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)

We report here a series of 16 highly malignant diffuse large B-cell lymphomas of the oral cavity with unique immunohistologic features. Fifteen of these developed in human immunodeficiency virus-positive patients. All cases displayed morphologic features of diffuse large-cell lymphomas but strikingly differed from them in that they showed a minimal or absent expression of the leukocyte common antigen as well as of the B-cell antigen CD20. Instead, the tumor cells showed a constant reaction with the plasma cell characteristic antibody VS38c and a frequent reaction with the CD79a antibody. This, in conjunction with a variable expression of cytoplasmic Ig and a monoclonal rearrangement of the Ig heavy chain gene in all of the three tested cases confirmed the B-cell nature, the clonal origin, and the plasmacellular differentiation of these neoplasms. The majority of these tumors were negative for the BCL-6 protein, with the remaining cases showing only a partial and weak expression of this antigen. An association with the Epstein-Barr virus (EBV) was found in 9 of 15 tested cases showing abundant EBV-encoded nuclear RNA transcripts in the absence of EBNA-2. Five of the EBV-positive cases variably expressed LMP-1. We propose to name these tumors plasmablastic lymphomas, in accordance with their morphologic and immunohistologic features. Knowledge of this lymphoma entity is important to avoid confusion with nonlymphoid malignancies due to the lack of commonly used lymphoid markers.
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PMID:Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. 902 65

Six Epstein-Barr virus (EBV)-related lymphoproliferative disorders were investigated to verify whether the EBV strain harbored by neoplastic cells had the same EBNA-2 and latent membrane protein-1 (LMP-1) DNA sequences of the virus carried by normal lymphocytes of the same patients. Within each case, the analysis of neoplastic lymph nodes, reactive lymphadenopathies, and/or EBV+ spontaneous lymphoblastoid cell lines gave concordant results with respect to type-specific EBNA-2 region and LMP-1 gene. In particular, five cases showed the same deletion in the 3' end of the LMP-1 gene in both normal and neoplastic cells. We also determined the prevalence of LMP-1 deletions in a large series of normal peripheral blood mononucleated cells (PBMCs) from Italian individuals. The analysis showed that 50% (9 of 18) of PBMCs from human immunodeficiency virus (HIV)-seronegative donors carried a 30-bp deletion in the C-terminal portion of the LMP-1 gene, whereas a nondeleted fragment was amplified in about 44% (8 of 18) of the cases. Only one sample (5.6%) showed the amplification of a full-length LMP-1 band together with a deleted fragment. Similarly, PBMCs from HIV-infected patients showed an almost equivalent prevalence of full-length (17 of 37, 46%) and deleted (16 of 37, 43.2%) LMP-1 fragments, whereas about 11% of samples (4 of 37) showed evidence of double infections. Of note, deletions in the LMP-1 gene were detected with similar prevalence values in EBV+ Hodgkin's disease (HD) (13 of 30, 43.3%) and non-Hodgkin's lymphoma (NHL) (2 of 5, 40%) cases from HIV-seronegative patients and in HIV-related, EBV+ NHLs (4 of 7, 57.1%). Conversely, a 30-bp LMP-1 deletion was found in 10 of 12 HIV-associated HD cases (83%), a prevalence significantly higher than that detected in HIV-unrelated HD (P = .01). These findings indicate that: (1) the same EBV strain carrying LMP-1 deletions is harbored by normal and neoplastic cells of patients with EBV+ disorders, ruling out that these mutations might result from immunoselection phenomena; (2) in the Italian population, the prevalence of LMP-1 deletion mutants is comparable to that of EBV strains with full-length LMP-1; (3) HIV-induced immunosuppression is not associated with an increased prevalence of LMP-1 deletions in PBMCs; and (4) HIV-related HD cases, but not those of HIV-seronegative Italian patients, are closely correlated with the presence of LMP-1 deletions, suggesting that infection with these strains may increase the risk of developing HD in the HIV setting.
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PMID:Epstein-Barr virus strains with latent membrane protein-1 deletions: prevalence in the Italian population and high association with human immunodeficiency virus-related Hodgkin's disease. 905 56

We examined 81 cases of primary gastrointestinal lymphomas in Korea, including 64 gastric lymphomas and 17 intestinal lymphomas, for EBV expression by EBER-1 in situ hybridization (ISH) and EBNA-1 PCR. In EBER-1 positive cases, we performed immunohistochemistry for latent membrane protein-1 (LMP-1) and EBV diffuse early antigen (EA(D)) to compare EBV latent gene expression and lytic process. EBER-1 was detected in 15 of 81 cases of lymphomas. EBER-1 expression showed three different patterns on tumour cells; diffuse 4/81 (5%), localized 4/81 (8%), and a few scattered pattern 7/81 (9%). We regarded diffuse pattern and localized pattern as EBER-1 positive group (8/81: 10%). Diffuse pattern of EBER-1 was shown in all three T-cell lymphomas and one B-cell lymphoma. A localized pattern was seen all in B-cell lymphomas. The EBER-1 expression was 11% in the stomach (7/64) and 6% in the intestine (1/17). Five of the eight EBER-1 positive gastric lymphomas were histologically diffuse large B-cell lymphomas, and the other three were peripheral T-cell lymphoma, unspecified, one angiocentric lymphoma, and one intestinal T-cell lymphoma by REAL classification. Eight MALT type gastric B-cell lymphomas showed no EBV association. EBV nuclear antigen (EBNA-1) was detected in 15 of 45 resected cases (33%) by PCR. EBER-1 positive cases were all EBNA-1 positive. Twelve EBNA-positive/EBER-negative cases consisted of seven cases showing a few scattered EBER-1 positive lymphocytes. LMP-1 and diffuse early antigen (EA(D)) was detected in five and three cases, respectively. Although follow-up information in our series was incomplete, it seemed that there was no significant difference in their staging or prognosis between EBER-positive cases and EBER-negative group. It is concluded that EBV is associated with some lymphomas among Koreans without overt pre-existing immunodeficiency, especially in T-cell lymphomas.
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PMID:Epstein-Barr virus-associated primary gastrointestinal lymphoma in non-immunocompromised patients in Korea. 908 52

Previously, we reported that the LMP 1 gene of Epstein-Barr virus (EBV) derived from nasopharyngeal carcinoma (NPC) tissues (i.e., NLMP 1 gene) was able to transform BALB/c3T3 cells. On the other hand, LMP 1 gene of B95-8 strain (i.e., BLMP 1 gene) was not able to transform these cells (Chen et aL, 1992). Further studies indicated that a 10-amino-acid deletion in the carboxyl terminus of NLMP 1 played an important role in transformation (Li et al., 1996). In this study, we tested if this 10-amino-acid deletion affected the induction of NF-kappaB activity by LMP 1. The long terminal repeat of the human immunodeficiency virus type 1 (HIV-1 LTR) contained two copies of NF-kappaB sites and was used to construct the Luc gene-based reporter plasmid, p kappaB-Luc. Plasmid p kappaB-Luc was co-transfected with plasmids containing the NLMP 1 gene, BLMP 1 gene, and their chimeric or deletion constructs, respectively, into C-33A and BALB/c3T3 cells. The activation was then measured by the luciferase activity. Results showed that the full-length proteins induced a similar level of NF-kappaB activity, the two 3' mutants (R15delta and D4delta) still induced a relatively high level of activity, and the two 5' deletion mutants (delta3058 and delta3243) of NLMP 1 gene did not show any significant activation in C-33A cells. However, none of these LMP 1 proteins induced NF-kappaB activity in BALB/c3T3 cells. Using subcellular fractionation analysis and an immunocytostaining method, the truncated proteins of delta3058 and delta3243 were detected in the cytoplasm of the cells whereas the full-length NLMP 1 protein was located at the cytoplasmic membrane. Stable BALB/c3T3 cell clones that expressed both truncated proteins were established and then their ability to induce tumors in nude mice was examined. Data showed that both truncated NLMP 1 proteins still maintained partial transformation activity. Our results suggested that there was no direct correlation between NF-kappaB activation and transformation activity of LMP 1 in BALB/c3T3 cell transformation and that the amino-terminal membrane-spanning domain was important for maintaining both functions of LMP 1.
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PMID:Sequence variations between two Epstein-Barr virus LMP 1 variants have no effect on the activation of NF-kappaB activity. 940 3

The association of Epstein-Barr virus (EBV) with B-cell lymphoma was examined in 72 human immunodeficiency virus-negative Japanese patients using the polymerase chain reaction (PCR) on DNA obtained from formalin-fixed paraffin-embedded tissues and an in situ hybridization (ISH) technique. EBV-encoded RNA 1 (EBER-1) was detected in 12 of 72 cases (17%); five of 33 cases (15%) of nodal B-cell lymphomas and seven of 39 cases (18%) of extranodal B-cell lymphomas. Three cases of post-bone marrow transplantation and one case of autoimmune disease (Evans syndrome) were included among seven EBER-1 positive extranodal lymphomas. A combined study of immunohistochemistry and EBER-1 revealed that some L26 positive cells were EBER-1 positive. A DNA band was also observed in 13 of 70 examined cases (19%) (four of 33 cases of nodal B-cell lymphomas (12%) and nine of 37 cases of extranodal B-lymphomas (24%)) in the PCR study using primers to detect the Bam HI-W fragment of EBV. In the immunohistochemical study using a monoclonal antibody to the latent membrane protein 1 (LMP-1) of the EBV, one of the EBV-encoded latent gene products, LMP-1, was expressed in six of 34 cases (18%) of extranodal B-lymphomas, but none of the cases with nodal B-cell lymphomas were shown to be LMP-1 positive. Oncoprotein bcl-2 was examined by immunohistochemistry and found to be expressed in seven cases of nodal lymphomas and three cases of extranodal lymphomas, and two of these nodal cases were EBER ISH positive. In EBV serology, only two cases of nodal and one case of extranodal EBER positive B-cell lymphomas revealed a reactivation pattern. In the PCR study using primers to detect the lymphocyte-determined membrane antigen (LYDMA), the same sized monoclonal bands were observed in case 36 in the PCR products from the nose and skin, suggesting the monoclonal proliferation of the tumor. These findings suggested a low incidence of EBV association with B-cell lymphomas unless patients were in an immunologically impaired condition such as post-organ transplantation or autoimmune diseases.
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PMID:Determination of Epstein-Barr virus association with B-cell lymphomas in Japan: study of 72 cases--in situ hybridization, polymerase chain reaction, immunohistochemical studies. 963 83

The extent of nucleotide sequence microheterogeneity varies among subgenomic regions of Epstein-Barr virus (EBV). We examined, in EBV-carrying lymphoid cell lines, the extent of polymorphism in EBV DNA fragments amplified from the BamHI E, K, N and Z regions, and then investigated the diversity of the more hypervariable regions in tissues and body fluids. In cell lines, sequence dissimilarities in a genotype-specifying fragment of the EBNA-3C gene varied from < 1-4% within each genotype; dissimilarities in the first intron of the BZLF- 1 gene were < 2% within each genotype. By contrast, dissimilarities in a C-terminal unique domain of the EBNA-1 gene, and in a fragment that encompasses and is upstream of the LMP-1 start codon, varied between 2 and 7% and were not genotype-specific. The sequence diversity in BamHI K and N regions was then examined in tissues and body fluids by single-strand conformation polymorphism (SSCP) analysis and cycle sequencing. Extensive inter-host diversity was observed, whether the host was co-infected by human immunodeficiency virus (HIV) or not. In the oral cavity of HIV-infected patients, inter-compartmental EBV diversity could be demonstrated, even between sites that were anatomically proximate. Studies of BamHI K clones derived from EBV in oral lesions revealed infection by multiple variants. Identification of hypermutable loci within the EBV genome such as those located in the BamHI K and N regions should permit fine discrimination of individual EBV variants.
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PMID:Diversity of naturally occurring Epstein-Barr virus revealed by nucleotide sequence polymorphism in hypervariable domains in the BamHI K and N subgenomic regions. 982 Jan 58

To evaluate the value of Epstein-Barr virus DNA (EBV-DNA) assay in cerebrospinal fluid (CSF) for monitoring the response to treatment in acquired immunodeficiency syndrome-related primary central nervous system lymphoma (AIDS-PCNSL), 9 human immunodeficiency virus-infected patients with biopsy-proven AIDS-PCNSL who underwent multimodal therapy were investigated for EBV-DNA detection in CSF by semiquantitative nested polymerase chain reaction (PCR). Tumoral tissue expression of bcl-6 oncogene protein and of EBV-encoded latent membrane protein (LMP-1) was also investigated. The 2 patients who had a response to chemotherapy showed a reduction of mean EBV-DNA concentration values after chemotherapy and displayed a large noncleaved morphology and a BCL-6+/LMP-1- phenotype. Conversely, the 4 patients with progressive disease after chemotherapy showed increasing mean values of EBV-DNA and displayed an immunoblastic morphology and a BCL-6-/LMP-1+ phenotype. No significant changes were observed for patients with stable disease. EBV-DNA burden reduction was significantly associated with prolonged survival. These results suggest that EBV-DNA monitoring might be helpful in predicting response to chemotherapy and in segregating distinct biological and prognostic categories of AIDS-PCNSL.
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PMID:Epstein-Barr virus in monitoring the response to therapy of acquired immunodeficiency syndrome-related primary central nervous system lymphoma. 998 31

Lymphoid hyperplasia of Waldeyer's ring (WR) is an often-symptomatic complication of human immunodeficiency virus (HIV) infection. A characteristic but not well explained finding is the presence of multinucleated giant cells (MNGCs) adjacent to crypt or surface epithelium. To further elucidate the MNGCs and assess their relationship to HIV and Epstein-Barr virus (EBV), 12 specimens from 11 HIV-positive patients were stained with antibodies to HIV-1 p24, EBV (latent membrane protein, LMP-1), histiocytes (CD68), and other antigen-presenting cells: S-100 protein, the Langerhans cell (LC) marker CD1a, and the follicular dendritic cell (FDC) marker (CD21). Double immunofluorescent staining to assess co-expression of p24 and cell-specific markers was performed and analyzed by laser-scanning confocal microscopy with 3-dimensional reconstruction. In situ hybridization for EBV-encoded small RNA (EBER) was performed in all cases. Immunostains showed MNGCs labeled for p24, S-100, and CD68, but not CD1a. In 1 case, rare MNGCs were CD21-positive. EBV LMP-1 was uniformly negative, although EBER-positive lymphocytes were seen by in situ hybridization in 9 of 12 specimens (numerous in only 3 specimens). Double immunofluorescent staining showed co-localization of p24 with CD68 and S-100. Our results suggest that MNGCs are generally HIV-infected, EBV-negative, and most likely represent an unusual S-100-positive histiocyte subset (not LC or FDC). Their exact pathophysiologic role remains uncertain. EBV does not appear to play a major role in the pathogenesis of WR lymphoid hyperplasias in HIV infection.
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PMID:HIV-associated Waldeyer's ring lymphoid hyperplasias: characterization of multinucleated giant cells and the role of Epstein-Barr virus. 1057 22

Inflammatory bowel disease (IBD) is associated with an increased risk of lymphoma, which is usually extraintestinal but sometimes may involve the diseased bowel itself. Most lymphomas described in this setting are of non-Hodgkin's type, but rare cases of Hodgkin's disease (HD) have been reported. We describe the clinicopathologic and molecular features of four patients with primary gastrointestinal HD. Three patients had preexistent Crohn's disease (CD), for which two of them had received immunosuppressive therapy. The fourth patient had a longstanding history of diverticulitis and myasthenia gravis and was receiving immunosuppressive therapy for the latter. Multifocal involvement of the bowel by HD was noted in all four cases. Disease was staged as IVA in one patient, IIIB in one patient, and IE in one patient, and the fourth patient died in the postoperative period before further workup. Two patients received chemotherapy, one of whom was dead at 9 months, whereas the other has no evidence of disease at 25 months' follow-up. The patient with IE disease did not receive any therapy because only a few microscopic foci of disease were present and is also without any evidence of disease at 17 months. The Reed-Sternberg (RS) cells in all four cases expressed CD30, CD15, EBER-1, and LMP-1; two of four were focally CD20-positive. VJ-polymerase chain reaction for immunoglobulin heavy chain (IgH) rearrangement showed a polyclonal pattern in all four cases. In two cases, laser capture microdissection was used to isolate individual RS and Hodgkin's cells, which contained rearranged immunoglobulin genes, confirming a B-cell genotype. Whereas one case showed a dominant clonal band present in all isolates, cells from the patient with stage IE disease clearly showed a polyclonal population of RS cells. Our findings indicate that HD arising in the setting of IBD or chronic inflammation is the result of an Epstein-Barr virus-driven lymphoproliferation, analogous to that found in other immunodeficient states. Disordered immunoregulation inherent to CD and immunosuppressive therapy for the latter may contribute to its development. The finding of polyclonal RS cells in a patient with early stage disease and apparent cure by surgical resection versus monoclonal RS cells in the patient with disseminated disease suggests that HD in the setting of immunodeficiency also may show molecular progression, in a manner similar to that occurring in conventional B-cell lymphoproliferative disorders arising in the same setting.
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PMID:Epstein-Barr virus-positive primary gastrointestinal Hodgkin's disease: association with inflammatory bowel disease and immunosuppression. 1063 89

Immunodeficiency-related B-cell disorders are seen after organ transplantation and in congenital and acquired immunodeficiency states. Post-transplant lymphoproliferative disorders (PTLD) comprise a histologic spectrum ranging from hyper-plastic appearing lesions to frank non-Hodgkin's lymphoma or multiple myeloma histology. Multiple clones may co-exist, representing a uniquely different mechanism for lymphomagenesis. The incidence varies from 1% in renal recipients to 8% in lung recipients, but can be markedly increased by the use of anti-T-cell therapies, or by T-cell depletion in bone marrow transplantation. Pre-transplant EBV seronegativity increases risk to as high as 30%-50%. More than 90% of tumors are EBV-associated. Mechanisms for viral lymphomagenesis remain incompletely defined; LMP-1 may function as an oncogene and coprecipitates with TRAF, BCL-2 overexpression has also been identified. A possible direct tumorigenic effect has recently been suggested for cyclosporine. PTLD has a highly variable clinical picture, certain patterns are however seen. Reversibility of PTLD with reduction in immunosuppressives has long been recognized. Predicting reversibility has been difficult. The presence or absence of BCL-6 mutations has recently been identified as being of predictive value. Surgical resection can be curative. Cytotoxics, although problematic, can also be curative. Long term remission has been achieved with anti CD21 and CD24 antibodies; efficacy has been reported anecdotally for interferon alpha and for rituximab. In vitro expanded EBV-specific T cells have been effective as treatment and as prophylaxis in the setting of bone marrow transplantation. EBV viral load measured in blood appears to correlate with the emergence of PTLD and may facilitate prophylactic studies. PTLD is a model of immunodeficiency related EBV lymphomagenesis. Pathogenetic, therapeutic, and prophylactic insights gained from the study of PTLD are likely to be applicable to other immunodeficiency states and to EBV-related lymphoid neoplasia in general.
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PMID:Diagnosis and treatment of transplant-related lymphoma. 1070 78


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