, and there was a significant increase in the number of CD8+ T cells that correlated with a loss of CD19+ and Ab-secreting cells in the BM. TCR Valphabeta usage was random and polyclonal among liver-infiltrating CD8 T cells, and multifocal CD8+ T cell infiltrates were resolved upon termination of anti-CD137 treatment. Anti-CD137-treated mice developed lymphopenia, thrombocytopenia, and anemia, and had lowered levels of hemoglobin and increased numbers of reticulocytes.
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PMID:Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice. 1737 76


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