Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hodgkin's disease (HD) is a malignant lymphoproliferative disease characterized by the presence of Hodgkin-Reed-Sternberg cells surrounded by a reactive infiltrate. In Epstein-Barr virus (EBV)-associated cases (40-60%), at least two EBV-encoded proteins [latent membrane protein 1 (LMP1) and LMP2] are expressed, which are potential targets for cytotoxic T-lymphocytes (CTLs). Although in EBV-positive cases significantly more activated (granzyme B-positive) CTLs and natural killer (NK) cells are present, the cytotoxic immune response is not sufficient for adequate killing of tumour cells. The production of immunomodulating cytokines within the tumour may be one of the mechanisms causing circumvention of the immune system. This study investigated by immunohistochemistry the presence of the immunosuppressive cytokine interleukin-10 (IL-10) and other Th1/Th2-associated cytokines [IL-2, IL-4, interferon-gamma (IFN-gamma)] in the neoplastic cells and reactive lymphocytes of nine EBV-positive and 18 EBV-negative cases of HD. The percentage of IL-10-expressing cells, both neoplastic and reactive, in EBV-positive cases was significantly higher (33.1% vs. 18.5% for the neoplastic cells and 21.6% and 12.2% for the reactive cells, p=0.003 and 0.04, respectively) than in EBV-negative cases. No difference in the percentage of IL-2-, IL-4- and IFN-gamma-expressing cells was observed. These results suggest that escape from local immune surveillance is not due to a shift from Th1 towards Th2, but may be caused by a direct effect of IL-10 on the cytotoxic cells.
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PMID:Quantitative immunohistochemical analysis of cytokine profiles in Epstein-Barr virus-positive and -negative cases of Hodgkin's disease. 1065 11

CD30 is a member of the TNF receptor superfamily, previously shown to be expressed on Hodgkin's lymphoma cells and on normal activated lymphocytes. We here show that CD30 is highly expressed on recently activated human gamma delta T cells. Elevated surface levels of this molecule persisted in long-term cultures of gamma delta cells, without further cell stimulation. CD30 acted as a co-stimulus in gamma delta T cells by potentiating the intracellular Ca(2+) fluxes induced by CD3 cross-linking. The engagement of CD30 enhanced the expression of several cytokines induced upon CD3 stimulation such as IL-4 and IFN-gamma but not IL-10. The CC chemokines RANTES and macrophage inflammatory protein-1beta were constitutively expressed and not affected by stimulation. The inducible expression of the neutrophil chemoattractant IL-8 was enhanced by CD30 co-stimulation, as well as that of the CC chemokines I-309 and MDC, whereas the secretion of the monocyte chemotactic protein-1 was not detected. Triggering of CD30 may therefore modulate the expression of several cytokines released by gamma delta cells; the expression of its physiologic ligand by APC and neutrophils at the site of infection may contribute to determine the outcome of an immune response.
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PMID:Engagement of CD30 shapes the secretion of cytokines by human gamma delta T cells. 1094 Sep 8

The tumor necrosis factor receptor family molecule CD30 is expressed by activated and memory T cells, depending on IL-4 stimulation preferentially in association with Th0- and Th2-type responses. It mediates pleiotropic effects primarily of the inhibitory type. Arguing that CD30(+) cells have a peculiar redistribution in disease, it is demonstrated here, in the Hodgkin-derived L540 cell line (an established model for studying CD30 signaling), that CD30 regulates the prototypic lymphoid chemokine receptor CXCR4 (CD184), which plays an important role in many organ systems and is a coreceptor for human immunodeficiency virus-1 entry. CD30 stimulation with agonistic antibodies in L540 cells led to the accumulation of CXCR4 mRNA, which reached a plateau after 4 hours and did not require protein synthesis. It has been reported recently that CD30 up-regulates the transcription of CCR7 mRNA in YT lymphoma cells. After mRNA transcription, membrane expression of CXCR4 in L540 cells increased as early as 12 hours, reached a plateau after 24 hours (MFI +/- SD, 839 +/- 122 vs basal 168 +/- 28; P <.01) and was still increased after 5 days, permitting enhanced sensitivity to the chemotactic activity of CXCR4-ligand CXCL12 (CI +/- SD, 10 +/- 1 vs basal 5 +/- 2; P <.01). CD30 cross-linking also induced the release of CCL5 and CCL3 and the up-regulation of membrane binding capacity for CCL3 and CCL4 and decreased proliferative activity. This new regulatory role of CD30 may be relevant for T-cell maturation and effector responses and for promoting cancer biology.
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PMID:CD30 triggering by agonistic antibodies regulates CXCR4 expression and CXCL12 chemotactic activity in the cell line L540. 1175 52

BCL-6 is an important regulator of the immune system. It is required for GC formation and T cell dependent antibody responses. Mice deficient in BCL-6 fail to form GC and mount reduced levels of T cell-dependent antibody responses. BCL-6 (-/-) mice, in addition, develop a massive inflammatory response in many organs characterized by eosinophilic infiltration and hyper-IgE production, a typical Th2 hyperimmune response. This suggests a negative role of BCL-6 in Th2 pathway. The BCL-6 gene encodes a POZ/zinc finger transcription repressor highly expressed in GC B cells, but not in pre-GC B cells or in more differentiated memory or plasma cells. By functioning as a potent transcriptional repressor of various target genes, BCL-6 modulates IL-4, BCR, and CD40L signals for normal B cell development. In B cell lymphomas, structural alterations of the BCL-6 promoter region, including chromosome translocation and somatic hypermutation, represent the most frequent genetic lesions associated with non-Hodgkin lymphoma, especially of diffuse large cell lymphoma, a malignancy often derived from germinal centre (GC) B cells. This suggests that deregulated expression of BCL-6 may contribute to lymphomagenesis.
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PMID:The proto-oncogene BCL-6 in normal and malignant B cell development. 1246 25

Activation-induced cytidine deaminase (AID) induces somatic hypermutation (SHM), class switch recombination (CSR), and immunoglobulin gene conversion in B-lymphocytes. Here we report for the first time the expression of AID in healthy human B-lymphocytes and in B-cell non-Hodgkin lymphomas (B-NHL). AID mRNA expression in humans is restricted to the CD19(+)CD38(+)IgD(-) germinal center cells, namely the CD19(+)CD38(+)CD44(-) centroblasts. After in vitro stimulation of naive human B cells by CD40-L and IL-4, AID mRNA is strongly induced for only 48 hours. In a survey of human B-NHL AID was found to be constitutively expressed in follicular lymphoma and in diffuse large B-cell lymphoma but to be absent in B-precursor lymphoblastic leukemia, in mantle cell lymphoma, and in plasma cell myeloma. In B-cell chronic lymphatic leukemia, in immunocytoma, and in extranodal marginal zone B-cell lymphoma of MALT, AID mRNA was expressed only in some samples. In follicular lymphoma and diffuse large B-cell lymphoma, the expression of AID mRNA was coincident with the presence of SHM in the variable region exons of the immunoglobulin heavy-chain gene. In human B-NHL, the AID mRNA is spliced into 4 different variants but does not contain point mutations. Thus AID, which is highly regulated during healthy B-cell development, is constitutively expressed in human germinal center B-NHL and in subsets of nongerminal center B-NHL. This constitutive expression of AID may promote illegitimate DNA recombinations and somatic mutations in B-NHL.
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PMID:Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas. 1251 17

IL-13 was first recognized for its effects on B cells and monocytes, where it upregulated class II expression, promoted IgE class switching and inhibited inflammatory cytokine production. It was also thought to be functionally redundant with IL-4. However, studies conducted with knockout mice, neutralizing antibodies, and novel antagonists demonstrate that IL-13 possesses several unique effector functions that distinguish it from IL-4. Resistance to most gastrointestinal nematodes is mediated by type-2 cytokine responses, in which IL-13 plays a dominant role. By regulating cell-mediated immunity, IL-13 modulates resistance to intracellular organisms including Leishmania major, Leishmania mexicana, and Listeria monocytogenes. In the lung, IL-13 is the central mediator of allergic asthma, where it regulates eosinophilic inflammation, mucus secretion, and airway hyperresponsiveness. Manipulation of IL-13 effector function may also prove useful in the treatment of some cancers like B-cell chronic lymphocytic leukemia and Hodgkin's disease, where IL-13 modulates apoptosis or tumor cell growth. IL-13 can also inhibit tumor immunosurveillance. As such, inhibitors of IL-13 might be effective as cancer immunotherapeutics by boosting type-1-associated anti-tumor defenses. Finally, IL-13 was revealed as a potent mediator of tissue fibrosis in both schistosomiasis and asthma, which indicates that it is a key regulator of the extracellular matrix. The mechanisms that regulate IL-13 production and/or function have also been investigated, and IL-4, IL-12, IL-18, IFN-gamma, IL-10, TGF-beta, TNF-alpha, and the IL-4/IL-13 receptor complex play important roles. This review highlights the effector functions of IL-13 and describes multiple pathways for modulating its activity in vivo.
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PMID:IL-13 effector functions. 1261 88

Primary mediastinal large B-cell lymphoma (PMBL), currently recognized as a diffuse large B-cell lymphoma (DLBCL) subtype, shows increased expression of interleukin 4 (IL-4)/IL-13 signaling effectors and targets, suggesting constitutive activation of these pathways. We therefore investigated the functional state of the signal transducer and activator of transcription 6 (STAT6), mediating IL-4/IL-13 transcriptional effects. Constitutive STAT6 phosphorylation and DNA-binding activity were detected in PMBL cell lines but not DLBCL cell lines. Moreover, immunohistochemical analysis revealed nuclear phosphorylated STAT6 (P-STAT6) in 8 of 11 PMBL, compared with 1 of 10 DLBCL primary tumors (P =.01). IL-4 and IL-13 transcripts were absent in PMBL cell lines and expressed at low levels in tumors, indicating that, contrary to classical Hodgkin lymphoma (cHL), STAT6 activation is not due to an autocrine IL-4/IL-13 secretion. We demonstrated an amplification of the JAK2 gene in 2 of 6 PMBL cases, and showed higher JAK2 mRNA levels in PMBL compared with DLBCL (P =.005). The Janus kinase 2 (JAK2) was constitutively phosphorylated in the PMBL MedB1 cell line. MedB1 treatment with JAK2 inhibitor AG490 partially decreased STAT6 phosphorylation, suggesting that JAK2 is partially involved in STAT6 activation in these cells. Our findings highlight phosphorylated STAT6 as a characteristic distinguishing PMBL from DLBCL, but a common feature to PMBL and cHL, supporting the hypothesis of common pathogenic events in these 2 lymphomas.
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PMID:Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma. 1504 51

In about 50% of classical Hodgkin lymphomas, the Hodgkin/Reed Sternberg (H/RS) cells carry Epstein-Barr virus (EBV). The viral gene expression in these cells is restricted to EBNA-1, EBERs, LMP-1 and LMP-2 (type II latency). The origin of H/RS cells was defined as crippled germinal center B cells that escaped apoptosis. In spite of numerous attempts, only few typical Hodgkin lymphoma (HL) lines have been established. This suggests that the cells require survival factors that they receive in the in vivo microenvironment. If EBV is expected to drive the cells for growth in culture, the absence of EBNA-2 may explain the incapacity of H/RS cells for in vitro proliferation. In EBV carrying B lymphocytes, functional EBNA-2 and LMP-1 proteins are required for in vitro growth. For analysis of the interaction between EBV and the H/RS cells, we infected the CD21-positive HL line KMH2 with the B958 and Akata viral strains. Only EBNA-1 expression was detected in a few cells in spite of the fact that all cells could be infected. Using a neomycin-resistance-tagged recombinant EBV strain (Akata-Neo) we established an EBV-positive subline that was carried on selective medium. In contrast to the type II EBV expression pattern of H/RS cells in vivo, the KMH2 EBV cells did not express LMP-1. The EBV expression pattern could be modified in this type I subline. LMP-1 could be induced by the histone deacetylase inhibitors TSA and n-butyrate, by 5-AzaC, a demethylating agent, and by phorbol ester. None of these treatments induced EBNA-2. Importantly, exposure to CD40 ligand and IL-4 induced LMP-1 without EBNA-2 expression and lytic replication. The KMH2 EBV cells expressed LMP-2A, but not LMP-2B mRNAs. This result is highly relevant for the type II expression pattern of H/RS cells in vivo, since these stimuli can be provided by the surrounding activated T lymphocytes.
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PMID:In vitro EBV-infected subline of KMH2, derived from Hodgkin lymphoma, expresses only EBNA-1, while CD40 ligand and IL-4 induce LMP-1 but not EBNA-2. 1551 68

Hodgkin lymphoma represents unique clinicopathologic features because Hodgkin and Reed-Sternberg (H-RS) cells produce a variety of cytokines, express a variety of cytokine receptors, and are surrounded by numerous nonmalignant immunoreactive cells. We found that receptors for interleukin-4 (IL-4R) are highly expressed in H-RS cells. To target interleukin-4 receptor (IL-4R), we used a recombinant protein fusing circularly permuted human IL-4 and Pseudomonas exotoxin termed IL4(38-37)-PE38KDEL, or IL-4 cytotoxin. The cytotoxic effect of IL-4 cytotoxin on H-RS cell lines was determined to be moderate to high in vitro. We developed an infiltrating model of Hodgkin disease (HD) by injecting an adherent population of HD-MyZ cells subcutaneously into the flanks of beige/nude/X-linked immunodeficient mice. The animal model exhibited spontaneous metastasis of H-RS cells to lymph nodes and dissemination to vital organs, including the lungs. Intraperitoneal or intratumoral treatment of these mice with IL-4 cytotoxin resulted in regression of the primary tumor mass and a decrease in the incidence of lymph node metastasis. Mice injected with HD-MyZ cells demonstrated 203% prolonged survival (mean survival, 63 days) compared with control (mean survival, 31 days) when they received systemic IL-4 cytotoxin treatment. Because numerous H-RS cell lines express receptors for IL-4, IL-4 cytotoxin may be a unique agent for the treatment of Hodgkin lymphoma.
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PMID:Hodgkin lymphoma therapy with interleukin-4 receptor-directed cytotoxin in an infiltrating animal model. 1562 35

The complex interactions between cancer and host cells are far from being fully elucidated. Assessment of Th1/Th2/Th3/Tr1 balance is an interesting approach to explain immunological disturbances in lymphomas. The aim of our study was to assess mRNA for pro- and anti-inflammatory cytokines in T-cells in 20 children with Hodgkin- and non-Hodgkin lymphomas. CD4+ and CD8+ cells were isolated from whole peripheral blood and four different cytokine mRNA levels (IFN-gamma, IL-10, IL-4, TGF-beta) were determined by real-time PCR technique. Comparing to the control group, we found lower expression of mRNA for IFN-gamma in CD4+ cells at the time of lymphoma diagnosis. It may be one of the pathogenetic mechanisms of impaired immunity in these patients.
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PMID:Lower expression of mRNA for interferon-gamma in T helper cells of children with newly diagnosed lymphomas. 1620 18


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