Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The importance of antibodies for elimination of polyomavirus infection and the prevention of virus induced oncogenesis was studied, X-linked immunodeficiency (XID) mice, IgM-/- single knockout and IgMI-/- CD8-/- double knockout mice, all defective in antibody production, and normal control mice were infected with polyomavirus as adults. The mice were followed for presence of polyoma DNA with a polyoma specific polymerase chain reaction (PCR) over 6 weeks post infection (p.i.), a time point at which polyomavirus DNA is no longer detected in normal adult infected mice. As expected, virus DNA was not detected in normal mice 6 weeks p.i. In both IgM-/- single knockout and IgM-/- CD8-/- double knockout mice a disseminated infection was still observed by 6 weeks p.i. and the latter group of mice succumbed around two months p.i. In XID mice, only one third of the mice were still positive for viral DNA 6 weeks p.i. No polyomavirus induced tumors were observed in any of the mice during the 2-4 month observation period.
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PMID:Adult X-linked immunodeficiency (XID) mice, IGM-/- single knockout and IGM-/- CD8-/- double knockout mice do not clear polyomavirus infection. 962 94

We have described 5 major subtypes of Epstein-Barr virus (EBV) based on variations in EBNA-1 sequences. These include P-ala (identical to the prototype B95.8 virus), P-thr, V-pro, V-leu, and V-val. Normal individuals often carry multiple EBV subtypes, the most common being P-ala, whereas EBV-associated tumors examined to date always contain a single subtype, which only on rare occasion is P-ala. The primary hypotheses that these observations generate are as follows: (1) Each of these EBV subtypes are naturally occurring, and in normal individuals the multiplicity of subtypes results from multiple infections. (2) EBV subtypes in normal individuals are generated in vivo from a single infecting virus subtype by mutations in EBNA-1. The second hypothesis essentially excludes the possibilities that the nonrandom association of certain subtypes with lymphomas is secondary to the geographic distribution of EBV subtypes and, if proven correct, could provide strong support for a direct role of EBV in tumorigenesis. In this report, we provide evidence for the latter hypothesis. We show that the P-ala EBV subtype present in most nasal lymphomas undergoes and accumulates multiple mutations consistent with the generation of variant species of EBNA-1 in vivo. This phenomenon is similar to the generation of quasispecies in RNA viruses and is the first description of in vivo generation of subtypes in DNA viruses. In RNA-based viruses, including human immunodeficiency virus and hepatitis C virus, the emergence of quasispecies is linked to replication infidelity and significantly influences disease processes through its effect on viral tropism, the emergence of viruses resistant to the host defenses or to therapy, and pathogenicity. The present data thus raise important questions relating to the mechanisms whereby these mutations are generated in EBV and their relevance to the pathogenicity of EBV-associated lymphomas.
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PMID:Epstein-Barr virus in nasal lymphomas contains multiple ongoing mutations in the EBNA-1 gene. 965 61

Although the exact incidence of cancers in human immunodeficiency virus (HIV)-infected children is not clear, an excess of non-Hodgkin's lymphomas and soft tissue tumors as well as a multitude of otherwise rare tumors in childhood, such as cervical, thyroid, or pulmonary carcinoma, has been reported. In contrast to the findings in HIV-infected adults, Kaposi's sarcoma is rare in children in industrialized countries but not in children living in the sub-Saharan area. Treatment of the neoplastic disease is often complicated by multiple HIV-associated organ dysfunctions as well as drug interactions and infectious complications secondary to severe immunosuppression. Nonetheless, preliminary results with dose-intensive, but brief, chemotherapeutic regimens have been encouraging, and HIV-infected children who develop cancer are likely to benefit from aggressive treatment combined with adequate supportive care. Furthermore, insights gained from the study and treatment of this very challenging group of patients may benefit other immunocompromised hosts as well as increase our understanding of oncogenesis in general.
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PMID:Cancers in human immunodeficiency virus-infected children. 970

Drug-induced DNA demethylation in normal human cells and inherited localized hypomethylation in mitogen-stimulated lymphocytes from patients with a rare recessive disease (ICF: immunodeficiency, centromeric region instability, facial anomalies) are associated with karyotypic instability. This chromosomal recombination is targeted to heterochromatin in the vicinity of the centromere (pericentromeric region) of human chromosome 1. Pericentromeric rearrangements in this chromosome as well as overall genomic hypomethylation are frequently observed in many kinds of cancer, including breast adenocarcinoma. We found that almost half of 25 examined breast adenocarcinomas exhibited hypomethylation in satellite 2 DNA, which is located in the long region of heterochromatin adjacent to the centromere of chromosome 1 and is normally highly methylated. One of the 19 examined non-malignant breast tissues displaying fibrocystic changes was similarly hypomethylated in this satellite DNA. We also looked at an opposing type of methylation alteration in these cancers, namely, hypermethylation in a tumor-suppressor gene region that is frequently hypermethylated in breast cancers. We found that increased methylation in the E-cadherin promoter region and decreased methylation in satellite 2 DNA were often present in the same breast cancers. While hypermethylation in certain tumor-suppressor gene regions may favor tumorigenesis by repressing transcription, demethylation of other DNA sequences may predispose to cancer-promoting chromosomal re-arrangements.
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PMID:Hypomethylation of pericentromeric DNA in breast adenocarcinomas. 971 50

Malignant lymphomas frequently develop in the pleural cavity of patients with long-standing pyothorax. Thus, the term pyothorax-associated lymphoma (PAL) has been proposed for this type of tumor. Most PAL are of the type diffuse lymphoma of B cell and contain Epstein-Barr virus (EBV) DNA. This article reviews the mechanism for the development of PAL. The possible contribution of EBV infection, inflammatory cytokines and other genetic lesions, including the p53 gene, towards the growth advantage of neoplastic cells is described. Although the presence of EBV is focused in PAL cells, the contribution of EBV-mediated growth promotion in PAL is limited. Another important characteristic of PAL is that the virus antigen-positive lymphoma develops in patients with pyothorax, in whom the systemic immunodeficiency is unlikely to be present. Therefore, in the course of the development of PAL, the mechanism for the evading host immune surveillance must be obvious. In this context, the production of an immunosuppressive cytokine from PAL cells, human histocompatibility leukocyte antigen class I alleles of patients with PAL, and the mutations of cytotoxic T lymphocyte epitopes in an EBV-latent antigen are described. These mechanisms could be involved in the development of PAL, an EBV-positive lymphoma developing in an immunocompetent host, and also shed light on the tumorigenesis of other EBV-positive neoplasms and on the lymphomagenesis of other inflammatory lesions.
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PMID:Mechanism for the development of pyothorax-associated lymphoma. 977 4

The DNA-dependent protein kinase (DNA-PK) consists of a heterodimer DNA-binding complex, Ku70 and Ku80, and a large catalytic subunit, DNA-PKcs. To examine the role of DNA-PKcs in lymphocyte development, radiation sensitivity, and tumorigenesis, we disrupted the mouse DNA-PKcs by homologous recombination. DNA-PKcs-null mice exhibit neither growth retardation nor a high frequency of T cell lymphoma development, but show severe immunodeficiency and radiation hypersensitivity. In contrast to the Ku70-/- and Ku80-/- phenotype, DNA-PKcs-null mice are blocked for V(D)J coding but not for signal-end joint formation. Furthermore, inactivation of DNA-PKcs leads to hyperplasia and dysplasia of the intestinal mucosa and production of aberrant crypt foci, suggesting a novel role of DNA-PKcs in tumor suppression.
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PMID:Catalytic subunit of DNA-dependent protein kinase: impact on lymphocyte development and tumorigenesis. 999 36

Lentiviruses are associated not only with immunodeficiency but also with malignancies. The mechanisms involved in tumorigenesis are still not fully understood. Cats infected with feline immunodeficiency virus (FIV) in the wild represent one model in which the role of viral load in the pathogenesis can be studied, since tumors, especially lymphomas, are quite often observed in cats infected with FIV. To be able to compare the viral load data among cats infected with different FIV isolates, the method used to obtain the viral load has to be unaffected by isolate-specific differences. This is especially true for the real-time polymerase chain reaction (PCR), a new method for viral load determination, since nucleotide sequence mismatches have been used for allelic discrimination with this method. To investigate the influence of these mismatches on PCR efficiency, we have used an FIV-specific real-time PCR and determined the influence of nucleotide sequence variation in several characterized FIV isolates as well as unknown isolates from naturally infected cats. We could demonstrate that minor mismatches, such as point mutations in the primer or the probe region, decrease overall PCR efficiency but do not abolish the quantification, in contrast to major mismatches of three or four nucleotides, which lead to complete inhibition of the real-time PCR detection. Based on these results, it will be possible to design real-time PCR systems allowing the quantification of a broad range of isolates, which is a prerequisite for the investigation of the impact of viral load in tumorigenesis.
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PMID:Proviral load determination of different feline immunodeficiency virus isolates using real-time polymerase chain reaction: influence of mismatches on quantification. 1019 36

This review is an update on the transforming genes of human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6). Both viruses have been implicated in the etiology of several human cancers. In particular, HCMV has been associated with cervical carcinoma and adenocarcinomas of the prostate and colon. In vitro transformation studies have established three HCMV morphologic transforming regions (mtr), i.e., mtrI, mtrII, and mtrIII. Of these, only mtrII (UL111A) is retained and expressed in both transformed and tumor-derived cells. The transforming and tumorigenic activities of the mtrII oncogene were localized to an open reading frame (ORF) encoding a 79-amino-acid (aa) protein. Furthermore, mtrII protein bound to the tumor suppressor protein p53 and inhibited its ability to transactivate a p53-responsive promoter. In additional studies, the HCMV immediate-early protein IE86 (IE2; UL122) was found to interact with cell cycle-regulatory proteins such as p53 and Rb. However, IE86 exhibited transforming activity in vitro only in cooperation with adenovirus E1A. HHV-6 is a T-cell-tropic virus associated with AIDS-related and other lymphoid malignancies. In vitro studies identified three transforming fragments, i.e., SalI-L, ZVB70, and ZVH14. Of these, only SalI-L (DR7) was retained in transformed and tumor-derived cells. The transforming and tumorigenic activities of SalI-L have been localized to a 357-aa ORF-1 protein. The ORF-1 protein was expressed in transformed cells and, like HCMV mtrII, bound to p53 and inhibited its ability to transactivate a p53-responsive promoter. HHV-6 has also been proposed to be a cofactor in AIDS because both HHV-6 and human immunodeficiency virus type 1 (HIV-1) have been demonstrated to coinfect human CD4(+) T cells, causing accelerated cytopathic effects. Interestingly, like the transforming proteins of DNA tumor viruses such as simian virus 40 and adenovirus, ORF-1 was also a transactivator and specifically up-regulated the HIV-1 long terminal repeat when cotransfected into CD4(+) T cells. Finally, based on the interactions of HCMV and HHV-6 transforming proteins with tumor suppressor proteins, a scheme is proposed for their role in oncogenesis.
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PMID:Human cytomegalovirus and human herpesvirus 6 genes that transform and transactivate. 1039 70

Castleman's disease (CD) is a rare atypical lymphoproliferative disorder whose morphology, soon after the original presentation of Castleman et al., has been definitely subdivided in a hyaline vascular (HV) and plasma cell (PC) histopathological pattern, with intermediate variants. The former occurs much more frequently than the latter and is usually localized to the mediastinum or pulmonary hilum. The latter involves lymph nodes separately or in aggregations and often displays multicentricity with systemic symptoms including autoimmune phenomena and aggressive course. Infections are the most frequent causes of patient demise in these cases, followed by malignancies such as Kaposi's sarcoma, malignant lymphoma or epithelial neoplasia. Increase of follicular dendritic reticulum cells (FDRC), often dysplastic, in the germinal center (GC) and marginal zone (MZ), broad MZ expansion with prominence of immunophenotypically aberrant B cells (Ki B3-negative, CD5-positive), possible predominance of paracortical plasma cells often with clusters of clonal l-light chain restricted plasma cells, increase of paracortical plasmacytoid monocytes, represent common hallmarks of CD. However, small hyalinized and hypervascular GCs with hypervascular interfollicular stroma and sinus effacement are common features of the HV variant, whereas hyperplastic GCs with plasma cell aggregates in lymph node paracortex and partially spared sinuses are characteristic features of the PC variant. The frequent concomitance of the HV and PC types at separate sites, together with transient morphological patterns from one type to the other and from the localized to multicentric form during the course of the disease, along with B and T cell impaired functions, with frequent development of autoantibodies, have suggested that CD is a single disorder related to immune dysregulation. A key event in the pathogenesis of CD has been recently suggested to be an abnormal production of a B cell growth factor, such as IL-6, leading to lymphoproliferation and plasma cell differentiation and being involved in the oncogenesis of plasmacytoma. In this event, Kaposi's sarcoma associated virus (HHV-8), which has been found in many cases of CD, especially in the multicentric form, could play a crucial role both in producing IL-6 and releasing angiogenic factors. A possible differentiation block may lead to the development of a malignant lymphoma. Kaposi's sarcoma or other malignant neoplasias can be supposed to be consequences of the immunodeficiency typical of CD.
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PMID:Castleman's disease. 1065 69

Previous in vitro studies have shown that bcl-2 expression can be induced by transfection of Epstein-Barr virus (EBV)-negative non-Hodgkin's lymphoma (NHL) cell lines with EBV. This induced expression of bcl-2 is important for the long survival of EBV-positive cells and might be a first step in tumorigenesis. The purpose of the present study was to investigate the possibility of similar correlation between bcl-2 expression and EBV infection in vivo in a cohort of patients with aggressive NHL, who were uniformly evaluated and treated with effective chemotherapy. The 42 patients included were 25-65 years old. None had prior treatment, discordant lymphoma, or human immunodeficiency virus seropositivity. Fresh biopsied samples were obtained and stored frozen for analysis of bcl-2 gene rearrangement major break point and of EBV DNA by PCR. Bcl-2 protein expression was estimated by Western blot, and enzyme immunoassay. With a median follow-up of 30 months, overall survival (OS) and disease-free survival (DFS) were measured to determine the prognostic significance of these variables. Analyzable DNA was present in all samples, 24% demonstrating bcl-2 rearrangement and 33% showing EBV DNA. Patients with bcl-2 gene rearrangement tended to have shorter DFS, and OS than patients without translocation. Bcl-2 protein expression was not correlated to gene rearrangement and had no significant influence on survival. The presence of EBV DNA in NHL had no prognostic significance but was correlated to bcl-2 expression. EBV-positive tumors showed higher bcl-2 expression than EBV-negative tumors did. Our results suggest a role of EBV infection in inducing bcl-2 expression as a survival factor for EBV-positive cells.
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PMID:Correlation between EBV DNA and rearrangement and expression of Bcl-2 gene in aggressive non-Hodgkin's lymphoma. 1079 3


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