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Biomedical subjects

J W Hartley

Publications and source records attributed to J W Hartley.

At least 19 recordsLinked to original sources
PubMed2006

Detection of Simkania negevensis by culture, PCR, and serology in respiratory tract infection in Cornwall, UK.

Respiratory tract infections are often treated empirically without investigation to detect the aetiological agent, which may be a virus or a bacterium, including atypical pathogens such as Chlamydophila pneumoniae or Mycoplasma pneumoniae. Recently, several types Chlamydia-like intracellular bacteria have been detected in environmental samples and clinical specimens. Little is known of their geographical distribution and potential pathogenicity. We describe the detection, by PCR and isolation in cell culture, of Simkania negevensis in nasopharyngeal aspirates of paediatric patients with bronchiolitis in Cornwall, UK. We also present serological evidence of exposure to the organism in 62% of adult patients and 46% of a sample of pregnant women. Empirical treatment of serious respiratory tract infection should consider the possible contribution of these organisms.

Adolescent↗
PubMed2001

Combined histologic and molecular features reveal previously unappreciated subsets of lymphoma in AKXD recombinant inbred mice.

Hematopoietic neoplasms developing in AKXD recombinant inbred, NFS.V(+) and ICSBP knockout mice were assessed using morphologic, cytologic and molecular criteria that relate these disorders to human lymphoma and leukemia. Lymphoma types included precursor T-cell and B-cell lymphoblastic, small lymphocytic, splenic marginal zone, follicular, and diffuse large cell (DLCL). In addition to previously defined subtypes of DLCL composed of centroblasts or immunoblasts, two additional subtypes are defined here: lymphoblastic lymphoma like (LL) and lymphoma characterized by a histiocytic reaction (HS). DLCL(HS) were distinguished from true histiocytic lymphomas by the presence of clonal Ig gene rearrangements.

Animals↗
PubMed2000

Genomic organisation and expression of BCL6 in murine B-cell lymphomas.

BCL6 encodes a transcription factor deregulated by chromosomal translocations in human diffuse large cell B lymphomas (DLCL). This study was designed to determine whether Bcl6 might also be involved in lymphomas of mice. BCL6 protein was expressed at high levels in 90% or more of DLCL but not in low grade B lymphomas. Southern hybridisation studies demonstrated altered organisation of Bcl6 in three primary DLCL and the WEHI 231 B-cell lymphoma cell line but not in low grade tumours. Chromosomal painting and fluorescence in situ hybridisation (FISH) analyses of the WEHI 231 metaphase spreads revealed a T(5;16) translocation with Bcl6 on Chromosome 16 at the translocation breakpoint. Deregulated expression of BCL6 is thus likely to contribute to the genesis of DLCL of mice as well as of humans.

Animals↗
PubMed2000

Accelerated appearance of multiple B cell lymphoma types in NFS/N mice congenic for ecotropic murine leukemia viruses.

Spontaneous lymphomas occur at high frequency in NFS x V+ mice, strains congenic for ecotropic murine leukemia virus (MuLV) proviral genes and expressing virus at high titer. In the present study, a total of 703 NFS x V+ lymphomas were studied by histopathology, immunophenotypic analysis, immunoglobulin heavy chain or T cell receptor beta chain rearrangements, and somatic ecotropic MuLV integrations; 90% of the lymphomas tested were of B cell lineage. Low-grade tumors included small lymphocytic, follicular, and splenic marginal zone lymphomas, while high-grade tumors comprised diffuse large-cell (centroblastic and immunoblastic types), splenic marginal zone, and lymphoblastic lymphomas. Comparison of mice of similar genetic background except for presence (NFS x V+) or absence (NFS x V-) of functional ecotropic MuLV genomes showed that NFS x V-clonal lymphomas developed at about one-half the rate of those occurring in NFS x V+ mice, and most were low-grade B cell lymphomas with extended latent periods. In NFS x V+ mice, clonal outgrowth, defined by Ig gene rearrangements, was associated with acquisition of somatic ecotropic proviral integrations, suggesting that, although generation of B cell clones can be virus independent, ecotropic virus may act to increase the rate of generation of clones and speed their evolution to lymphoma. The mechanism remains undefined, because only rare rearrangements were detected in several cellular loci previously associated with MuLV insertional mutagenesis.

Animals↗
PubMed2000

Lymphomas and high-level expression of murine leukemia viruses in CFW mice.

Historically, Swiss Webster mice of the CFW subline, both inbred and random-bred stocks, have been considered to have a low spontaneous occurrence of hematopoietic system tumors, and previous reports of infectious expression of murine leukemia viruses (MuLVs) have been rare and unremarkable. In marked contrast, in the present study of CFW mice from one source observed by two laboratories over a 2-year period, nearly 60% developed tumors, 85% of which were lymphomas, the majority of B-cell origin. All tumors tested expressed ecotropic MuLVs, and most expressed mink cell focus-inducing (MCF) MuLVs. Among normal mice of weanling to advanced age, over one-half were positive for ecotropic virus in tail or lymphoid tissues, and MCF virus was frequently present in lymphoid tissue, less often in tail. Patterns of ecotropic proviral integration indicated that natural infection occurred by both genetic and exogenous routes. Lymphomas were induced in NIH Swiss mice infected as neonates with tissue culture-propagated MuLVs isolated from normal and tumor tissue of CFW mice.

Animals↗
PubMed1999

Splenic marginal zone lymphomas of mice.

Splenic marginal zone lymphomas (MZLs) have been found to occur at a high frequency in NFS.N mice congenic for high-expressing ecotropic murine leukemia virus (MuLV) genes from AKR and C58 mice. Based on morphological, immunological, and molecular studies of these mice, MZL is clearly recognizable as a distinct disease with a characteristic clinical behavior. MZL was staged according to the degree of accumulation and morphological change of cells within the splenic marginal zone, as follows: 1) a moderate increase in normal-looking MZ cells, judged to be prelymphomatous, and 2) MZL in three variants: i) distinct enlargement of MZ by normal-looking cells (MZL), ii) distinct enlargement of MZ by basophilic centroblast-like cells (MZL+), and iii) extensive splenic involvement by centroblast-like cells (MZL++). The rate of mitosis and apoptosis increases with lymphoma grade. In most cases, emergence of a dominant IgH clonal pattern in paired splenic biopsy and necropsy samples was correlated with progression. MZLs were transplantable and homed to the spleen. MZL may constitute a commonly occurring lymphoma type unrecognized, in part, because of the centroblastic morphology of high-grade MZL and possible overgrowth of lower-grade MZL by more aggressive follicular lymphomas.

Animals↗
PubMed1999

Core-binding factor influences the disease specificity of Moloney murine leukemia virus.

The core site in the Moloney murine leukemia virus (Moloney MLV) enhancer was previously shown to be an important determinant of the T-cell disease specificity of the virus. Mutation of the core site resulted in a significant shift in disease specificity of the Moloney virus from T-cell leukemia to erythroleukemia. We and others have since determined that a protein that binds the core site, one of the core-binding factors (CBF) is highly expressed in thymus and is essential for hematopoiesis. Here we test the hypothesis that CBF plays a critical role in mediating pathogenesis of Moloney MLV in vivo. We measured the affinity of CBF for most core sites found in MLV enhancers, introduced sites with different affinities for CBF into the Moloney MLV genome, and determined the effects of these sites on viral pathogenesis. We found a correlation between CBF affinity and the latent period of disease onset, in that Moloney MLVs with high-affinity CBF binding sites induced leukemia following a shorter latent period than viruses with lower-affinity sites. The T-cell disease specificity of Moloney MLV also appeared to correlate with the affinity of CBF for its binding site. The data support a role for CBF in determining the pathogenic properties of Moloney MLV.

3T3 Cells↗
PubMed1998

Murine cytomegalovirus infection-induced polyclonal B cell activation is independent of CD4+ T cells and CD40.

The results of this study demonstrate that murine cytomegalovirus (MCMV) induces polyclonal B cell activation in mice during the acute phase of primary infection. First flow cytometric analysis revealed that surface expression of CD45R, IgM, and IgK by splenocytes from MCMV-infected mice was significantly reduced with a concomitant increase in the frequency of surface IgG-expressing cells. Second, ELIspot assays demonstrated that the changes revealed by flow cytometry were paralleled by increases in the numbers of IgG-producing cells, especially those secreting IgG2a. Third, the IgG antibodies from MCMV-infected animals reacted against a variety of self and foreign antigens. MCMV-induced B cell activation was independent of CD4+ T-cell-mediated help and CD40, since activation was observed in two models of mice deficient for this T cell subset and in mice deficient for CD40. Reverse transcription-polymerase chain reaction analysis showed that mRNA transcripts for the cytokines IL-6, IL-10, and IFN-gamma were rapidly induced following infection with MCMV, but only IL-6 and IFN-gamma proteins were detectable by ELISA. In addition, the numbers of cells producing IL-6 and IFN-gamma were significantly increased in the spleen. The magnitude of the polyclonal B cell activation response was diminished by 50% in IL-6-deficient mice but not in mice lacking IFN-gamma. In the absence of IFN-gamma, surface expression and serum levels of IgG2a were reduced while IgG1 expression was increased.

3T3 Cells↗
PubMed1998

Expression of cyclin D1 in mouse B cell lymphomas of different histologic types and differentiation stages.

The G1 cyclin, cyclin D1, has been implicated in the development of human and mouse tumors. Here we describe immunohistochemical analyses of cyclin D1 for a large panel of mouse B cell tumors. In addition, we characterize cyclin D1 expression in a series of cultured cell lines that represent transformed B cells at different stages of development. Immunohistochemical analysis showed that for low-grade lymphomas, cyclin D1 was expressed by 83% of centroblastic centrocytic (CBCC) and 14% of small lymphocytic lymphomas (SLL). For high-grade tumors, 28% of B lymphoblastic and 23% of centroblastic tumors expressed cyclin D1, while all immunoblastic lymphomas were negative. Studies of RNA and protein prepared from cultured B lineage tumors showed that cyclin D1 was expressed by all pre-B and most B cell tumors but not by cell lines representative of late B cell differentiation or by plasma cells. Expression of cyclin D1 in the lymphomas was not associated with alterations in the genomic structure of the Fis-1 (Bcl-1) common proviral integration site or cyclin D1 itself or with cell growth activity as assessed by expression of proliferating cell nuclear antigen (PCNA).

Animals↗
PubMed1997

Control of immunodeficiency and lymphoproliferation in mouse AIDS: studies of mice deficient in CD8+ T cells or perforin.

CD8+ T cells were previously shown to be important in preventing lymphoproliferation and immunodeficiency following infection of murine AIDS (MAIDS)-resistant mice with the LP-BM5 mixture of murine leukemia viruses. To further evaluate the mechanisms contributing to MAIDS resistance, we studied mice lacking CD8+ T cells or deficient in perforin due to knockout of the beta2-microglobulin (beta2M) or perforin gene, respectively. In contrast to wild-type, MAIDS-resistant controls, B10.A mice homozygous for the beta2M mutation and B10.D2 mice homozygous for the perforin mutation were diagnosed as having MAIDS by 5 to 8 weeks after infection by the criteria of lymphoproliferation, impaired proliferative responses to mitogens, and changes in cell populations as judged by histopathology and flow cytometry. Unexpectedly, there was no progression of lymphoproliferation through 24 weeks, even though immune functions were severely compromised. Expression of the defective virus responsible for MAIDS was enhanced in spleens of the knockouts in comparison with wild-type mice. These results demonstrate that perforin-dependent functions of CD8+ T cells contribute to MAIDS resistance but that other, non-CD8-dependent mechanisms are of equal or greater importance.

Animals↗
PubMed1997

Charlotte Friend Memorial Lecture: murine leukemia virus (MuLV) tumorigenesis.

Recent analysis of over 500 lymphomas occurring in NFS.V mice, congenic for Akv-type ecotropic MuLV structural genes, has revealed that about 90% are of B cell lineage as determined by demonstration of clonal rearrangements of Ig heavy chain genes, phenotyping by immunocytochemistry or cytofluorometric analysis, and by site and morphology of tumor. At least 40% of the B cell lymphomas were found to have their origin in the splenic marginal zone, a site only once before described for mouse lymphomas. Clonal somatic integrations of ecotropic MuLV occurred in 85% of tumors.

Animals↗
PubMed1997

Immunologic havoc induced by the 60 kD Gag protein of the MAIDS defective virus.

The mechanisms responsible for development of profound immunodeficiency and extensive lymphoproliferation that characterize infection of different species with retroviruses are only partially understood. In mice, it has been shown the activities of an unusual Gag protein are necessary and sufficient to induce these abnormalities in a syndrome designated mouse AIDS (MAIDS). Current studies suggest that complex, antigen-driven interactions between T cells and B cells result in polyclonal activation of both types of lymphocytes, aberrant cytokine production and late lymphomas.

Animals↗
PubMed1996

Induction of murine acquired immunodeficiency syndrome (MAIDS) in allophenic mice generated from strains susceptible and resistant to disease.

To examine whether a retroviral disease can be controlled in animals in which cells from a resistant strain coexist in a state of immunological tolerance with cells from a susceptible strain, allophenic mice were constructed and infected with LP-BM5 murine leukemia viruses which induce a fatal disorder, termed murine acquired immunodeficiency syndrome (MAIDS), characterized by lymphoproliferation and immunodeficiency in susceptible inbred strains of mice. We found that in two different strain combinations, resistance to MAIDS was contingent on the presence in individual animals of >50% of lymphocytes of resistant strain origin and correlated with reduction or elimination of retrovirus. In contrast, animals harboring substantial, but less than predominant, numbers of genetically resistant lymphocytes developed disease and died within the same time frame as susceptible control mice with uncontained proliferation of retrovirus.

Animals↗
PubMed1996

Quinolinic acid levels in a murine retrovirus-induced immunodeficiency syndrome.

Mice infected with the retrovirus mixture designated LP-BM5 murine leukemia virus (MuLV) develop an immunosuppressive disease. Quinolinic acid (QUIN) is an endogenous neurotoxic N-methyl-D-aspartate agonist that may contribute to the pathogenesis of HIV-associated neurologic disease. In the present study, the levels of QUIN in brain and blood were measured in mice infected with LP-BM5 MuLV and compared with those in uninfected mice and mice infected with the nonpathogenic strain of ecotropic MuLV (helper component of LP-BM5 MuLV). Infection with LP-BM5 MuLV resulted in progressive increases in blood QUIN levels beginning 2 weeks after inoculation that peaked by 16 weeks postinfection. QUIN levels were also increased in cerebral cortex, hippocampus, and striatum. In systemic tissues, QUIN levels were increased in lung, liver, and spleen. In contrast, infection with the ecotropic viral component of the LP-BM5 MuLV mixture was not associated with any changes in brain, blood, or systemic tissue QUIN levels, even though helper virus burdens were comparable to those in mice infected with LP-BM5 MuLV. Treatment of LP-BM5 MuLV-infected mice with the antiretroviral agent zidovudine (azidothymidine) significantly reduced blood and brain QUIN levels in association with reductions in viral load in brain and spleen. These observations suggest that elevated QUIN production is not attributable to productive infection with retrovirus per se but occurs in response to an agent or agents, such as cytokines, that are produced by the host in response to virus infection.

AIDS Dementia Complex↗
PubMed1996

Endogenous Mtv-encoded superantigens are not required for development of murine AIDS.

Immune activation in murine AIDS (MAIDS) has been suggested to involve a superantigen (SAG). The possibility that SAGs encoded by mammary tumor virus (MTV) might be the source of stimulation was studied by using Mtv mice. Mtv- mice developed typical MAIDS, excluding a requirement for Mtv-encoded SAGs in the pathogenesis of this disorder.

Animals↗