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Atae Utsunomiya,
Toshihiko Izumi,
Steven Jacobson,
Tomoo Sato,
Ryoji Fujii,
Kazuko Azakami,
Hidetoshi Fujita,
Toshihiro Nakajima,
Yoshihisa Yamano,
Naoko Yagishita,
Daisuke Hasegawa,
Natsumi Araya, Kusuki Nishioka,
Satoko Aratani
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ABSTRACT: Human T cell lymphotropic virus type 1 (HTLV-1) infection can lead to development of adult T cell leukemia/lymphoma (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a subset of infected subjects. HTLV-1 basic leucine zipper factor (HBZ) gene has a critical role in HTLV-1 infectivity and the development of ATL and HAM/TSP. However, little is known about the immune response against HBZ in HTLV-1-infected individuals. In this study, we examined antibody responses against HBZ in serum/plasma samples from 436 subjects including HTLV-1 seronegative donors, asymptomatic carriers (AC), ATL, and HAM/TSP patients using the luciferase immunoprecipitation system.
Immunoreactivity against HBZ was detected in subsets of all HTLV-1-infected individuals but the test did not discriminate between AC, ATL and HAM/TSP. However, the frequency of detection of HBZ-specific antibodies in the serum of ATL patients with the chronic subtype was higher than in ATL patients with the lymphomatous subtype. Antibody responses against HBZ were also detected in cerebrospinal fluid of HAM/TSP patients with anti-HBZ in serum. Antibody responses against HBZ did not correlate with proviral load and HBZ mRNA expression in HAM/TSP patients, but the presence of an HBZ-specific response was associated with reduced CD4+ T cell activation in HAM/TSP patients. Moreover, HBZ-specific antibody inhibited lymphoproliferation in the PBMC of HAM/TSP patients.
This is the first report demonstrating humoral immune response against HBZ associated with HTLV-I infection. Thus, a humoral immune response against HBZ might play a role in HTLV-1 infection.
Retrovirology 01/2013; 10:19. · 6.47 Impact Factor
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ABSTRACT: Translocator protein (18 kDa) (TSPO) is a marker of inflammation in the brain. Positron emission tomography (PET) scans with ligands for this receptor show increased expression of TSPO in many neuropathologic conditions. However, expression of TSPO in the periphery and its possible correlation to central nervous system (CNS) inflammation has been largely unstudied. In this paper PBR28, a recently synthesized ligand for TSPO that is shown to have 80-fold higher specific binding than its predecessor PK11195, is used to quantify peripheral TSPO. Data presented in this study show that monocytes account for the majority of TSPO measured in peripheral blood mononuclear cells (PBMC), and that TSPO expression is stable over time in healthy individuals. Previous studies show that areas of increased PBR28 binding in the brains of multiple sclerosis (MS) patients correlate with active demylinating lesions found during magnetic resonance imaging (MRI). To measure peripheral TSPO expression in an inflammatory disease of the CNS, PBR28 is used in an in vitro radioligand binding assay to measure the amount of TSPO in the PBMC of MS and healthy donor cohorts. Surprisingly, MS patients are found to have a significantly lower amount of peripheral TSPO than healthy donors. We suggest that TSPO protein expression is a potential peripheral biomarker of MS, more research is needed to determine if peripheral TSPO expression may also be altered in other neuroinflammatory conditions.
Journal of Neuroimmune Pharmacology 09/2012; · 4.57 Impact Factor
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ABSTRACT: Adult T-cell leukemia (ATL) and human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are known to be caused by HTLV-I infection. However, current methods used to determine HTLV-I infection do not differentiate between HTLV-I asymptomatic carriers (ACs) and ATL and HAM/TSP patients. Using the luciferase immunoprecipitation system, a highly sensitive, quantitative technology that can efficiently detect HTLV-I Ab responses, we examined Ab responses for HTLV-I in serum/plasma samples from 439 subjects in Jamaica, including HTLV-I-seronegative donors, ACs, and ATL and HAM/TSP patients. The Ab responses of HTLV-I-infected subjects differed significantly from those of seronegative donors for all 3 immunodominant proteins, Gag, Env, and Tax. HAM/TSP patients had significantly higher Ab responses for Gag and Env compared with ACs, and Ab responses for all 3 Ags were higher in HAM/TSP patients than in ATL patients. Moreover, immunoreactivities for HTLV-I Ags as determined by the luciferase immunoprecipitation system could distinguish HAM/TSP patients from ACs at a true-positive rate of 85.42% and from ATL patients at a true-positive rate of 75.00%, and modeled in conjunction with subject information to distinguish HAM/TSP patients from ACs (odds ratio = 14.12) and from ATL patients (odds ratio = 7.00). The relative risk assessment resulting from these significant differences between Ab responses in HTLV-I-infected groups may be a useful diagnostic tool in the future.
Blood 02/2012; 119(12):2829-36. · 9.90 Impact Factor
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ABSTRACT: BACKGROUND: Human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a disabling neurological disorder characterized by inflammatory changes in the spinal cord. We used a semiautomatic technique to quantify spinal cord volume from 3-dimensional MR images of patients with HAM/TSP. METHODS: Five patients and 5 matched healthy volunteers (HVs) underwent MRI of the cervical and thoracic spinal cord at 1.5 T. Quantification of the spinal cord volume was obtained from 3-dimensional MR images using a semiautomatic technique based on level sets. An unpaired t-test was used to assess statistical significance. RESULTS: Significant differences were found between mean spinal cord volume of HVs and HAM/TSP patients. The thoracic spinal cord volume was 14,050 ± 981 mm(3) for HVs and 8,774 ± 2,218 mm(3) for HAM/TSP patients (P= .0079), a reduction of 38%. The cervical spinal cord volume was 9,721 ± 797 mm(3) for HVs and 6,589 ± 897 mm(3) for HAM/TSP patients (P= .0079), a reduction of 32%. These results suggest that atrophy is evident throughout the spinal cord not routinely quantified. CONCLUSIONS: Semiautomatic spinal cord volume quantification is a sensitive technique for quantifying the extent of spinal cord involvement in HAM/TSP. J Neuroimaging 2012;XX:1-5.
Journal of neuroimaging: official journal of the American Society of Neuroimaging 02/2012; · 1.72 Impact Factor
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ABSTRACT: The activation of mononuclear phagocytes (MPs), including monocytes, macrophages and dendritic cells, contributes to central nervous system inflammation in various neurological diseases. In HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), MPs are reservoirs of HTLV-I, and induce proinflammatory cytokines and excess T cell responses. The virus-infected or activated MPs may play a role in immuneregulation and disease progression in patients with HTLV-I-associated neurological diseases.
Phenotypic analysis of CD14⁺ monocytes in HAM/TSP patients demonstrated high expression of CX3CR1 and HLA-DR in CD14lowCD16⁺ monocytes, compared to healthy normal donors (NDs) and asymptomatic carriers (ACs), and the production of TNF-α and IL-1β in cultured CD14⁺ cells of HAM/TSP patients. CD14⁺ cells of HAM/TSP patients also showed acceleration of HTLV-I Tax expression in CD4⁺ T cells. Minocycline, an inhibitor of activated MPs, decreased TNF-α expression in CD14⁺ cells and IL-1β release in PBMCs of HAM/TSP patients. Minocycline significantly inhibited spontaneous lymphoproliferation and degranulation/IFN-γ expression in CD8⁺ T cells of HAM/TSP patients. Treatment of minocycline also inhibited IFN-γ expression in CD8⁺ T cells of HAM/TSP patients after Tax11-19 stimulation and downregulated MHC class I expression in CD14⁺ cells.
These results demonstrate that minocycline directly inhibits the activated MPs and that the downregulation of MP function can modulate CD8⁺ T cells function in HAM/TSP patients. It is suggested that activated MPs may be a therapeutic target for clinical intervention in HAM/TSP.
Retrovirology 01/2012; 9:16. · 6.47 Impact Factor
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ABSTRACT: Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that is the causative agent of adult T cell leukemia/lymphoma (ATL) and associated with multiorgan inflammatory disorders, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. HTLV-1-infected T cells have been hypothesized to contribute to the development of these disorders, although the precise mechanisms are not well understood. HTLV-1 primarily infects CD4(+) T helper (Th) cells that play a central role in adaptive immune responses. Based on their functions, patterns of cytokine secretion, and expression of specific transcription factors and chemokine receptors, Th cells that are differentiated from naïve CD4(+) T cells are classified into four major lineages: Th1, Th2, Th17, and T regulatory (Treg) cells. The CD4(+)CD25(+)CCR4(+) T cell population, which consists primarily of suppressive T cell subsets, such as the Treg and Th2 subsets in healthy individuals, is the predominant viral reservoir of HTLV-1 in both ATL and HAM/TSP patients. Interestingly, CD4(+)CD25(+)CCR4(+) T cells become Th1-like cells in HAM/TSP patients, as evidenced by their overproduction of IFN-γ, suggesting that HTLV-1 may intracellularly induce T cell plasticity from Treg to IFN-γ(+) T cells. This review examines the recent research into the association between HTLV-1 and Treg cells that has greatly enhanced understanding of the pathogenic mechanisms underlying immune dysregulation in HTLV-1-associated neuroinflammatory disease.
Viruses 09/2011; 3(9):1532-48. · 1.50 Impact Factor
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Unsong Oh,
Masahiro Fujita,
Vasiliki N Ikonomidou,
Iordanis E Evangelou,
Eiji Matsuura,
Erin Harberts,
Yota Fujimura,
Nancy D Richert,
Joan Ohayon,
Victor W Pike,
Yi Zhang,
Sami S Zoghbi,
Robert B Innis, Steven Jacobson
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ABSTRACT: Glial activation in the setting of central nervous system inflammation is a key feature of the multiple sclerosis (MS) pathology. Monitoring glial activation in subjects with MS, therefore, has the potential to be informative with respect to disease activity. The translocator protein 18 kDa (TSPO) is a promising biomarker of glial activation that can be imaged by positron emission tomography (PET). To characterize the in vivo TSPO expression in MS, we analyzed brain PET scans in subjects with MS and healthy volunteers in an observational study using [(11)C]PBR28, a newly developed translocator protein-specific radioligand. The [(11)C]PBR28 PET showed altered compartmental distribution of TSPO in the MS brain compared to healthy volunteers (p = 0.019). Focal increases in [(11)C]PBR28 binding corresponded to areas of active inflammation as evidenced by significantly greater binding in regions of gadolinium contrast enhancement compared to contralateral normal-appearing white matter (p = 0.0039). Furthermore, increase in [(11)C]PBR28 binding preceded the appearance of contrast enhancement on magnetic resonance imaging in some lesions, suggesting a role for early glial activation in MS lesion formation. Global [(11)C]PBR28 binding showed correlation with disease duration (p = 0.041), but not with measures of clinical disability. These results further define TSPO as an informative marker of glial activation in MS.
Journal of Neuroimmune Pharmacology 09/2011; 6(3):354-61. · 4.57 Impact Factor
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ABSTRACT: Viruses have been implicated in the development of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and multiple sclerosis. Human herpesvirus-6 (HHV-6) is a neurotropic virus that has been associated with a wide variety of neurologic disorders, including encephalitis, mesial temporal lobe epilepsy, and multiple sclerosis. Currently, the route of HHV-6 entry into the CNS is unknown. Using autopsy specimens, we found that the frequency of HHV-6 DNA in the olfactory bulb/tract region was among the highest in the brain regions examined. Given this finding, we investigated whether HHV-6 may infect the CNS via the olfactory pathway. HHV-6 DNA was detected in a total of 52 of 126 (41.3%) nasal mucous samples, showing the nasal cavity is a reservoir for HHV-6. Furthermore, specialized olfactory-ensheathing glial cells located in the nasal cavity were demonstrated to support HHV-6 replication in vitro. Collectively, these results support HHV-6 utilization of the olfactory pathway as a route of entry into the CNS.
Proceedings of the National Academy of Sciences 08/2011; 108(33):13734-9. · 9.68 Impact Factor
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ABSTRACT: Human T-lymphotropic virus type I (HTLV-I) infects an estimated 15-20 million persons worldwide. A number of diseases have been associated with the virus including adult T-cell leukemia (ATL), HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-I uveitis, and HTLV-I-associated infective dermatitis. Once it was shown that there is an increased risk for developing HAM/TSP associated with blood transfusion, screening for HTLV-1 among blood banks was implemented in Japan, United States, France, and the Netherlands. This process includes detection by an enzyme immunoassay (EIA) followed by a confirmatory Western blot (WB) in which recombinant proteins specific for HTLV-I Env glycoproteins are incorporated into WB strips. HTLV-I seropositive results are defined by the presence of antibodies against either gp46 or gp62/68 (both Env protein bands) and either p19, p24, or p53 (one of the gag bands). HTLV-II seropositivity is confirmed by the presence of rgp46-II. However, numerous cases have been documented in which serum samples are reactive by EIA, but an incomplete banding pattern is displayed by subsequent confirmatory WB. Although the significance of these HTLV-I/II seroindeterminates is unclear, it may suggest a much higher incidence of exposure to HTLV-I/II than previously estimated.
Viruses 08/2011; 3(8):1320-31. · 1.50 Impact Factor
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Unsong Oh,
Masahiro Fujita,
Vasiliki N Ikonomidou,
Iordanis E Evangelou,
Eiji Matsuura,
Erin Harberts,
Yota Fujimura,
Nancy D Richert,
Joan Ohayon,
Victor W Pike,
Yi Zhang,
Sami S Zoghbi,
Robert B Innis, Steven Jacobson
Journal of Neuroimmune Pharmacology 04/2011; · 4.57 Impact Factor
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Wei Ju,
Meili Zhang,
Jian-kang Jiang,
Craig J Thomas,
Unsong Oh,
Bonita R Bryant,
Jing Chen,
Noriko Sato,
Yutaka Tagaya,
John C Morris,
John E Janik, Steven Jacobson,
Thomas A Waldmann
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ABSTRACT: The retrovirus, human T-cell-lymphotrophic virus-1 (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL) and the neurological disorder HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-I-encoded protein tax constitutively activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems that in turn activate the Jak3 (Janus kinase 3)/STAT5 (signal transducers and activators of transcription 5) pathway, suggesting a therapeutic strategy that involves targeting Jak3. We evaluated the action of the Jak3 inhibitor CP-690,550 on cytokine dependent ex vivo proliferation that is characteristic of peripheral blood mononuclear cells (PBMCs) from select patients with smoldering or chronic subtypes of ATL, or from those with HAM/TSP whose PBMCs are associated with autocrine/paracrine pathways that involve the production of IL-2, IL-9, IL-15, and their receptors. CP-690,550 at 50 nM inhibited the 6-day ex vivo spontaneous proliferation of PBMCs from ATL and HAM/TSP patients by 67.1% and 86.4%, respectively. Furthermore, CP-690,550 inhibited STAT5 phosphorylation in isolated ATL T cells ex vivo. Finally, in an in vivo test of biological activity, CP-690,550 treatment of mice with a CD8 T-cell IL-15-transgenic leukemia that manifests an autocrine IL-15/IL-15Rα pathway prolonged the survival duration of these tumor-bearing mice. These studies support further evaluation of the Jak3 inhibitor CP-690,550 in the treatment of select patients with HTLV-I-associated ATL and HAM/TSP.
Blood 02/2011; 117(6):1938-46. · 9.90 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a central nervous system inflammatory disorder with evidence of peripheral immune dysregulation. Abnormalities of the immune suppressive cytokine TGF-β have been reported, but not fully defined, in MS. Through a pathway-focused expression profiling of the peripheral blood, we found abnormalities of TGF-βRII, SMAD4 and SMAD7 expression in subjects with MS, and reduction in the levels of TGF-β regulated genes, indicating an overall reduction in TGF-β signaling in MS. The response to exogenous TGF-β was intact, however, indicating an extrinsic defect of TGF-β signaling in MS. These results indicate that TGF-β control is diminished in MS.
Journal of neuroimmunology 01/2011; 230(1-2):164-8. · 2.84 Impact Factor
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Unsong Oh,
Matthew J McCormick,
Dibyadeep Datta,
Richard V Turner,
Kathryn Bobb,
Dileep D Monie,
D Robert Sliskovic,
Yuetsu Tanaka,
Jie Zhang,
Jeffrey Meshulam, Steven Jacobson
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ABSTRACT: The human T-lymphotropic virus type I (HTLV-I) causes a chronic inflammatory disorder of the central nervous system termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-I encodes a protein known to activate several host-signaling pathways involved in inflammation, such as the nuclear factor-κB (NF-κB). The contribution of the NF-κB pathway to the pathogenesis of HAM/TSP, however, has not been fully defined. We show evidence of canonical NF-κB activation in short-term cultures of peripheral blood mononuclear cells (PBMCs) from subjects with HAM/TSP. NF-κB activation was closely linked to HTLV-I viral protein expression. The NF-κB activation in HAM/TSP PBMCs was reversed by a novel small-molecule inhibitor that demonstrates potent and selective NF-κB antagonist activity. Inhibition of NF-κB activation led to a reduction in the expression of lymphocyte activation markers and resulted in reduced cytokine signaling in HAM/TSP PBMCs. Furthermore, NF-κB inhibition led to a reduction in spontaneous lymphoproliferation, a key ex vivo correlate of the immune activation associated with HAM/TSP. These results indicate that NF-κB activation plays a critical upstream role in the immune activation of HAM/TSP, and identify the NF-κB pathway as a potential target for immunomodulation in HAM/TSP.
Blood 01/2011; 117(12):3363-9. · 9.90 Impact Factor
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ABSTRACT: HTLV-1 is a T lymphotropic human retrovirus that is the causative agent of adult T cell leukemia/lymphoma and is associated
with multiorgan immunological disorders such as chronic myelitis, uveitis, Sjögren syndrome, bronchoalveolitis, arthritis,
and polymyositis. HTLV-1 infection of T-cells induces a variety of abnormalities such as cellular activation, proinflammatory
changes, and proliferation. Here, we discuss the mechanism of HTLV-1 infection-induced immune dysregulation. Since the majority
of autoimmune diseases are of unknown etiology, the discovery of HTLV-1 and its association with these immunological disorders
has greatly enhanced our understanding of the pathogenic mechanisms of organ-specific immune abnormalities.
KeywordATL-CD4+CD25+CCR4+ T cell-exFoxp3+ cell-HAM/TSP-HTLV-1-Regulatory T cell
12/2010: pages 189-198;
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Journal of Medical Virology 10/2010; 82(10):1669-78. · 2.82 Impact Factor
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Journal of Neuroimmune Pharmacology 09/2010; 5(3):267-70. · 4.57 Impact Factor
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ABSTRACT: The membrane co-factor protein CD46 is the cellular receptor for a number of pathogens including the human herpesvirus 6 (HHV-6). In addition to its function as an inhibitory complement receptor, engagement of CD46 in the context of T-cell receptor (TCR) signaling influences T-cell activation. Simultaneous cross-linking of the CD3/CD46 molecules led to differentiation of a unique population of CD4+ T-cell subset characterized by enhanced expressions of IFN-gamma, IL-10, granzyme B, adhesion molecule MAdCAM-1 (alpha-4-beta-7), surface-bound cytokine LIGHT, and chemokine receptor CCR9. Multiple sclerosis is a chronic inflammatory neurodegenerative disorder of the central nervous system (CNS) with unknown etiology. The HHV-6 is a candidate pathogen in MS and uses the CD46 molecule as its receptor. We hypothesize that binding of the HHV-6 glycoprotein to CD46 may trigger a pro-inflammatory response that could contribute to CNS tissue damage. To address this question, we examined immunological parameters such as proliferation, cytokine production and cytotoxic functions in CD4+ T cells of healthy individuals and MS patients following CD3/CD46 co-engagement by using anti-CD3 and anti-CD46 monoclonal antibodies as surrogates to mimic T-cell receptor and CD46 signaling. Our results demonstrated that CD3/CD46 cross-linking induced expression of IL-1beta and IL-17A in multiple sclerosis patient T cells. Additionally, increase in transient surface expression of lysosomal associated protein CD107a suggested enhanced CD4+ T-cell cytotoxic functions following CD3/CD46 co-stimulation. Collectively, this study demonstrated evidence to suggest a potential mechanism of virus-induced neuroinflammation that may be involved in MS disease pathogenesis.
Journal of Neuroimmune Pharmacology 09/2010; 5(3):469-78. · 4.57 Impact Factor
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ABSTRACT: Human T-lymphotrophic virus type I (HTLV-I) is an oncogenic retrovirus and its infection is associated with a variety of human diseases including HTLV-I-associated myelopathy/tropic spastic paraparesis (HAM/TSP). Large numbers of epidemiological, virological, immunological, and clinical studies on HTLV-I- and HTLV-I-associated diseases have been published, although the pathogenesis of HAM/TSP remains to be fully understood. In the last several years, researchers have shown that several key factors are important in HTLV-I-associated neurologic disease including high HTLV-I proviral load and a strong immune response to HTLV-I. Here, we review pathophysiological findings on HAM/TSP and focus on viral-host immune responses to the virus in HTLV-I infected individuals. In particular, the role of HTLV-I-specific CD8+ T cell response is highlighted.
Journal of Neuroimmune Pharmacology 05/2010; 5(3):310-25. · 4.57 Impact Factor
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Shari N Gordon,
Anna R Weissman,
Valentina Cecchinato,
Claudio Fenizia,
Zhong-Min Ma,
Tzong-Hae Lee,
Lorenzo Zaffiri,
Vibeke Andresen,
Robyn Washington Parks,
Kathryn S Jones,
Jean Michel Heraud,
Maria Grazia Ferrari,
Hye Kyung Chung,
David Venzon,
Renaud Mahieux,
Edward L Murphy, Steven Jacobson,
Christopher J Miller,
Francis W Ruscetti,
Genoveffa Franchini
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ABSTRACT: Coinfection with human T-cell lymphotropic virus type 2 (HTLV-2) and human immunodeficiency virus type 1 (HIV-1) has been reported to have either a slowed disease course or to have no effect on progression to AIDS. In this study, we generated a coinfection animal model and investigated whether HTLV-2 could persistently infect macaques, induce a T-cell response, and impact simian immunodeficiency virus SIV(mac251)-induced disease. We found that inoculation of irradiated HTLV-2-infected T cells into Indian rhesus macaques elicited humoral and T-cell responses to HTLV-2 antigens at both systemic and mucosal sites. Low levels of HTLV-2 provirus DNA were detected in the blood, lymphoid tissues, and gastrointestinal tracts of infected animals. Exposure of HTLV-2-infected or naïve macaques to SIV(mac251) demonstrated comparable levels of SIV(mac251) viral replication, similar rates of mucosal and peripheral CD4(+) T-cell loss, and increased T-cell proliferation. Additionally, neither the magnitude nor the functional capacity of the SIV-specific T-cell-mediated immune response was different in HTLV-2/SIV(mac251) coinfected animals versus SIV(mac251) singly infected controls. Thus, HTLV-2 targets mucosal sites, persists, and importantly does not exacerbate SIV(mac251) infection. These data provide the impetus for the development of an attenuated HTLV-2-based vectored vaccine for HIV-1; this approach could elicit persistent mucosal immunity that may prevent HIV-1/SIV(mac251) infection.
Journal of Virology 03/2010; 84(6):3043-58. · 5.40 Impact Factor
