-
[show abstract]
[hide abstract]
ABSTRACT: Chronic hepatitis C virus (HCV) infection is associated with cirrhosis, autoimmunity and lymphoproliferative disorders. We have previously reported a differential regulation of T and B lymphocytes by HCV core protein in vitro. In this report, we employed a translational approach to characterize the activation status of peripheral B cells from individuals with chronic HCV infection and to explore potential mechanisms for B-cell dysregulation in the setting of HCV infection. In contrast to the T-cell suppression observed in HCV-infected individuals, B cells exhibit a non-specific polyclonal activation phenotype, characterized by significantly higher levels of (1) the early activation marker, CD69, (2) the costimulatory molecule, CD86, and (3) the CCR5 chemokine receptor, CD195, when compared with B cells from healthy donors in response to phytohaemagglutinin (PHA) stimulation. Importantly, tumour necrosis factor- and Apo-L-related leucocyte-expressed ligand-1 (TALL-1), also known as B-lymphocyte stimulator (BLYS), was found to be up-regulated on the surface of B cells from HCV patients in response to PHA as well as HCV core antigen stimulation. This up-regulation of TALL-1 was associated with vigorous memory B-cell responses to viral antigenic stimulation. Additionally, suppressor of cytokine signalling-1 (SOCS-1), a negative feedback immunoregulator that is inhibited in B lymphocytes by HCV core in vitro, was also inhibited in B cells from HCV patients when compared with healthy donors. These findings suggest that TALL-1 over-expression and SOCS-1 suppression are associated with aberrant B-cell activation, providing a plausible basis for the B-cell clonal expansion underlying the lymphoproliferative disorders and autoimmune phenomena observed during chronic HCV infection.
Immunology 11/2009; 128(2):227-35. · 3.32 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The mechanisms by which opioids affect progression of human immunodeficiency virus type 1 (HIV-1) infection are not well-defined. HIV-1 gp120 is important in the apoptotic death of uninfected, bystander T cells. In this study, we show that co-treatment of human peripheral blood mononuclear cells (PBMC) with HIV-1 gp120/morphine synergistically induces apoptosis in PBMC. Co-treatment of murine splenocytes from mu opiate receptor knockout mice with gp120/morphine resulted in decreased apoptosis when compared to splenocytes from wild type mice. Co-treatment of human PBMC or murine splenocytes with gp120/morphine led to decreased expression of beta-arrestin 2, a protein required for opioid-mediated signaling. The role of beta-arrestin 2 was confirmed in Jurkat lymphocytes, in which 1) over-expression of beta-arrestin 2 inhibited gp120/morphine-induced apoptosis and 2) RNA interference of beta-arrestin 2 expression enhanced gp120/morphine-induced apoptosis. These data suggest a novel mechanism by which HIV-1 gp120 and opioids induce lymphocyte cell death.
Biochimica et Biophysica Acta 06/2009; 1793(8):1366-71. · 4.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: An increased susceptibility to infectious diseases in the setting of opiate use has long been noted. Studies on the specific
roles of opiates in immune cells using opioid agonists and antagonists reveal a broad array of effects that include altered
T and B cell proliferation, antibody production, natural killer cell activity, and cytokine production. The complexity of
these effects in the setting of multiple opioid receptor subtypes has only recently been recognized. Novel, receptor-specific
opioid antagonists permit more robust studies on the protean effects of these agents on immune cells. This chapter will emphasize
what is known about the biologic and clinical effects of opioids on immune function with a focus on the role of opioid antagonists.
KeywordsOpioids–Immunity–Antagonists–Lymphocyte–Infection
12/2008: pages 67-80;
-
[show abstract]
[hide abstract]
ABSTRACT: Persistent lip swelling can be a diagnostic challenge. We report an unusual case of lip edema in the setting of lip surgery 30 years before presentation and because of retained foreign material. This case highlights the importance of accurate historical information and aggressive diagnostic methods in assessing persistent lip swelling.
Southern medical journal 07/2008; 101(6):651-3. · 0.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Strongyloidiasis can present with a wide variety of symptoms and can lead to a potentially fatal hyperinfection. Although any factors that suppress the host defense mechanisms can potentially trigger hyperinfection, prolonged steroid use has been quite well described. A patient with disseminated small cell lung cancer suffered a Strongyloides stercoralis hyperinfection syndrome complicating ectopic adrenocorticotropic hormone (Cushing syndrome). Evaluation revealed lymphopenia, elevated levels of adrenocorticotropic hormone in the setting of elevated cortisol levels, a normal pituitary, and metastatic malignancy. S. stercoralis larval forms were seen in the stool and sputum. At autopsy, S. stercoralis larval forms were seen in the lung along with evidence of metastatic small cell lung carcinoma.
Southern medical journal 07/2008; 101(7):750-2. · 0.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hepatitis C virus (HCV) infection is characterized by a strong propensity toward chronicity, autoimmune phenomena and lymphomagenesis, supporting a role for lymphocyte dysregulation during persistent viral infection. We have shown that HCV core protein inhibits T-cell functions through interaction with a complement receptor, gC1qR. Here, we further report that B cells also express gC1qR that can be bound by HCV core protein. Importantly, using flow cytometry, we demonstrated differential regulation of B and T lymphocytes by the HCV core-gC1qR interaction, with down-regulation of CD69 activation in T cells but up-regulation of CD69 activation and cell proliferation in B cells. HCV core treatment led to decreased interferon-gamma production in CD8+ T cells but to increased immunoglobulin M and immunoglobulin G production as well as cell surface expression of costimulatory and chemokine receptors, including CD86 (B7-2), CD154 (CD40L) and CD195 (CCR5), in CD20+ B cells. Finally, we showed down-regulation of suppressor of cytokine signalling-1 (SOCS-1) using real-time reverse transcription-polymerase chain reaction, accompanied by up-regulation of signal transducer and activator of transcription-1 (STAT1) phosphorylation in B cells in response to HCV core protein, with the opposite pattern observed in HCV core-treated T cells. This study demonstrates differential regulation of B and T lymphocytes by HCV core and supports a mechanism by which lymphocyte dysregulation occurs in the course of persistent HCV infection.
Immunology 05/2008; 125(2):197-207. · 3.32 Impact Factor
-
Yi Zhang,
Michael Woodruff,
Ying Zhang,
Junying Miao,
Gregory Hanley,
Charles Stuart,
Xiao Zeng,
Savita Prabhakar, Jonathan Moorman,
Baoxiang Zhao,
Deling Yin
[show abstract]
[hide abstract]
ABSTRACT: Stress, either physical or psychological, can have a dramatic impact on the immune system. Little progress, however, has been made in understanding stress-induced immune suppression. We report here that mice subjected to chronic 12-hour daily physical restraint for two days significantly increased the expression of Toll-like receptor 4 (TLR4). Interestingly, TLR4-deficient mice are resistant to stress-induced lymphocyte reduction. In addition, restraint stress caused dramatic decrease in T help 1 (Th1) cytokine IFN-gamma and IL-2 levels but increase in Th2 cytokine IL-4 in wild type mice. Moreover, the restraint stress significantly inhibits changes of Th1 and Th2 cytokines in TLR4-deficient mice compared with the wild type mice. Therefore, stress modulates the immune system through a TLR4-dependent mechanism.
Journal of Neuroimmunology 03/2008; 194(1-2):115-22. · 2.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Reports have shown that a negative T cell costimulatory pathway mediated by PD-1 (programmed death-1) and PDL-1 (programmed death ligand-1) is associated with T cell exhaustion and persistent viral infection. Persistent hepatitis C virus (HCV) infection in humans is also characterized by impaired T lymphocyte function, but the role of the PD-1 and PDL-1 pathway in HCV infection is unknown. Here we report that T cells isolated from chronically HCV-infected patients express significantly higher levels of PD-1 when compared with healthy donors. In addition, PD-1 and PDL-1 expression is upregulated on healthy donor T cells exposed to HCV core, a nucleocapsid protein that is immunosuppressive; upregulation of PD-1 is mediated through interaction of HCV core with the complement receptor, gC1qR. Importantly, T cell functions that are dysregulated by HCV core, including T cell activation, proliferation, and apoptosis, can be restored by blocking PD-1 and PDL-1 engagement. Our results indicate that HCV core can upregulate a key negative T cell signaling pathway associated with viral persistence and highly expressed on the T cells of persistently infected individuals. This upregulation of the PD-1 and PDL-1 pathway in humans represents a novel and perhaps common mechanism by which a virus usurps host machinery to facilitate persistence.
Viral Immunology 02/2007; 20(2):276-87. · 1.97 Impact Factor
-
Deling Yin,
Ying Zhang,
Charles Stuart,
Junying Miao,
Yi Zhang,
Chuanfu Li,
Xiao Zeng,
Gregory Hanley, Jonathan Moorman,
Zhiqiang Yao,
Michael Woodruff
[show abstract]
[hide abstract]
ABSTRACT: Psychological and physical stress can alter the immune system in both humans and animals. We have reported that mice subjected to chronic 12-h daily physical restraint for 2 days showed dramatic apoptosis in splenocytes. To identify genes that contribute to the splenocyte apoptosis, we compare gene expression in the spleens of restrained and unstressed mice using oligo microarrays consisting of 226 genes. We report here that mice subjected to chronic 12-h daily physical restraint for 2 days exhibited significantly altered expression of 50 of 226 genes. These genes included pro-apoptotic genes. We selected 5 genes of interest and confirmed the microarray results by real-time PCR. In this study, we identify a potentially important component of pro-apoptotic activity in restraint stress and suggest a possible target for anti-apoptotic therapy to protect splenocytes against stress-induced apoptosis.
Journal of Neuroimmunology 09/2006; 177(1-2):11-7. · 2.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Central nervous system (CNS) infection with Morganella morganii is very rare. We describe a 38-year-old female patient with frontal brain abscess caused by M morganii who was unsuccessfully treated. We also review all reported cases of Morganella CNS infections with an emphasis on treatment modalities and outcomes. Aggressive surgical management and appropriate antimicrobial therapy can lead to cure, but the mortality rate for these infections remains high.
The American Journal of the Medical Sciences 02/2006; 331(1):44-7. · 1.39 Impact Factor
-
New England Journal of Medicine 12/2005; 353(18):e16. · 53.30 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hepatitis C virus (HCV) infection is a chronic blood-borne disease that affects > 4,000,000 individuals in the United States. The majority of individuals with HVC infection acquire a chronic hepatitis that predisposes them to the complications of cirrhosis and hepatoma. Chronic HCV infection is, however, associated with multiple extrahepatic manifestations as well, including recently recognized effects on the lung. These include primary effects on lung function, as well as secondary effects in the settings of progressive liver disease and drug treatment for HCV. In this article, we discuss the emerging clinical data that support a role for HCV infection in lung disease, describe the multiple pulmonary manifestations of this viral infection, and outline the therapies available for specific pulmonary complications of chronic HCV infection.
Chest 10/2005; 128(4):2882-92. · 5.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Actinomycotic infections involving the oesophagus are uncommon but have been reported in both immunocompromised and immunocompetent individuals. We report a case of actinomycosis oesophagitis in a patient with lung cancer who received chemo- and radiotherapy. This patient was admitted with severe dysphagia and odynophagia and biopsy from an oesophageal ulcer found on oesophagogastroduodenoscopy (EGD) revealed actinomycosis. The patient was treated with intravenous penicillin G followed by ceftriaxone with clinical improvement and repeat EGD showed reduction in the size of the oesophageal ulcer, but he relapsed due to non-compliance. We review the English literature regarding the clinical features, diagnosis, and management of actinomycotic infections of the oesophagus.
The Journal of infection 09/2005; 51(2):E39-43. · 4.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Acute flaccid paralysis (AFP) has recently emerged as a major central nervous system complication associated with West Nile virus (WNV) infection. The spectrum of clinical presentations of AFP in WNV infection and its sequelae have not been well-studied.
We describe three patients with AFP due to WNV infection and review the clinical presentations of 56 patients with this complication derived from published studies.
Patients with AFP and WNV presented with a spectrum of illness ranging from single extremity paralysis to quadriparalysis with cranial nerve involvement. Patients commonly developed respiratory failure (54%) and bladder dysfunction (22%). While fever was nearly universal (92%), signs of meningismus were less common (17%). Cerebrospinal fluid (CSF) analysis generally revealed a modest pleocytosis, and imaging studies were not diagnositic. Persistent neurologic impairment occurred in all survivors; overall mortality rate was high (22%) and was associated with both the extent of paralysis and advanced age.
AFP in the setting of WNV is associated with significant mortality and long-term morbidity.
The Journal of infection 09/2005; 51(2):120-7. · 4.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Abstract
Background
Recent studies suggest that HCV infection is associated with progressive declines in pulmonary function in patients with underlying pulmonary diseases such as asthma and chronic obstructive pulmonary disease. Few molecular studies have addressed the inflammatory aspects of HCV-associated pulmonary disease. Because IL-8 plays a fundamental role in reactive airway diseases, we examined IL-8 signaling in normal human lung fibroblasts (NHLF) in response to the HCV nucleocapsid core protein, a viral antigen shown to modulate intracellular signaling pathways involved in cell proliferation, apoptosis and inflammation.
Methods
NHLF were treated with HCV core protein and assayed for IL-8 expression, phosphorylation of the p38 MAPK pathway, and for the effect of p38 inhibition.
Results
Our studies demonstrate that soluble HCV core protein induces significant increases in both IL-8 mRNA and protein expression in a dose- and time-dependent manner. Treatment with HCV core led to phosphorylation of p38 MAPK, and expression of IL-8 was dependent upon p38 activation. Using TNFα as a co-stimulant, we observed additive increases in IL-8 expression. HCV core-mediated expression of IL-8 was inhibited by blocking gC1qR, a known receptor for soluble HCV core linked to MAPK signaling.
Conclusion
These studies suggest that HCV core protein can lead to enhanced p38- and gC1qR-dependent IL-8 expression. Such a pro-inflammatory role may contribute to the progressive deterioration in pulmonary function recently recognized in individuals chronically infected with HCV.
Respiratory Research. 01/2005;
-
Jonathan P. Moorman
[show abstract]
[hide abstract]
ABSTRACT: Co-infection of patients with hepatitis C virus (HCV) and HIV is prevalent. HCV disease is clearly exacerbated in the setting of HIV disease, and the long-term effects of HCV have become an increasing concern as patients live longer on highly active antiretroviral therapy. Although treatment for HCV disease is evolving rapidly, its role in the HIV-infected patient is not well delineated. This review will focus on the major issues in the HIV/HCV co-infected patient and discuss therapy for HCV in the era of highly active antiretroviral therapy.
Current Infectious Disease Reports 05/2001; 3(2):131-136.
-
[show abstract]
[hide abstract]
ABSTRACT: The mechanisms by which opioids affect progression of human immunodeficiency virus type 1 (HIV-1) infection are not well-defined. HIV-1 gp120 is important in the apoptotic death of uninfected, bystander T cells. In this study, we show that co-treatment of human peripheral blood mononuclear cells (PBMC) with HIV-1 gp120/morphine synergistically induces apoptosis in PBMC. Co-treatment of murine splenocytes from μ opiate receptor knockout mice with gp120/morphine resulted in decreased apoptosis when compared to splenocytes from wild type mice. Co-treatment of human PBMC or murine splenocytes with gp120/morphine led to decreased expression of β-arrestin 2, a protein required for opioid-mediated signaling. The role of β-arrestin 2 was confirmed in Jurkat lymphocytes, in which 1) over-expression of β-arrestin 2 inhibited gp120/morphine-induced apoptosis and 2) RNA interference of β-arrestin 2 expression enhanced gp120/morphine-induced apoptosis. These data suggest a novel mechanism by which HIV-1 gp120 and opioids induce lymphocyte cell death.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.
