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1.
Philos Trans R Soc Lond B Biol Sci ; 375(1810): 20190507, 2020 10 26.
Article in English | MEDLINE | ID: mdl-32892728

ABSTRACT

In Europe, three widespread extreme summer drought and heat (DH) events have occurred in 2003, 2010 and 2018. These events were comparable in magnitude but varied in their geographical distribution and biomes affected. In this study, we perform a comparative analysis of the impact of the DH events on ecosystem CO2 fluxes over Europe based on an ensemble of 11 dynamic global vegetation models (DGVMs), and the observation-based FLUXCOM product. We find that all DH events were associated with decreases in net ecosystem productivity (NEP), but the gross summer flux anomalies differ between DGVMs and FLUXCOM. At the annual scale, FLUXCOM and DGVMs indicate close to neutral or above-average land CO2 uptake in DH2003 and DH2018, due to increased productivity in spring and reduced respiration in autumn and winter compensating for less photosynthetic uptake in summer. Most DGVMs estimate lower gross primary production (GPP) sensitivity to soil moisture during extreme summers than FLUXCOM. Finally, we show that the different impacts of the DH events at continental-scale GPP are in part related to differences in vegetation composition of the regions affected and to regional compensating or offsetting effects from climate anomalies beyond the DH centres. This article is part of the theme issue 'Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale'.


Subject(s)
Carbon Dioxide/analysis , Climate Change , Droughts , Ecosystem , Extreme Weather , Hot Temperature , Carbon Cycle , Europe , Extreme Heat , Models, Theoretical , Seasons
2.
Sci Adv ; 6(24): eaba2724, 2020 06.
Article in English | MEDLINE | ID: mdl-32577519

ABSTRACT

In summer 2018, central and northern Europe were stricken by extreme drought and heat (DH2018). The DH2018 differed from previous events in being preceded by extreme spring warming and brightening, but moderate rainfall deficits, yet registering the fastest transition between wet winter conditions and extreme summer drought. Using 11 vegetation models, we show that spring conditions promoted increased vegetation growth, which, in turn, contributed to fast soil moisture depletion, amplifying the summer drought. We find regional asymmetries in summer ecosystem carbon fluxes: increased (reduced) sink in the northern (southern) areas affected by drought. These asymmetries can be explained by distinct legacy effects of spring growth and of water-use efficiency dynamics mediated by vegetation composition, rather than by distinct ecosystem responses to summer heat/drought. The asymmetries in carbon and water exchanges during spring and summer 2018 suggest that future land-management strategies could influence patterns of summer heat waves and droughts under long-term warming.

3.
Opt Express ; 26(4): 4738-4750, 2018 Feb 19.
Article in English | MEDLINE | ID: mdl-29475320

ABSTRACT

We employ an extended finite-element model as a design tool capable of incorporating the interaction between plasmonic antennas and magneto-optical effects, specifically the magneto-optical Kerr effect (MOKE). We first test our model in the absence of an antenna and show that for a semi-infinite thin-film, good agreement is obtained between our finite-element model and analytical calculations. The addition of a plasmonic antenna is shown to yield a wavelength dependent enhancement of the MOKE. The antenna geometry and its separation from the magnetic material are found to impact the strength of the observed MOKE signal, as well as the antenna's resonance wavelength. Through optimization of these parameters we achieved a MOKE enhancement of more than 100 when compared to a magnetic film alone. These initial results show that our modeling methodology offers a tool to guide the future fabrication of hybrid plasmonic magneto-optical devices and plasmonic antennas for magneto-optical sensing.

5.
Leukemia ; 29(4): 886-94, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25306898

ABSTRACT

Failure to undergo activation-induced cell death due to global dysregulation of apoptosis is the pathogenic hallmark of large granular lymphocyte (LGL) leukemia. Consequently, immunosuppressive agents are rational choices for treatment. This first prospective trial in LGL leukemia was a multicenter, phase 2 clinical trial evaluating methotrexate (MTX) at 10 mg/m(2) orally weekly as initial therapy (step 1). Patients failing MTX were eligible for treatment with cyclophosphamide at 100 mg orally daily (step 2). The overall response in step 1 was 38% with 95% confidence interval (CI): 26 and 53%. The overall response in step 2 was 64% with 95% CI: 35 and 87%. The median overall survival for patients with anemia was 69 months with a 95% CI lower bound of 46 months and an upper bound not yet reached. The median overall survival for patients with neutropenia has not been reached 13 years from study activation. Serum biomarker studies confirmed the inflammatory milieu of LGL but were not a priori predictive of response. We identify a gene expression signature that correlates with response and may be STAT3 mutation driven. Immunosuppressive therapies have efficacy in LGL leukemia. Gene signature and mutational profiling may be an effective tool in determining whether MTX is an appropriate therapy.


Subject(s)
Anemia/drug therapy , Gene Expression Regulation, Leukemic , Immunosuppressive Agents/therapeutic use , Leukemia, Large Granular Lymphocytic/drug therapy , Methotrexate/therapeutic use , Neutropenia/drug therapy , STAT3 Transcription Factor/genetics , Aged , Aged, 80 and over , Anemia/complications , Anemia/genetics , Anemia/mortality , Cyclophosphamide/therapeutic use , Drug Monitoring , Female , Finland , Humans , International Cooperation , Leukemia, Large Granular Lymphocytic/complications , Leukemia, Large Granular Lymphocytic/genetics , Leukemia, Large Granular Lymphocytic/mortality , Male , Middle Aged , Mutation , Neutropenia/complications , Neutropenia/genetics , Neutropenia/mortality , STAT3 Transcription Factor/metabolism , Survival Analysis , Transcriptome , United States
6.
Oncogene ; 34(3): 334-45, 2015 Jan 15.
Article in English | MEDLINE | ID: mdl-24362528

ABSTRACT

The retroviral oncoprotein Tax from human T-cell leukemia virus type 1 (HTLV-1), an etiological factor that causes adult T-cell leukemia and lymphoma, has a crucial role in initiating T-lymphocyte transformation by inducing oncogenic signaling activation. We here report that Tax is a determining factor for dysregulation of autophagy in HTLV-1-transformed T cells and Tax-immortalized CD4 memory T cells. Tax facilitated autophagic process by activating inhibitor of κB (IκB) kinase (IKK) complex, which subsequently recruited an autophagy molecular complex containing Beclin1 and Bif-1 to the lipid raft microdomains. Tax engaged a crosstalk between IKK complex and autophagic molecule complex by directly interacting with both complexes, promoting assembly of LC3+ autophagosomes. Moreover, expression of lipid raft-targeted Bif-1 or Beclin1 was sufficient to induce formation of LC3+ autophagosomes, suggesting that Tax recruitment of autophagic molecules to lipid rafts is a dominant strategy to deregulate autophagy in the context of HTLV-1 transformation of T cells. Furthermore, depletion of autophagy molecules such as Beclin1 and PI3 kinase class III resulted in impaired growth of HTLV-1-transformed T cells, indicating a critical role of Tax-deregulated autophagy in promoting survival and transformation of virally infected T cells.


Subject(s)
Autophagy , Gene Products, tax/metabolism , Human T-lymphotropic virus 1/metabolism , Membrane Microdomains/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Beclin-1 , Cell Line, Tumor , Cells, Cultured , Gene Products, tax/genetics , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Host-Pathogen Interactions , Human T-lymphotropic virus 1/genetics , Human T-lymphotropic virus 1/physiology , Humans , I-kappa B Kinase/genetics , I-kappa B Kinase/metabolism , Immunoblotting , Jurkat Cells , Membrane Microdomains/virology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Microscopy, Fluorescence , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Mutation , Phagosomes/metabolism , Phagosomes/virology , Phosphatidylinositol 3-Kinases , T-Lymphocytes/metabolism , T-Lymphocytes/virology
7.
Ann Oncol ; 25(10): 2030-2035, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25096606

ABSTRACT

BACKGROUND: The 2008 World Health Organization (WHO) classification distinguishes three entities among the large granular lymphocytic leukemia (LGL leukemia): T-cell LGL leukemia (T-LGL leukemia), aggressive natural killer (NK) cell leukemia, and chronic NK lymphoproliferative disorders (LPD), the later considered as a provisional entity. Only a few and small cohorts of chronic NK LPD have been published. PATIENTS AND METHODS: We report here clinicobiological features collected retrospectively from 70 cases of chronic NK LPD, and compared with those of T-LGL leukemia. RESULTS: There were no statistical differences between chronic NK LPD and T-LGL leukemia concerning median age [61 years (range 23-82 years)], organomegaly (26%), associated autoimmune diseases (24%), and associated hematological malignancies (11%). Patients with chronic NK LPD were significantly less symptomatic (49% versus 18%, P < 0.001) and the association with rheumatoid arthritis was more rarely observed (7% versus 17%, P = 0.03). The neutropenia (<0.5 × 10(9)/l) was less severe in chronic NK LPD (33% versus 61%, P < 0.001) without difference in the rate of recurrent infections. STAT3 mutation was detected in 12% of the cohort, which is lower than the frequency observed in T-LGL leukemia. Thirty-seven percent of the patients required specific therapy. Good results were obtained with cyclophosphamide. Overall and complete response rates were, respectively, 69% and 56%. Overall survival was 94% at 5 years. CONCLUSION: This study suggests very high similarities between chronic NK LPD and T-LGL leukemias. Since chronic NK LPD is still a provisional entity, our findings should be helpful when considering further revisions of the WHO classification.


Subject(s)
Killer Cells, Natural/pathology , Leukemia, Large Granular Lymphocytic/pathology , Lymphoproliferative Disorders/pathology , Adult , Aged , Aged, 80 and over , Female , Humans , Leukemia, Large Granular Lymphocytic/classification , Leukemia, Large Granular Lymphocytic/genetics , Lymphoproliferative Disorders/classification , Lymphoproliferative Disorders/genetics , Male , Middle Aged , Retrospective Studies , STAT3 Transcription Factor/genetics , World Health Organization
9.
Blood Cancer J ; 3: e168, 2013 Dec 06.
Article in English | MEDLINE | ID: mdl-24317090

ABSTRACT

T-cell large granular lymphocytic (T-LGL) leukemia is a clonal disease characterized by the expansion of mature CD3+CD8+ cytotoxic T cells. It is often associated with autoimmune disorders and immune-mediated cytopenias. Our recent findings suggest that up to 40% of T-LGL patients harbor mutations in the STAT3 gene, whereas STAT5 mutations are present in 2% of patients. In order to identify putative disease-causing genetic alterations in the remaining T-LGL patients, we performed exome sequencing from three STAT mutation-negative patients and validated the findings in 113 large granular lymphocytic (LGL) leukemia patients. On average, 11 CD8+ LGL leukemia cell-specific high-confidence nonsynonymous somatic mutations were discovered in each patient. Interestingly, all patients had at least one mutation that affects either directly the STAT3-pathway (such as PTPRT) or T-cell activation (BCL11B, SLIT2 and NRP1). In all three patients, the STAT3 pathway was activated when studied by RNA expression or pSTAT3 analysis. Screening of the remaining 113 LGL leukemia patients did not reveal additional patients with same mutations. These novel mutations are potentially biologically relevant and represent rare genetic triggers for T-LGL leukemia, and are associated with similar disease phenotype as observed in patients with mutations in the STAT3 gene.

10.
Leukemia ; 27(4): 897-906, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23072779

ABSTRACT

Telomeres are specialized structures providing chromosome integrity during cellular division along with protection against premature senescence and apoptosis. Accelerated telomere attrition in patients with myelodysplastic syndrome (MDS) occurs by an undefined mechanism. Although the MDS clone originates within the myeloid compartment, T-lymphocytes display repertoire contraction and loss of naive T-cells. The replicative lifespan of T-cells is stringently regulated by telomerase activity. In MDS cases, we show that purified CD3+ T-cells have significantly shorter telomere length and reduced proliferative capacity upon stimulation compared with controls. To understand the mechanism, telomerase enzymatic activity and telomerase reverse transcriptase (hTERT), gene expression were compared in MDS cases (n=35) and healthy controls (n=42) within different T-cell compartments. Telomerase activity is greatest in naive T-cells illustrating the importance of telomere repair in homeostatic repertoire regulation. Compared with healthy controls, MDS cases had lower telomerase induction (P<0.0001) that correlated with significantly lower hTERT mRNA (P<0.0001), independent of age and disease stratification. hTERT mRNA deficiency affected naive but not memory T-cells, and telomere erosion in MDS occurred without evidence of an hTERT-promoter mutation, copy number variation or deletion. Telomerase insufficiency may undermine homeostatic control within the hematopoietic compartment and promote a change in the T-cell repertoire in MDS.


Subject(s)
Myelodysplastic Syndromes/immunology , T-Lymphocytes/immunology , Telomerase/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Bromodeoxyuridine , Case-Control Studies , Cell Proliferation , Female , Humans , Male , Middle Aged , Myelodysplastic Syndromes/enzymology , Myelodysplastic Syndromes/genetics , Telomerase/metabolism , Telomere , Young Adult
11.
Leukemia ; 25(2): 348-58, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21052088

ABSTRACT

Natural killer (NK) cell lymphomas/leukemias are rare neoplasms with an aggressive clinical behavior. The majority of the cases belong to extranodal NK/T-cell lymphoma, nasal type (ENKTL) in the current WHO classification scheme. Gene-expression profiling (GEP) of 21 ENKTL and NK-cell lymphoma/leukemia patients, 17 NK- and T-cell lines and 5 indolent NK-cell large-granular-lymphocytic proliferation was performed and compared with 125 peripheral T-cell lymphoma (PTCL) patients previously studied. The molecular classifier derived for ENKTL patients was comprised of 84 transcripts with the majority of them contributed by the neoplastic NK cells. The classifier also identified a set of γδ-PTCLs both in the ENKTL cases as well as in cases initially classified as PTCL-not otherwise specified. These γδ-PTCLs expressed transcripts associated with the T-cell receptor (TCR)/CD3 complex, suggesting T cell rather than NK-cell lineage. They were very similar to NK-cell tumors by GEP, but were distinct from cytotoxic (αß)-PTCL and hepatosplenic T-cell lymphoma, indicating derivation from an ontogenically and functionally distinct subset of γδ T cells. They showed distinct expression of Vγ9, Vδ2 transcripts and were positive for TCRγ, but negative for TCRß by immunohistochemistry. Targeted inhibition of two oncogenic pathways (AURKA and NOTCH-1) by small-molecular inhibitors induced significant growth arrest in NK-cell lines, thus providing a rationale for clinical trials of these inhibitors in NK-cell malignancies.


Subject(s)
Killer Cells, Natural/pathology , Lymphoma, Non-Hodgkin/pathology , Lymphoma, T-Cell, Peripheral/pathology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptors, Antigen, T-Cell, gamma-delta , Adolescent , Adult , Aged , Aged, 80 and over , Aurora Kinase A , Aurora Kinases , Humans , Male , Middle Aged , Protein Kinase Inhibitors/pharmacology , Receptors, Notch/antagonists & inhibitors , Signal Transduction , Tumor Cells, Cultured , Young Adult
12.
Leuk Res ; 32(1): 45-8, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17544120

ABSTRACT

We report on the clinico-biological characteristics of 20 cases of gammadelta T cell large granular lymphocyte (LGL) leukemia. All the data were compared to that of 196 cases with alphabeta T cell subtype, which represents the majority of T cell LGL leukemias. Clinical findings were quite similar in the two groups regarding age, sex ratio, recurrent infections, and association with auto-immune diseases especially rheumatoid arthritis. Gammadelta LGL predominantly expressed a CD3+/CD4-/CD8+/CD16+/CD57+ phenotype, in 50% of cases. Clinical outcome was favorable for these patients with overall survival of 85% at 3 years. Fifty percent of gammadelta patients required treatment and the response to therapy was estimated at 55%. gammadelta and alphabeta T cell LGL leukemia harbor a very similar clinico-biological behavior and represent part of an antigen-driven T cell lymphoproliferation.


Subject(s)
Leukemia, T-Cell/diagnosis , Receptors, Antigen, T-Cell, gamma-delta , Adult , Aged , Aged, 80 and over , Autoimmune Diseases/complications , Clone Cells , Female , Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor , Humans , Immunophenotyping , Leukemia, T-Cell/immunology , Leukopenia/diagnosis , Male , Middle Aged , Receptors, Antigen, T-Cell, alpha-beta , Splenomegaly/diagnosis
13.
Article in English | MEDLINE | ID: mdl-11722988

ABSTRACT

This review covers the diagnosis and management of natural killer and peripheral T-cell lymphomas (PTCL). Problems with PTCL include their rarity, representing usually 10-15% of non-Hodgkin's lymphomas in the Western Hemisphere, morphologic heterogeneity, and lack of immunophenotypic markers for clonality. Additionally, their clinical behavior is variable and may not correlate with morphology. Dr. Kinney gives a general overview of the diagnosis of PTCL and NK cell neoplasms. Emphasis will be placed on extranodal T cell and natural killer (NK) cell lymphomas such as hepatosplenic lymphoma, subcutaneous panniculitis-like lymphoma and nasal/nasal type T/NK-cell lymphoma. The use of ALK gene regulation in the classification of anaplastic large cell lymphoma is also reviewed. Dr. Loughran describes current understanding of the pathogenesis of large granular lymphocyte (LGL) leukemia. The discussion focuses on LGL leukemia as an instructive model of dysregulated apoptosis causing both malignant and autoimmune disease. Current management options and mechanisms of therapeutic response are also described. Dr. Greer addresses whether PTCL should be treated differently from the more common diffuse large B cell lymphomas. He discusses the therapeutic options for anaplastic large cell lymphoma (ALCL), from a conservative approach for primary cutaneous ALCL to combination chemotherapy for the highly chemosensitive ALCL expressing anaplastic lymphoma kinase. He reviews therapy options for the extranodal subtypes of PTCL by drawing from series in adults, pediatrics, dermatology, and the Far East.


Subject(s)
Killer Cells, Natural/pathology , Lymphoma, T-Cell, Peripheral/pathology , Lymphoproliferative Disorders/pathology , Antineoplastic Agents/therapeutic use , Humans , Leukemia, T-Cell/etiology , Leukemia, T-Cell/pathology , Leukemia, T-Cell/therapy , Lymphoma, T-Cell, Peripheral/etiology , Lymphoma, T-Cell, Peripheral/therapy , Lymphoproliferative Disorders/etiology , Lymphoproliferative Disorders/therapy , T-Lymphocytes/pathology
14.
J Immunol ; 166(12): 7486-95, 2001 Jun 15.
Article in English | MEDLINE | ID: mdl-11390502

ABSTRACT

Polymorphonuclear neutrophils (PMN) are phagocytic cells constitutively programmed for apoptotic cell death. Exposure to GM-CSF delays apoptosis as measured by annexin-V staining and cell morphological change. We found that STAT5B, STAT1, and STAT3 DNA-binding activity was induced by GM-CSF. We also detected activation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway after GM-CSF treatment which was inhibited by treatment with the PI 3-kinase inhibitors, wortmannin and LY294002. We investigated whether STAT or PI 3-kinase activity was necessary for the pro-survival response of GM-CSF in PMN. Exposure of PMN to GM-CSF in the presence of either AG-490, antisense STAT3 oligonucleotides, or wortmannin resulted in a partial inhibition of GM-CSF-mediated pro-survival activity. GM-CSF induced a time-dependent increase in the mRNA and protein expression of the anti-apoptotic Bcl-2-family protein, Mcl-1. We examined the hypothesis that Janus kinase/STAT and PI 3-kinase regulation of Mcl-1 contributed to GM-CSF-delayed apoptosis. Using either AG-490 or wortmannin alone, we observed a dose-dependent inhibition of GM-CSF-induced Mcl-1 expression. Using suboptimal doses of AG-490 and wortmannin, we found that both drugs together had an additive effect on delayed apoptosis and Mcl-1 expression. These data suggest that cooperative regulation of Mcl-1 by the Janus kinase/STAT and PI 3-kinase pathways contribute to GM-CSF-delayed apoptosis.


Subject(s)
Apoptosis , Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Neoplasm Proteins/metabolism , Neutrophils/cytology , Neutrophils/enzymology , Phosphatidylinositol 3-Kinases/physiology , Protein-Tyrosine Kinases/physiology , Signal Transduction , Apoptosis/drug effects , Cell Survival/drug effects , Cells, Cultured , DNA-Binding Proteins/genetics , DNA-Binding Proteins/physiology , Drug Synergism , Enzyme Inhibitors/pharmacology , Humans , Janus Kinase 1 , Janus Kinase 2 , Janus Kinase 3 , Kinetics , Myeloid Cell Leukemia Sequence 1 Protein , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasm Proteins/physiology , Neutrophils/metabolism , Oligonucleotides, Antisense/pharmacology , Precipitin Tests , Protein-Tyrosine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Messenger/biosynthesis , STAT3 Transcription Factor , Signal Transduction/drug effects , Trans-Activators/genetics , Trans-Activators/physiology , Tyrphostins/pharmacology , bcl-2-Associated X Protein
15.
J Clin Invest ; 107(3): 351-62, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11160159

ABSTRACT

Large granular lymphocyte (LGL) leukemia is characterized by the expansion of antigen-activated cytotoxic T lymphocytes. These leukemic cells are resistant to Fas-mediated apoptosis despite expressing high levels of Fas. We found that leukemic LGL from 19 patients displayed high levels of activated STAT3. Treatment of leukemic LGL with the JAK-selective tyrosine kinase inhibitor AG-490 induced apoptosis with a corresponding decrease in STAT-DNA binding activity. Moreover, using an antisense oligonucleotide approach to diminish STAT3 expression, we found that Fas sensitivity was restored in leukemic LGL. AG-490-induced apoptosis in leukemic LGL was independent of Bcl-xL or Bcl-2 expression. However, we found that the Bcl-2-family protein Mcl-1 was significantly reduced by AG-490 treatment. Activated STAT3 was shown to bind an SIE-related element in the murine mcl-1 promoter. Using a luciferase reporter assay, we demonstrated that v-src overexpression in NIH3T3 induced STAT3-dependent transcriptional activity from the mcl-1 promoter and increased endogenous Mcl-1 protein levels. We conclude that STAT3 activation contributed to accumulation of the leukemic LGL clones. These findings suggest that investigation should focus on novel strategies targeting STAT3 in the treatment of LGL leukemia.


Subject(s)
CD8-Positive T-Lymphocytes/physiology , DNA-Binding Proteins/antagonists & inhibitors , Leukemia/physiopathology , Neoplasm Proteins/biosynthesis , Proto-Oncogene Proteins c-bcl-2 , Trans-Activators/antagonists & inhibitors , Apoptosis/drug effects , Blotting, Western , CD8-Positive T-Lymphocytes/drug effects , Cell Line , DNA-Binding Proteins/metabolism , Dimerization , Enzyme Inhibitors/pharmacology , Gene Expression Regulation , Humans , Myeloid Cell Leukemia Sequence 1 Protein , Neoplasm Proteins/genetics , Oncogene Protein pp60(v-src) , Phosphorylation , STAT3 Transcription Factor , Signal Transduction , Trans-Activators/metabolism , Tumor Cells, Cultured , Tyrphostins/pharmacology
16.
Br J Haematol ; 109(1): 64-70, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10848783

ABSTRACT

The primate T-cell lymphoma/leukaemia viruses (PTLV) and bovine leukaemia virus (BLV) comprise a unique genus of retroviruses, infection with which induces seroreactivity in the host against conserved epitopes in their p24 gag and gp21 env cognate proteins. Herein, we have confirmed this serocrossreactivity. Patients with large granular lymphocyte (LGL) leukaemia have frequent seroreactivity to the p24 and gp21 env proteins of human T-cell lymphoma/leukaemia virus I (HTLV-I), one of the species in the genus. However, only a small minority of patients are actually infected with prototypic HTLV-I or HTLV-II, another species within the group. In an attempt to determine whether LGL leukaemia might be associated with other members of the PTLV/BLV genus, we examined the peripheral blood mononuclear cell DNA of 22 HTLV p24 and/or gp21 seropositive LGL leukaemia patients via PCR using degenerate and specific primer pair/probe systems capable of detecting all known members of the PTLV/BLV genus. None of the samples was positive. These data indicate that although HTLV-II may be associated with some cases of LGL leukaemia most patients are not infected with a PTLV or BLV virus.


Subject(s)
DNA, Viral/blood , Deltaretrovirus/genetics , Leukemia Virus, Bovine/genetics , Leukemia, Myeloid/virology , Autoradiography , Cross Reactions , DNA Primers , DNA Probes , Deltaretrovirus/immunology , Gene Products, gag/immunology , Humans , Leukemia Virus, Bovine/immunology , Leukemia, Myeloid/immunology , Polymerase Chain Reaction/methods , Viral Envelope Proteins/immunology
17.
Br J Haematol ; 108(4): 717-23, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10792274

ABSTRACT

Fas ligand triggers cell death after interaction with its receptor Fas. Altered expression of Fas has been associated with lymphoproliferation and autoimmune disorders in both mice and man. Apoptosis of lung and liver tissue is seen in Fas ligand transgenic mice. It is not known whether constitutive expression of Fas ligand can cause a similar human disease. Four patients with aggressive large granular lymphocyte (LGL) leukaemia involving lung and liver were studied. All four patients were severely ill with pulmonary involvement. Two patients presented with hypoxia and were oxygen dependent; the other two patients had severe pulmonary hypertension. Lung biopsies showed interstitial infiltration by leukaemic LGL. The infiltrating lymphocytes expressed both Fas and Fas ligand, whereas normal pneumocytes expressed only Fas. Similar findings were observed in liver biopsies from these patients. Features mimicking the pathological changes of graft-versus-host disease were observed, including pneumocyte apoptosis. All four patients had high levels of circulating Fas ligand. Successful treatment with oral methotrexate or 2-chlorodeoxyadenosine was associated with disappearance or marked reduction of circulating Fas ligand. These results suggest that dysregulated expression of Fas ligand can lead to human disease with pathological features resembling graft-versus-host disease.


Subject(s)
Leukemia, Lymphoid/metabolism , Liver/metabolism , Lung/metabolism , Membrane Glycoproteins/genetics , fas Receptor/genetics , Adult , Animals , Antimetabolites, Antineoplastic/therapeutic use , Apoptosis , Fas Ligand Protein , Female , Gene Expression , Humans , Immunophenotyping , Leukemia, Lymphoid/drug therapy , Leukemia, Lymphoid/pathology , Leukemic Infiltration , Liver/pathology , Lung/pathology , Male , Methotrexate/therapeutic use , Mice , Mice, Transgenic , Middle Aged
19.
Rheumatology (Oxford) ; 39(4): 393-8, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10817772

ABSTRACT

OBJECTIVE: To investigate the role of HLA class I in susceptibility to Felty's syndrome (FS) and large granular lymphocyte (LGL) syndrome. METHODS: Fifty caucasoid FS patients, and 55 patients with LGL syndrome, of whom 26 had arthritis and 29 did not, were studied. Complete HLA class I and HLA-DR typing including, where relevant, DRB1*04 subtyping was carried out by molecular methods. Comparison was made with 78 unselected healthy caucasoid controls and a further 29 DRB1*0401+ individuals. RESULTS: A significant association was found between HLA-A*02 and FS [odds ratio (OR) 3.9, 95% confidence interval (95% CI) 1.8-8.4, P = 0.0004]. At the B locus, there was an association between B*44 and LGL with arthritis [OR 3.5 (1.3-9.2), P = 0.01]. For HLA-Cw*0501, there was an association with FS [OR 4 (1. 7-9.2) P = 0.0008]. For both FS and LGL with arthritis, the extended haplotype HLA-A*02;B*44;Cw*0501;DRB1*0401 was significantly associated [OR 9.5 (2.6-35), P = 0.0001; OR 4.6 (1-22.4), P = 0.05, respectively]. There was no association between HLA class I or II and LGL without arthritis. All the allelic and haplotypic associations were lost on comparison with HLA-DRB1*0401+ controls. The strongest HLA association was with HLA-DRB1*0401 for FS [OR 27.9 (10.3-75.5), P = 10(-13)], and LGL with arthritis [OR 35.4 (9.6-131. 3), P = 10(-10)]. CONCLUSIONS: The major histocompatibility locus (MHC) associations with FS reported here are due to linkage disequilibrium with HLA-DRB1*0401. LGL syndrome with arthritis shows identical class II associations with FS, although there may be subtle immunogenetic differences between the two in the class I region. One of the extended haplotypes reported in a number of studies for FS and rheumatoid arthritis (summarized as HLA-A*02;Cw*0501; B*44;TNFb5;TNFa6;TNFd4;C4A*3;C4BQ*0;DRB1*0 401;DQB1*0301) is likely to be attributable to strong primary association with HLA-DRB1*0401, rather than to epistatic interaction between these loci.


Subject(s)
Arthritis, Rheumatoid/complications , Felty Syndrome/genetics , Felty Syndrome/immunology , HLA-DR Antigens/genetics , Major Histocompatibility Complex/genetics , Adult , Aged , Alleles , Arthritis, Rheumatoid/genetics , Female , Genetic Predisposition to Disease , HLA-DRB1 Chains , Haplotypes , Humans , Leukemia, Lymphoid/genetics , Linkage Disequilibrium , Major Histocompatibility Complex/immunology , Male , Middle Aged , Syndrome
20.
Blood ; 95(10): 3219-22, 2000 May 15.
Article in English | MEDLINE | ID: mdl-10807792

ABSTRACT

Chronic neutropenia, often associated with rheumatoid arthritis, is a characteristic finding in large granular lymphocyte (LGL) leukemia. The mechanism of neutropenia is not known. Normal neutrophil survival is regulated by the Fas-Fas ligand apoptotic system. We hypothesized that neutropenia in LGL leukemia is mediated by dysregulated expression of Fas ligand. Levels of Fas ligand in serum samples from patients with LGL leukemia were measured with a Fas ligand enzyme-linked immunosorbent assay. The effects of serum from patients with LGL leukemia on apoptosis of normal neutrophils were determined by flow cytometry and morphologic assessment. High levels of circulating Fas ligand were detected in 39 of 44 serum samples from patients with LGL leukemia. In contrast, Fas ligand was undetectable in 10 samples from healthy donors. Serum from the patients triggered apoptosis of normal neutrophils that depended partly on the Fas pathway. Resolution of neutropenia was associated with disappearance or marked reduction in Fas ligand levels in 10 of 11 treated patients. These data suggest that high levels of Fas ligand are a pathogenetic mechanism in human disease. (Blood. 2000;95:3219-3222)


Subject(s)
Leukemia, Lymphoid/pathology , Membrane Glycoproteins/genetics , Neutropenia/genetics , Neutropenia/pathology , fas Receptor/genetics , Apoptosis/genetics , Chronic Disease , Fas Ligand Protein , Gene Expression Regulation, Neoplastic , Humans , Leukemia, Lymphoid/genetics , Membrane Glycoproteins/blood , fas Receptor/blood
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