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)

A high frequency of lymphoma in human immunodeficiency virus-infected individuals has been reported since the outbreak of the acquired immunodeficiency syndrome (AIDS) epidemic in 1982. AIDS-associated non-Hodgkin's lymphoma (AIDS-NHL) is almost invariably derived from B cells and is classified as high- or intermediate-grade NHL, according to the working formulation. Two main histologic types are recognized, including small noncleaved cell lymphoma (SNCCL) and diffuse large cell lymphoma (DLCL). Pre-existing host factors putatively involved in lymphoma development include disrupted immunosurveillance, deregulated cytokine production, chronic antigen stimulation, and infection by Epstein-Barr virus (EBV). These alterations are associated with the development of multiple oligoclonal expansions which correspond to the clinical phase known as persistent generalized lymphadenopathy (PGL). The appearance of a true AIDS-NHL is characterized by the presence of a monoclonal B-cell population displaying several genetic lesions, including monoclonal EBV infection, c-MYC and BCL-6 rearrangements, RAS mutations, p53 inactivation, and 6q deletions. These genetic lesions cluster into two distinct molecular pathways, which specifically associate with the different histologic subtypes of AIDS-NHL, i.e., AIDS-SNCCL and AIDS-DLCL. The presence of distinct genetic pathways for AIDS-SNCCL and AIDS-DLCL correlate with a number of clinical features which distinguish these two groups of tumors, including differences in the age of onset, CD4 counts at the time of presentation, time elapsed since HIV infection, and clinical outcome.
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PMID:Molecular pathology of AIDS-related lymphomas. Biologic aspects and clinicopathologic heterogeneity. 799 35

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

Acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHL), a major source of morbidity and mortality among human immunodeficiency virus (HIV)-infected individuals, are derived from B cells and are classified into two major categories, Burkitt's lymphoma (BL) and diffuse large cell lymphoma (DLCL). Anaplastic large cell lymphoma (ALCL) and body-cavity-based lymphoma (BCBL) represent less frequent AIDS-NHL types. The molecular pathogenesis of AIDS-NHL is characterized by distinct genetic pathways, including chromosomal rearrangements of c-MYC and BCL-6 in AIDS-BL and AIDS-DLCL, respectively. In addition to gross rearrangements, recent evidence has suggested that BCL-6 may also be affected by mutations of the gene 5' noncoding regions. Here we have investigated the distribution of BCL-6 mutations in a panel representative of all the AIDS-NHL subtypes. Forty-three AIDS-NHL were analyzed for mutations in the first exon-first intron boundary region of BCL-6. Mutations were detected in all categories of AIDS-NHL (25 of 43 cases; 58%), including 12 of 20 AIDS-BL, 10 of 15 AIDS-DLCL, two of three AIDS-ALCL, and one of five of AIDS-BCBL. BCL-6 mutations occurred independent of BCL-6 rearrangements and presence of other genetic lesions frequently associated with AIDS-NHL. These results indicate that mutations of BCL-65' noncoding regions represent the most common genetic alteration presently detectable in AIDS-NHL. The frequency of these mutations, as well as their location in the proximity of BCL-6 regulatory sequences, suggest that they may play a role in AIDS-related lymphomagenesis.
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PMID:Frequent mutation of the 5' noncoding region of the BCL-6 gene in acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas. 916 Jun 81

Primary central nervous system lymphoma (PCNSL) is a major cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected individuals. The precise histogenetic derivation and the molecular pathogenesis of PCNSL is poorly understood. In an attempt to clarify the histogenesis and pathogenesis of these lymphomas, 49 PCNSL (26 acquired immunodeficiency syndrome [AIDS]-related and 23 AIDS-unrelated) were analyzed for multiple biologic markers, which are known to bear histogenetic and pathogenetic significance for mature B-cell neoplasms. PCNSL associated frequently (50.0%) with mutations of BCL-6 5' noncoding regions, which are regarded as a marker of B-cell transition through the germinal center (GC). Expression of BCL-6 protein, which is restricted to GC B cells throughout physiologic B-cell maturation, was detected in 100% AIDS-unrelated PCNSL and in 56.2% AIDS-related cases. Notably, among AIDS-related PCNSL, expression of BCL-6 was mutually exclusive with expression of Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP)-1 and, with few exceptions, also of BCL-2. All but one PCNSL expressed hMSH2, which among mature B cells selectively stains GC B cells. These data suggest that PCNSL may be frequently related to GC B cells and may be segregated into two major biologic categories based on the expression pattern of BCL-6, LMP-1, and BCL-2. BCL-6(+)/LMP-1(-)/BCL-2(-) PCNSL occur both in the presence and in the absence of HIV infection and consistently display a large noncleaved cell morphology. Conversely, BCL-6(-)/LMP-1(+)/BCL-2(+) PCNSL are restricted to HIV-infected hosts and are represented by lymphomas with immunoblastic features. These data are relevant for the pathogenesis and histogenesis of PCNSL and may be helpful to segregate distinct biologic and prognostic categories of these lymphomas.
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PMID:The molecular and phenotypic profile of primary central nervous system lymphoma identifies distinct categories of the disease and is consistent with histogenetic derivation from germinal center-related B cells. 968 Mar 71

Primary effusion lymphoma (PEL; also known as body cavity-based lymphoma) is recognized as a new and unique lymphoma entity occurring predominantly, but not exclusively in human immunodeficiency virus (HIV)-seropositive patients with acquired immunodeficiency syndrome (AIDS). PEL grows exclusively in body cavities as serous lymphomatous effusion without evidence of mass disease or dissemination. Their most unique feature is infection with the newly discovered human herpesvirus-8 (HHV-8; also known as Kaposi's sarcoma-associated herpesvirus), often accompanied by co-infection with Epstein-Barr virus (EBV). A number of continuous lymphoma cell lines have been established from the malignant pleural effusion, ascitic fluid and peripheral blood of patients with AIDS- and non-AIDS-associated PEL. While all cell lines are HHV-8+, about half of them also contain EBV sequences. Stimulation of the cell lines causes switch from latent to lytic HHV-8 infection. The cells are generally negative for T and B cell immunomarkers (except for CD138 suggesting a pre- or terminal plasma cell stage) and positive for some activation and adhesion markers; they are genotypically B cells with their immunoglobulin genes rearranged. Complex, hyperdiploid karyotypes with multiple structural abnormalities are seen in the cell lines examined. No alterations of known proto-oncogenes are detected in PEL, with the exception of BCL-6 mutations occurring in a large percentage of cases. Heterotransplantation of the cell lines into immunodeficient mice leads to the development of lymphomatous effusion and marked angiogenesis. As HHV-8 contains DNA sequences of several protein homologues, the cell lines express various cytokines, cytokine receptors, chemokines, cell cycle and anti-apoptosis modulators which are upregulated upon stimulation. Indeed, some cell lines produce high levels of (human) interleukin-6 and interleukin-10. Taken together, these cell lines represent very important model systems for the elucidation of the pathobiology of PEL; furthermore, the cell lines are extremely useful scientific tools providing a resource to pursue studies of HHV-8-mediated pathogenic mechanisms.
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PMID:Lymphoma cell lines: in vitro models for the study of HHV-8+ primary effusion lymphomas (body cavity-based lymphomas). 976 92

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

Human immunodeficiency virus-associated Hodgkin's disease (HIV-HD) displays several peculiarities when compared with HD of the general population. These include overrepresentation of clinically aggressive histologic types and frequent infection of Reed-Sternberg (RS) cells by Epstein-Barr virus (EBV). Recently, we have reported that the histogenesis of HD of the general population may be assessed by monitoring the expression pattern of BCL-6, a transcription factor expressed in germinal center (GC) B cells, and of CD138/syndecan-1 (syn-1), a proteoglycan associated with post-GC, terminal B-cell differentiation. In this study, we have applied these two markers to the study of HIV-HD histogenesis and correlated their expression status to the virologic features of this disease. We have found that RS cells of all histologic categories of HIV-HD consistently display the BCL-6(-)/syn-1(+) phenotype and thus reflect post-GC B cells. Although BCL-6(-)/syn-1(+) RS cells of HIV-HD express CD40, they are not surrounded by CD40 ligand-positive (CD40L+) reactive T lymphocytes, which, in HD of the general population, are thought to regulate the disease phenotype through CD40/CD40L interactions. Conversely, RS cells of virtually all HIV-HD express the EBV-encoded latent membrane protein 1 (LMP1), which, being functionally homologous to CD40, may contribute, at least in part, to the modulation of the HIV-HD phenotype.
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PMID:Human immunodeficiency virus-associated Hodgkin's disease derives from post-germinal center B cells. 1009 Sep 42

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

Common-variable immunodeficiency (CVI) patients develop non-Hodgkin's lymphomas (NHL), mainly B-lineage diffuse large-cell lymphomas (DLCL), with a high relative risk. The molecular pathogenesis of CVI-related NHL (CVI-NHL) is unknown. Here we aimed at providing a detailed molecular characterization of CVI-NHL. Rearrangements of BCL-6 were detected in two thirds of CVI-NHL cases examined. All 3 CVI-NHL also harbored point mutations of the BCL-6 5' noncoding regions, which constitute a marker of B-cell transit through the germinal center (GC). The number and molecular pattern of BCL-6 mutations in CVI-NHL were similar to that detected in DLCL of immunocompetent hosts and in DLCL arising in other immunodeficiency settings. Microsatellite instability occurred in one CVI-NHL devoid of a BCL-6 rearrangement. All CVI-NHL scored negative for genetic lesions of BCL-2, p53, c-MYC, REL as well as for viral infection by EBV and HHV-8. Overall, these data indicate that: similarly to other immunodeficiency-related NHL, involvement of BCL6 occurs frequently also in CVI-NHL; and because BCL-6 mutations are acquired by B cells during GC transit, their occurrence in CVI-NHL suggest that these lymphomas are histogenetically related to GC B cells.
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PMID:Common-variable immunodeficiency-related lymphomas associate with mutations and rearrangements of BCL-6: pathogenetic and histogenetic implications. 1092 27

This study was aimed at defining the histogenesis of the pathologic spectrum of lymphoma arising in the context of human immunodeficiency virus (HIV) infection. Toward this aim, 87 AIDS-related non-Hodgkin lymphomas (AIDS-NHL) and 16 Hodgkin lymphomas arising in HIV+ patients (HIV-HL) were comparatively analyzed for the expression pattern of several B-cell histogenetic markers, including BCL-6 (expressed by centroblasts and centrocytes), MUM1/IRF4 (expressed by late centrocytes and post-germinal center [GC] B cells), and CD138/syn-1 (expressed by post-GC B cells). Expression of MUM1, BCL-6, and syn-1 segregated 3 major phenotypic patterns among AIDS-NHL and HIV-HL: (1) the BCL-6+/MUM1-/syn-1- pattern, selectively clustering with a large fraction of AIDS-Burkitt lymphoma (17 of 19) and of systemic AIDS-diffuse large cell lymphoma (12 of 16); (2) the BCL-6-/MUM1+/syn-1- pattern, associated with a fraction of AIDS-immunoblastic lymphoma (8 of 24); and (3) the BCL-6-/MUM1+/syn-1+ pattern, associated with systemic and primary central nervous system immunoblastic lymphoma (14 of 24) and with primary effusion lymphoma (10 of 10), plasmablastic lymphoma of the oral cavity (7 of 7), and HIV-HL (15 of 16). Analysis of nonneoplastic lymph nodes showed that the 3 phenotypic patterns detected in AIDS-NHL and HIV-HL correspond to distinct stages of physiologic B-cell development-centroblasts (BCL-6+/MUM1-/syn-1-), late GC/early post-GC B cells (BCL-6-/MUM1+/syn-1-), and post-GC B cells (BCL-6-/MUM1+/syn-1+). Expression of the Epstein-Barr virus-encoded latent membrane protein-1 clustered with the BCL-6-/MUM1+/syn-1+ profile throughout the clinicopathologic spectrum of AIDS-NHL and HIV-HL. Overall, these results define novel histogenetic subsets of AIDS-NHL and HIV-HL and may provide novel tools for refining the diagnosis of these disorders.
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PMID:Expression profile of MUM1/IRF4, BCL-6, and CD138/syndecan-1 defines novel histogenetic subsets of human immunodeficiency virus-related lymphomas. 1115 93


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