Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CD30 antigen was originally described as a specific surface marker for Hodgkin's lymphoma. Recent work established CD30 as a member of the tumor necrosis factor/nerve growth factor receptor superfamily whose ligand (CD30L) has also been cloned and expressed; CD30L is active as membrane-bound type II glycoprotein. Here, CD30L mRNA expression was studied in a panel of 102 continuous human leukemia-lymphoma cell lines and was found only in four Burkitt lymphoma, one Burkit-type acute lymphoblastic leukemia and one non-Hodgkin's lymphoma (NHL) cell line. The product of CD30L mRNA is expressed as a membrane protein on the surface of these malignant B-cell lines. Treatment of these cell lines with soluble CD27L, phorbol ester or staphylococcus aureus Cowan antigen resulted in the enhancement of cell surface CD30L protein expression. CD30L mRNA was not detected in normal unstimulated peripheral blood (PB) monocytes, monocyte-derived macrophages, or T-cells, but was detected in primary granulocytes; exposure to activating reagents induced and upregulated CD30L transcription in these different PB populations. While CD40 and CD30L surface protein expression on PB monocytes could be enhanced or induced by treatment with gamma-interferon, these cells remained negative for CD30, both at the mRNA and at the protein level. Similarly, PB monocyte-derived macrophages and granulocytes remained negative for CD30 mRNA and protein expression, regardless of stimulation. Only activated T-cells expressed CD30 mRNA and surface protein. CD30L-transfected cells and cells constitutively expressing CD30L delivered a similar stimulus for proliferation of the CD30+ Hodgkin's disease (HD)-derived cell line HDLM-2, but inhibited proliferation of the CD30+ large cell anaplastic lymphoma cell line KARPAS-299. These data provide strong evidence for the involvement in growth regulation of recombinant and natural CD30L through its interaction with the CD30 receptor. Collectively, these data suggest that the CD30L-CD30 interaction has potent biological activity and might play a critical role in the immune response and pathogenesis of HD and some NHL, in particular Burkitt lymphomas.
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PMID:Expression and regulation of CD30 ligand and CD30 in human leukemia-lymphoma cell lines. 752 56

Members of the TNF receptor superfamily are type I membrane glycoproteins with limited homology (overall homologies: 25%-30%) in the extracellular domain containing variable numbers of cysteine-rich repeats. In contrast, the TNF ligand superfamily members (with the exception of LT-alpha) are type II membrane glycoproteins with limited homology to TNF (overall homologies: 20%) in the extracellular region. TNF and LT-alpha are trimeric proteins and are composed of beta-strands forming a beta-jellyroll, the homology of the beta-strand regions for the TNF ligand superfamily members suggests a similar trimeric or multimeric complex formation for the other members. A genetic linkage, as evidence for evolutionary relatedness, is also found by chromosomal cluster for CD30, CD120b, 4-1BB and OX40 to 1p36; CD27, CD120a and TNFR-RP to 12p13; TNF, LT-alpha and LT-beta to 6p21; CD27L and 4-1BBL to 19p13; CD95L and OX40L to 1q25. TNF, LT-alpha and LT-beta and their receptors (CD120a, CD120b, TNFR-RP) interact in a complex fashion. Other family members, however, show a one ligand/one receptor binding principle. Signals can also be transduced through at least some of the ligands. TNF superfamily ligands are involved in induction of cytokine secretion, upregulation of adhesion molecules, activation antigens and costimulatory proteins, all known to amplify stimulatory and regulatory signals that occur during immune responses. On the other hand, differences in the distribution, kinetics of induction and requirements for induction support the view of a defined role for each of the ligands for T-cell-mediated immune activities. The shedding of members of the TNF receptor superfamily could limit the signals mediated by the corresponding ligands, as a functional regulatory mechanism. Induction of cytotoxic cell death is another common functional feature of this cytokine family (TNF, LT-alpha, CD30L, CD95L and 4-1BBL). Further studies have to identify unique versus redundant biological and physiological functions for each of the TNF superfamily ligands. In addition to other cytokines primary H-RS cell frequently express at least TNF, LT-alpha, CD27L and CD30L, but not CD40L. Furthermore, H-RS cells express several TNF receptors, such as CD30, CD40, CD95, CD120a, CD120b and 4-1BB. The TNF-like ligands might support growth and activation of HD-associated tumor cells and/or interact with surrounding reactive bystander cells, particularly T-cells. The different interactions between H-RS cells and surrounding reactive bystander cells are part of the pathobiology of HD. Detailed functional analysis have to confirm the predicted biological activities of TNF, LT-alpha, CD27L, CD30L, CD40L, CD95L, 4-1BBL and gp34/OX40L for the H-RS cell/T-cell interactions with impact on tumor growth and pathogenesis of HD. TNF and LT-alpha/CD120a and CD120b, CD30/CD30L, and CD40/CD40L are clearly critical elements in the deregulated network of interactive signals between H-RS cells and surrounding bystander cells with membrane-associated and cytokine-mediated events. Several TNFR superfamily members are also candidates for novel treatment protocols, including CD30 and CD40.
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PMID:Structural and biological features of the TNF receptor and TNF ligand superfamilies: interactive signals in the pathobiology of Hodgkin's disease. 883 4

The tumor necrosis factor receptor superfamily at present consists of ten different transmembrane (type I) glycoproteins with characteristic limited sequence homology for the cysteine-rich repeats in the extracellular domain. In parallel the tumor necrosis factor ligand super-family has been recognized by discovery of ligands for all members of the receptor superfamily. These molecules are also transmembrane (type II) glycoproteins, with the exception of lymphotoxin-alpha which is the only entirely secreted protein of the tumor necrosis factor-like proteins. Several members of the ligand superfamily, including tumor necrosis factor and CD95L also exist in a biologically active soluble form. The tumor necrosis factor ligand superfamily contains at present ten different proteins. In addition, NGFR p75 binds to a second family of proteins (neurotrophins). These nerve growth factor-like dimeric soluble molecules are basic neurotrophic factors and the five members (NGF, BDNF, NT-3, NT-4, NT-5) are not related to the tumor necrosis factor superfamily ligands. The members of the tumor necrosis factor ligand superfamily (TNF, LT-alpha, LT-beta, CD27L, CD30L, CD40L, CD95L, 4-IBB, OX40L, TRAIL) share common biological activities, but some properties are shared by only some ligands, while others are unique. The diverse biological activities triggered through tumor necrosis factor receptors have been linked to the regulation of cellular activation, including immune responses and inflammatory reactions, but also with the pathology of a series of human diseases.
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PMID:Molecular, structural, and biological characteristics of the tumor necrosis factor ligand superfamily. 890 47

CD27 is a member of the tumor necrosis factor receptor superfamily that is expressed primarily on T cells, as well as on subsets of B cells and NK cells. CD70, which is expressed on activated B and T cells, but not on resting lymphocytes, is a ligand for CD27. Cell surface CD27 can be proteolytically cleaved to produce a 32-kDa soluble CD27 (sCD27) molecule. Elevated levels of sCD27 are seen in a number of disease states and malignancies. Although it has been reported that cerebrospinal fluid sCD27 levels were elevated in people who had AIDS dementia, little is known about CD27 expression in HIV disease. To determine if sCD27 levels were elevated in those with HIV infection, and/or in those with AIDS-associated non-Hodgkin's lymphoma (AIDS-NHL), sCD27 levels were measured in HIV-negative and HIV-positive subjects as well as in people who developed AIDS-NHL. Serum sCD27 levels were seen to be elevated in HIV+ subjects. Furthermore, sCD27 levels were particularly elevated in those subjects who went on to develop AIDS-NHL, with serum sCD27 levels in AIDS-NHL subjects being significantly higher than those in HIV+ subjects who did not develop lymphoma. Most AIDS-NHL cell lines and primary AIDS-NHL tumor specimens expressed both CD27 and its ligand, CD70. The proportion of circulating B cells that expressed cell surface CD27 was substantially reduced in those with HIV infection, and B cells from HIV-infected subjects produced decreased levels of sCD27 in culture. Together, these results indicate that CD27/sCD27 expression is abnormal in HIV infection and suggest that this molecule merits further examination as a potential marker for AIDS-NHL.
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PMID:Aberrant expression of CD27 and soluble CD27 (sCD27) in HIV infection and in AIDS-associated lymphoma. 1052 87

Natural killer cells mediate spontaneously secretory/necrotic killing against rare leukemia cell lines and a nonsecretory/apoptotic killing against a large variety of tumor cell lines. The molecules involved in nonsecretory/apoptotic killing are largely undefined. In the present study, freshly isolated, nonactivated, human NK cells were shown to express TNF, lymphotoxin (LT)-alpha, LT-beta, Fas ligand (L), CD27L, CD30L, OX40L, 4-1BBL, and TNF-related apoptosis-inducing ligand (TRAIL), but not CD40L or nerve growth factor. Complementary receptors were demonstrated to be expressed on the cell surface of solid tumor cell lines susceptible to apoptotic killing mediated by NK cells. Individually applied, antagonists of TNF, LT-alpha1beta2, or FasL fully inhibited NK cell-mediated apoptotic killing of tumor cells. On the other hand, recombinant TNF, LT-alpha1beta2, or FasL applied individually or as pairs were not cytotoxic. In contrast, a mixture of the three ligands mediated significant apoptosis in tumor cells. These findings demonstrate that human NK cells constitutively express several of the TNF family ligands and induce apoptosis in tumor cells by simultaneous engagement of at least three of these cytotoxic molecules.
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PMID:Constitutive expression and role of the TNF family ligands in apoptotic killing of tumor cells by human NK cells. 1055 60

Mantle cell lymphoma (MCL) is a non-Hodgkin's lymphoma of B-cell lineage. The blastoid variant of MCL, characterized by high mitotic rate, is clinically more aggressive than common MCL. We used the cDNA array technology to examine the gene expression profiles of both blastoid variant and common MCL. The data was analysed by regression analysis, principal component analysis and the naive Bayes' classifier. Eight genes were identified as differentially deregulated between the two groups. Oncogenes CMYC, BCL2 and PIM1 were upregulated more frequently in the blastoid variant than in common MCL. This implied that the gp130-mediated signal transducer and activator of transcription 3 (STAT3) signalling pathway was involved in the blastoid variant transformation of MCL. Other differentially deregulated genes were TOP1, CD23, CD45, CD70 and NFATC. By using the eight differentially deregulated genes, we created a classifier to distinguish the blastoid variant from common MCL with high accuracy. We also identified 18 genes that were deregulated in both groups. Among them, BCL1, CALLA/CD10 and GRN were suggested to be oncogenes. The products of RGS1, RGS2, ANX2 and CD44H were suggested to promote tumour metastasis. CD66D was suggested to be a tumour suppressor gene.
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PMID:Investigatory and analytical approaches to differential gene expression profiling in mantle cell lymphoma. 1247 67

Death ligands induce apoptosis, which is a cell suicide program leading mainly to selective elimination of an organism's useless cells. Importantly, the dying cell is an active participant in its own demise ("cellular suicide"). Under physiological conditions, apoptosis is most often found during normal cell turnover and tissue homeostasis, embryogenesis, induction and maintenance of immune tolerance, development of the nervous system, and endocrine-dependent tissue atrophy. However, apoptotic processes have also been suggested to contribute to the pathology of the autoimmune demyelinating disease multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis. Here, apoptosis plays a double role. On one hand, impaired apoptosis may result in increased numbers or persistence of activated myelinspecific T cells. On the other hand, local tissue damage involves apoptosis of oligodendrocytes and neurons, leading to the clinical symptoms. In this article, an overview is given of the current knowledge of the roles of apoptosis-mediating and immune regulatory death ligands of the tumor necrosis factor (TNF) family (TNF, lymphotoxin-beta, OX40L [CD134L], CD154 [CD40L], CD95L, CD70 [CD27L], CD153 [CD30L], 4-1BBL [CD137L], TRAIL, TWEAK, BAFF, GITRL) in the pathogenesis of MS and of their implications for related therapeutic strategies.
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PMID:Death ligands and autoimmune demyelination. 1684 Jul 7

Using biopsy specimens from patients with B-cell non-Hodgkin's lymphoma, we observed a significantly low frequency of T(H)17 cells, including several samples with no detectable amount of interleukin (IL)-17-producing cells present in the tumor microenvironment. We found that, in the absence of lymphoma B cells, treatment with IL-1beta/IL-6 or lipopolysaccharide (LPS) enhanced IL-17 expression in CD4(+) T cells and this enhancement was attenuated when CD4(+) T cells were cocultured with lymphoma B cells. Blockade of CD27-CD70 or CD28-CD80/86 interactions by anti-CD70 or anti-CD80/86 antibodies restored LPS-mediated induction of IL-17 expression in CD4(+) T cells cocultured with lymphoma B cells. Because a subset of lymphoma B cells express IL-2 and given that IL-2 signaling is critically important in the development of regulatory T (T(reg)) cells, we tested the role of IL-2 signaling in T(H)17 cell development. We found that treatment with anti-IL-2 antibody to interrupt IL-2 signaling significantly inhibited Foxp3 expression in CD4(+) T cells. In contrast, interruption of IL-2 signaling up-regulated IL-17 expression in CD4(+) T cells and restored lymphoma-mediated down-regulation of IL-17-producing cells. Furthermore, the reversal of T(reg) cell activity by LPS or CpG-A resulted in an enhancement of IL-17-producing cells. Taken together, our study indicated that lymphoma B cells play an important role in skewing the balance between T(reg) and T(H)17 cells resulting in the establishment of a profoundly inhibitory tumor microenvironment.
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PMID:Malignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkin's lymphoma. 1950 24

There is mounting evidence that innate and adaptive immunity are critical for periodontal disease-mediated bone resorption. These studies examined the role of B and CD4 T cells in adaptive immunity of rats infected with Aggregatibacter actinomycetemcomitans (Aa). Sprague-Dawley male rats were fed Aa-containing mash or control-mash for 2 weeks. B and CD4 T cells were obtained from draining lymph nodes at 2, 4 and 12 weeks, postinoculation. Quantitative polymerase chain reaction-based messenger RNA expression was conducted for 89 cytokine family genes. Disease-relevance of the differentially expressed genes was assessed using a biological interaction pathway analysis software. B and CD4 T cells of Aa-infected rats increased and were activated, resulting in enhanced isotype-switched serum immunoglobulin G by 2 weeks postinoculation. Bone resorption was evident 12 weeks after Aa-feeding. In B cells, interleukin-2 (IL-2), macrophage-inhibiting factor, IL-19, IL-21, tumor necrosis factor (TNF), CD40 ligand (CD40L), CD70, bone morphogenetic protein 2 (BMP2), BMP3, and BMP10 were upregulated early; while IL-7, Fas ligand (FasL), small inducible cytokine subfamily E1, and growth differentiation factor 11 (GDF11; BMP11) were upregulated late (12 weeks). BMP10 was sustained throughout. In CD4 T cells, IL-10, IL-16, TNF, lymphotoxin-beta (LTbeta), APRIL, CD40L, FasL, RANKL and osteoprotegerin were upregulated early, whereas IL-1beta, IL-1RN, IL-1F8, IL-24, interferon-alpha1, GDF11 (BMP11), and GDF15 were upregulated late (12 weeks). Adaptive immunity appears crucial for bone resorption. Several of the deregulated genes are, for the first time, shown to be associated with bone resorption, and the results indicate that activated B cells produce BMP10. The study provides a rationale for a link between periodontal disease and other systemic diseases.
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PMID:Adaptive immune response in osteoclastic bone resorption induced by orally administered Aggregatibacter actinomycetemcomitans in a rat model of periodontal disease. 2061 1