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)

The lymphocyte-predominant (LP) type of Hodgkin's lymphoma (HL) is a unique subtype with characteristic tumor cells (lymphocytic and/or histiocytic [L&H] cells) in associated macronodular structures that resemble progressively transformed germinal centers (PTGCs). Immunohistochemical studies have provided strong evidence that L&H cells are of B-cell lineage and recent molecular studies suggested they are transformed centroblasts. A major clonal population is detectable at presentation, with the immunoglobulin heavy-chain gene often showing evidence of continued somatic hypermutation. In developed nations, Epstein-Barr virus (EBV) is infrequently associated with L&H cells and is probably not involved in the pathogenesis of this disease. L&H cells are frequently surrounded by CD3+, CD4+, CD57+, and CD40L- T cells, but the significance of this T-cell rosetting is unclear. LPHL may be associated with concurrent or subsequent large B-cell lymphoma, and there is evidence of a clonal relationship between the two entities. LPHL may also have nodules or large areas that resemble histiocyte-rich B-cell lymphoma (HRBCL). It is likely that at least some cases of HRBCL arise from LPHL. The same may be true of T-cell-rich B-cell lymphoma. Little is known about cytogenetic abnormalities, the cytokine expression profile, and the expression of several functionally important molecules that have been demonstrated in the Reed-Sternberg (RS) cells of classical HL. The challenge for the future is to obtain a more comprehensive molecular profile of L&H cells and their associated T lymphocytes, so as to provide a framework for eventual elucidation of the pathogenesis of this type of HL.
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PMID:Cellular origin of nodular lymphocyte-predominant Hodgkin's lymphoma: immunophenotypic and molecular studies. 1046 24

The expression of CD40L was investigated in HD involved lymph nodes by flow cytometry (FCM) and reverse transcriptase polymerase chain reaction (RT-PCR). Also an investigation of the role of CD40L in upregulation of the anti-apoptotic gene BclxL in a Hodgkin's disease (HD) derived cell line was undertaken. HD patients (n = 18) had significantly higher numbers of activated CD4+ and CD8+ T cells in the tumor microenvironment as compared to controls (n = 8). HD patients also demonstrated higher numbers of CD4+, CD8+ and CD19+ lymphocytes co-expressing CD40L as compared to controls. The CD40L signal was consistently and significantly upregulated in HD patients (n = 5) as compared to controls (n = 3) at the mRNA level. RT-PCR and FCM analysis revealed that soluble CD40L upregulated BclxL levels in the Fas-sensitive HD cell line HDLM2. We conclude that CD40L can act as an important anti-apoptotic molecule by upregulating BclxL expression in Reed-Sternberg cells of HD and may be partly responsible for their survival 'in-vivo'.
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PMID:CD40 Ligand--an anti-apoptotic molecule in Hodgkin's disease. 1127 1

In cultures, and in tissues as well, Hodgkin's and Reed-Sternberg (H-RS) cells and anaplastic large cell lymphoma (ALCL) cells are known to express a variety of cytokines, including IL-1, -5, -6, -8, -9, TNF-alpha, GM-CSF, M-CSF, TGF-beta, CD70, CD80, and CD86. Various numbers of H-RS/ALCL cells may express cytokine receptors (R), such as CD30, CD40, IL-2R (CD25/CD122), IL-6R (CD126), IL-7R (CD127), TNF-R (CD120), TGF-beta-R (CD 105/endoglin), M-CSF-R (CD115), and SCF-R (CD117/c-kit receptor). All of these cytokines and cytokine receptors are implicated in the growth regulation of H-RS/ALCL cells, the histopathologic alterations in tissues, and the clinical manifestations in patients with Hodgkin's disease (HD) or ALCL. Many of these cytokines or cytokine receptors also play an important role in the pathogenesis of other types of lymphomas. In this review, we describe the cytokine or cytokine-receptor expression that is diacritic for H-RS/ALCL cells. The identification of such unique cytokine-cytokine receptor interactions is likely to explain the biologic property that distinguishes HD/ALCL from other types of lymphomas. These interactions include those of CD30L-CD30, CD40L-CD40, CD70-CD27, CD80/CD86- CD28, SCF-CD117, IL-9-IL-9R, and IL-7-IL-7R. The H-RS/ALCL cells express IL-9 and two cytokine receptors, CD30 and CD117, which are observed infrequently in NHLs. Although IL-7 expression is not restricted to H-RS/ALCL cells, the expression of IL-7 in conjunction with IL-9 and/or CD117 may be regarded as unique for HD/ALCL because of an unusual combination and a synergistic activity among these cytokines. The expression of CD70 and CD80/CD86 (as cytokines) may exert a unique effect in HD because of intimate contact between H-RS cells and CD27/CD28-positive T cells. The expression of these costimulators (CD70 and CD80/CD86) and other adhesion/constimulator molecules such as CD54 and CD58, along with the secretion of soluble cytokines such as IL-1, IL-6, IL-7, or TNFs by H-RS/ALCL cells, could result in the profound T-cell proliferation often seen in lymph nodes involved by HD and some ALCL. On the other hand, the expression of CD30L and CD40L by surrounding T cells may affect the proliferation of H-RS/ALCL cells. The cytokine-cytokine receptor interaction between H-RS cells and T cells via direct cell-cell contact is bidirectional, a situation not commonly seen in NHLs. Copyright 1995 S. Karger AG, Basel
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PMID:Hodgkin's Disease and Anaplastic Large Cell Lymphoma Revisited. 1. unique cytokine and cytokine receptor profile distinguished from that of non-hodgkin's lymphomas. 1172 67

B cell lineage non-Hodgkin's lymphomas (NHL-B) are neoplastic B cells that show dysregulated B lymphocyte growth characteristics. Unlike normal B cells, aggressive NHL-B cells show constitutive expression of nuclear NF-kappaB by maintaining an assembled, scaffold-like signaling platform, called a Signalosome within the lipid raft microdomain, extending from the cell membrane. The CD40 Signalosome appears to be initiated through autochthonous production and cognate binding of CD154 (CD40L, gp39) to CD40 by the lymphoma cell. Constitutive expression of NF-kappaB in NHL-B can be downregulated by treatment with antibodies to CD40 or CD154 that disrupt Signalosomes, inhibit lymphoma cell growth, and induce cell death. CD40 Signalosomes may provide a potentially vulnerable target for therapeutic intervention in NHL-B cells.
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PMID:A CD40 Signalosome anchored in lipid rafts leads to constitutive activation of NF-kappaB and autonomous cell growth in B cell lymphomas. 1182 64

Little is known about the distribution in normal cells of CLIP-170, a linkage mediator between endocytic vesicles and microtubules, and restin, a splice variant encoded by the same gene and marker for Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin disease. Although only trace amounts of CLIP-170/restin are present in peripheral blood mononuclear cell subpopulations, monocyte-derived dendritic cells (DCs) and interleukin-4 (IL-4) + CD40L-activated B cells express high levels of CLIP-170/restin. CLIP-170/restin colocalizes preferentially with membranes of intermediate macropinocytic vesicles, suggesting a new function of CLIP-170/restin in the trafficking of macropinosomes to the cytoskeleton, which is a crucial step in antigen presentation. The strong expression of CLIP-170/restin in HRS cells, DCs, and activated B cells underscores their functional similarities supporting a function-based concept of HRS cells as professional antigen-presenting cells.
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PMID:Hodgkin and Reed-Sternberg cell-associated autoantigen CLIP-170/restin is a marker for dendritic cells and is involved in the trafficking of macropinosomes to the cytoskeleton, supporting a function-based concept of Hodgkin and Reed-Sternberg cells. 1243 98

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

The CD40L expressed on activated CD4+ T cells delivers contact-dependent proliferative and anti-apoptotic signals to B lymphocytes. Little is known about molecular mechanisms of constitutive expression of CD40L on some non-Hodgkin's lymphomas, especially about involvement of two signal pathways regulating its expression in normal cells; one involving calcineurin, and the other protein kinase C. We analyzed by flow cytometry the effects of 6-hour stimulation of both pathways (stimuli: PMA and ionomycin) and their inhibitors: cyclosporin A and chelerythrine, on CD40L expression. Two Jurkat clones differing in CD40L surface expression: clone 217.6 (CD40L-) and 217.7 (CD40L+) were studied. Our experiments showed that high level of CD40L expression on the surface of 217.7 cells was reduced after stimulation with PMA. The same effect was observed for combination of PMA and chelerythrine or for PKC inhibitor alone. In 217.6 cells, only chelerythrine used alone induced low level of CD40L expression, while PMA and ionomycin were without effect. These results suggest that CD40L surface expression is mainly dependent on protein kinase C activity. By using PepTag Assay we have confirmed that in both Jurkat clones PKC activity is higher than in normal blood lymphocytes.
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PMID:Modulation of CD40L antigen expression in Jurkat cells: involvement of protein kinase C activity. 1467 64

Mantle cell lymphoma (MCL) is a CD5+ non-Hodgkin's B-cell lymphoma characterized by the infiltration of intermediate sized B-cells into the mantle zones. Interaction between CD40L and CD40 is important for B cell proliferation and differentiation. CD40L stimulation can induce both growth arrest and proliferation of B cell lines according to their differentiation state. Previous reports examining the effect of stimulation via the CD40 cascade on ex vivo MCL cells have provided conflicting results. In this study, two MCL lines, SP49 and SP53, were examined for response to CD40L and/or IL-10. Co-cultivation with CD40L-expressing mouse L cells reduced the BrdU incorporation of SP49 and SP53 cells by half to one-third, while BrdU incorporation of control cell lines, including Ramos, BJAB and BALL-1, was not affected or increased. Anti-CD40L antibody blocked the CD40L inhibition of SP49 cell proliferation in a dose-dependent manner in the range from 0 to 20 ng/ml. IL-10 did not affect MCL cell proliferation in the presence or absence of CD40L-expressing cells, while Ramos proliferation was promoted by CD40L and IL-10. These results suggested the possibility that CD40L may also inhibit MCL proliferation in vivo.
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PMID:CD40 ligand stimulation inhibits the proliferation of mantle cell lymphoma lines. 1516 Oct 13

Classic Hodgkin's Disease (cHD) is a lymphoid neoplasia characterized by a few malignant Hodgkin and Reed-Sternberg (H-RS) cells embedded in an abundant background of non-tumor cells. In this context, fibrosis is a common morphologic feature of HD lesions, being found more frequently in cHD subtypes. The clinical and histopathologic features of cHD are thought to be largely due to the effects of a wide variety of cytokines and chemokines primarily produced by H-RS cells, as well as by the surrounding reactive component. In the present review, first we propose three mechanisms putatively explaining fibroblast activation and fibrosis in HD: (1) unbalanced production of the pro-fibrogenic Th2 over Th1 cytokines; (2) production of TGF-beta, b-FGF and IL-13 by H-RS cells; (3) activation of fibroblasts by CD40L-expressing cells of the HD microenvironment. Second, we suggest some molecular pathways involving cytokines produced by HD-derived fibroblasts (SCF, IL-7, IL-6) supposedly responsible for H-RS proliferation and rescue from apoptosis. Finally, we describe the role of specific molecules produced by H-RS cells in the regulation of HD-derived fibroblast production of chemokines, in turn involved in T-lymphocytes and recruitment of eosinophils.
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PMID:Interactions between tissue fibroblasts in lymph nodes and Hodgkin/Reed-Sternberg cells. 1522 30

Abnormalities in B-lymphocyte CD40 ligand (CD154) expression have been described for a number of immunologic diseases, including B-cell lymphomas. Although functional analysis of the CD154 gene and protein has been extensive, little is known about the mechanisms controlling CD154 expression in activated T cells, and even less is known for normal and malignant B cells. In this study we describe the transcriptional mechanism controlling CD154 expression in large B-cell lymphoma (LBCL). We show that the nuclear factor of activated T cells (NFAT) transcription factor is also constitutively activated in LBCL. We demonstrate that the constitutively active NFATc1 and c-rel members of the NFAT and nuclear factor-kappaB (NF-kappaB) families of transcription factors, respectively, directly interact with each other, bind to the CD154 promoter, and synergistically activate CD154 gene transcription. Down-regulation of NFATc1 or c-rel with small interfering RNA (siRNA) or chemical inhibitors inhibits CD154 gene transcription and lymphoma cell growth. These findings suggest that targeting NF-kappaB and NFAT, by inhibiting the expression of these transcription factors, or interdicting their interaction may provide a therapeutic rationale for patients with non-Hodgkin lymphoma of B-cell origin, and possibly other disorders that display dysregulated CD154 expression.
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PMID:Constitutive NF-kappaB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival. 1609 73


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