Biomedical subjects

Elizabeth C Jones

Publications and source records attributed to Elizabeth C Jones.

10 recordsLinked to original sources

PubMed2006

Cooperative molecular and cellular networks regulate Toll-like receptor-dependent inflammatory responses.

Viral and bacterial pathogens cause inflammation via Toll-like receptor (TLR) signaling. We have shown that effective responses to LPS may depend on cooperative interactions between TLR-expressing leukocytes and TLR-negative tissue cells. The aim of this work was to determine the roles of such networks in response to agonists of TLRs associated with antiviral and autoimmune responses. The TLR3 agonist poly(I:C) activated epithelial cells, primary endothelial cells, and two types of primary human smooth muscle cells (airway [ASMC] and vascular) directly, while the TLR7/8 agonist R848 required the presence of leukocytes to activate ASMC. In keeping with these data, ASMC expressed TLR3 but not TLR7 or TLR8. Activation of ASMC by poly(I:C) induced a specific cytokine repertoire characterized by induction of CXCL10 generation and the potential to recruit mast cells. We subsequently explored the ability of TLR agonists to cooperate in the induction of inflammation. Dual stimulation with LPS and poly(I:C) caused enhanced cytokine generation from epithelial and smooth muscle cells when in the presence of leukocytes. Thus, inflammatory responses to pathogens are regulated by networks in which patterns of TLR expression and colocalization of tissue cells and leukocytes are critical.

Cells, Cultured↗

PubMed2005

Endotoxin tolerance induces selective alterations in neutrophil function.

Endotoxin tolerance has the potential to limit phagocyte responses to Toll-like receptor (TLR) agonists, but the role of tolerance in regulating neutrophil responses is unknown. We investigated neutrophil responses to prolonged lipopolysaccharide (LPS) exposure and observed induction of tolerance in intracellular signaling pathways and respiratory burst. These effects were not prevented by granulocyte macrophage-colony stimulating factor (GM-CSF) pretreatment, and tolerized neutrophils retained the ability to respond to GM-CSF and other survival factors with a delay in apoptosis. In addition, LPS-exposed neutrophils showed continued generation of CXC chemokine ligand 8, which was not reduced in tolerized cells. Induction of tolerance was associated with a loss of TLR4 surface expression. Tolerance, therefore, induces a selective reprogramming of neutrophil function, but cells retain a predominantly proinflammatory phenotype.

Cell Differentiation↗

PubMed2005

Age-dependent incidence, time course, and consequences of thymic renewal in adults.

Homeostatic regulation of T cells involves an ongoing balance of new T cell generation, peripheral expansion, and turnover. The recovery of T cells when this balance is disrupted provides insight into the mechanisms that govern homeostasis. In a long-term, single cohort study, we assessed the role of thymic function after autologous transplant in adults, correlating serial computed tomography imaging of thymic size with concurrent measurements of peripheral CD4(+) T cell populations. We established the age-dependent incidence, time course, and duration of thymic enlargement in adults and demonstrated that these changes were correlated with peripheral recovery of naive CD45RA(+)CD62L(+) and signal-joint TCR rearrangement excision circle-bearing CD4(+) populations with broad TCR diversity. Furthermore, we demonstrated that renewed thymopoiesis was critical for the restoration of peripheral CD4(+) T cell populations. This recovery encompassed the recovery of normal CD4(+) T cell numbers, a low ratio of effector to central memory cells, and a broad repertoire of TCR Vbeta diversity among these memory cells. These data define the timeline and consequences of renewal of adult thymopoietic activity at levels able to quantitatively restore peripheral T cell populations. They further suggest that structural thymic regrowth serves as a basis for the regeneration of peripheral T cell populations.

Adult↗

PubMed2005

Regulation of human neutrophil chemokine receptor expression and function by activation of Toll-like receptors 2 and 4.

Neutrophil chemokine receptor expression can be altered by exposure to Toll-like receptor (TLR) agonists, a process that is thought to have the potential to localize neutrophils to sites of infection. In order to investigate this process in more detail, we examined the regulation of highly pure neutrophil CXCR1 and CXCR2 expression and function by selective agonists of TLR2 (Pam(3)CSK(4)) and TLR4 (lipopolysaccharide, LPS). CXCR1 and CXCR2 were down-regulated by TLR engagement. CXCR2 loss was more rapid and showed a dependence upon soluble helper molecules (LPS binding protein and CD14) that was not evident for CXCR1, suggesting differential coupling of LPS signalling to CXCR1 and CXCR2 loss. However, TLR engagement in highly pure neutrophils did not result in complete loss of chemokine receptors, and LPS-treated neutrophils remained able to mount a respiratory burst to CXCL8 and CXCL1, and were able to migrate towards CXCL8 in assays of under-agarose chemotaxis. Thus, although treatment of purified human neutrophils with TLR2 and TLR4 agonists modifies chemokine receptor expression, remaining receptors remain functionally competent.

Acute-Phase Proteins↗

PubMed2004

The role of interleukin-1beta in direct and toll-like receptor 4-mediated neutrophil activation and survival.

The regulation of systemic and local neutrophil activation is crucial to the clearance of infections and the successful resolution of inflammation without progress to tissue damage or disseminated inflammatory reactions. Using purified lipopolysaccharide (pLPS) and highly purified neutrophils, we have previously shown that Toll-like receptor 4 signaling is a potent neutrophil activator, but a poor stimulator of survival. In the presence of peripheral blood mononuclear cells (PBMCs), however, pLPS becomes a potent neutrophil survival factor. Interleukin (IL)-1beta has been identified as an important neutrophil activator and prosurvival cytokine, and is produced in abundance by LPS-stimulated PBMCs. We now show that IL-1beta fails to activate highly purified neutrophils or enhance their survival, but in the presence of PBMCs, IL-1beta induces neutrophil survival. We hypothesized that LPS-primed neutrophils might become responsive to IL-1beta, but were unable to demonstrate this. Moreover, IL-1ra failed to prevent pLPS + PBMC-dependent neutrophil survival. In studies of IL-1R1(-/-) mice, we found that LPS was still able to mediate neutrophil survival, and neutrophil survival was enhanced by the addition of monocytic cells. Thus an important paradigm of neutrophil regulation needs to be viewed in the context of a cellular network in which actions of IL-1beta on neutrophils are indirect and mediated by other cells.

Animals↗

PubMed2003

Increases in CD4+ T lymphocytes occur without increases in thymic size in HIV-infected subjects receiving interleukin-2 therapy.

OBJECTIVE: To examine the potential contribution of the thymus to CD4+ T-lymphocyte increases in HIV-infected patients receiving intermittent interleukin-2 (IL-2) therapy. DESIGN: Fifteen HIV-infected patients treated with antiretroviral regimens who were enrolled in a study of intermittent IL-2 therapy and were willing to undergo serial thymic computed tomography (CT) were prospectively studied. METHODS: Thymic CT was performed before and approximately 6 and 12-17 months after intermittent IL-2 therapy was started. Scans were graded in a blinded manner. Changes in lymphocyte subpopulations were determined by flow cytometry. RESULTS: Statistically significant increases in CD4+ T lymphocytes occurred with IL-2 administration, with a preferential increase in naive relative to memory CD4+ T cells. Despite this increase in naive CD4+ T cells, overall there was a modest decrease in thymic volume observed during the study period. No correlation was found between changes in thymic volume indices and total, naive, or memory CD4+ T-lymphocyte counts. CONCLUSIONS: These findings demonstrate that the profound CD4+ T-lymphocyte increases seen with intermittent IL-2 administration are not associated with increases in thymic volume and more likely are due to peripheral expansion rather than increased thymic output.

Adult↗

PubMed2003

Selective roles for Toll-like receptor (TLR)2 and TLR4 in the regulation of neutrophil activation and life span.

Neutrophil responses to commercial LPS, a dual Toll-like receptor (TLR)2 and TLR4 activator, are regulated by TLR expression, but are amplified by contaminating monocytes in routine cell preparations. Therefore, we investigated the individual roles of TLR2 and TLR4 in highly purified, monocyte-depleted neutrophil preparations, using selective ligands (TLR2, Pam(3)CysSerLys(4) and Staphylococcus aureus peptidoglycan; TLR4, purified LPS). Activation of either TLR2 or TLR4 caused changes in adhesion molecule expression, respiratory burst (alone, and synergistically with fMLP), and IL-8 generation, which was, in part, dependent upon p38 mitogen-activated protein kinase signaling. Neutrophils also responded to Pam(3)CysSerLys(4) and purified LPS with down-regulation of the chemokine receptor CXCR2 and, to a lesser extent, down-regulation of CXCR1. TLR4 was the principal regulator of neutrophil survival, and TLR2 signals showed relatively less efficacy in preventing constitutive apoptosis over short time courses. TLR4-mediated neutrophil survival depended upon signaling via NF-kappa B and mitogen-activated protein kinase cascades. Prolonged neutrophil survival required both TLR4 activation and the presence of monocytes. TLR4 activation of monocytes was associated with the release of neutrophil survival factors, which was not evident with TLR2 activation, and TLR2 activation in monocyte/neutrophil cocultures did not prevent late neutrophil apoptosis. Thus, TLRs are important regulators of neutrophil activation and survival, with distinct and separate roles for TLR2 and TLR4 in neutrophil responses. TLR4 signaling presents itself as a pharmacological target that may allow therapeutic modulation of neutrophil survival by direct and indirect mechanisms at sites of inflammation.

Cell Adhesion Molecules↗

PubMed2002

High prevalence of osteonecrosis of the femoral head in HIV-infected adults.

BACKGROUND: Osteonecrosis has been reported to occur occasionally among HIV-infected patients. The diagnosis of symptomatic osteonecrosis of the hip in two of the authors' patients, together with reports from community physicians, raised a concern that the prevalence of osteonecrosis is increasing. OBJECTIVE: To determine the prevalence of osteonecrosis of the hip in asymptomatic HIV-infected patients and to identify potential risk factors associated with osteonecrosis. DESIGN: Survey and comparison study. SETTING: The Clinical Center of the U.S. National Institutes of Health. PARTICIPANTS: 339 asymptomatic HIV-infected adults (of 364 asked to participate) and 118 age- and sex-matched HIV-negative volunteers enrolled between 1 June and 15 December 1999. MEASUREMENTS: Osteonecrosis of the hip, as documented by magnetic resonance imaging. Data from clinic records and a patient questionnaire administered before magnetic resonance imaging were used in an analysis of risk factors. A subset of patients was evaluated for hypercoagulable state. RESULTS: Fifteen (4.4% [95% CI, 2.5% to 7.2%]) of 339 HIV-infected participants had osteonecrosis lesions on magnetic resonance imaging, and no HIV-negative participants had similar lesions. Among HIV-infected participants, osteonecrosis occurred more frequently in those who used systemic corticosteroids, lipid-lowering agents, or testosterone; those who exercised routinely by bodybuilding; and those who had detectable levels of anticardiolipin antibodies. CONCLUSIONS: Patients infected with HIV have an unexpectedly high occurrence of osteonecrosis of the hip. Although screening asymptomatic patients is not warranted, HIV-infected patients with persistent groin or hip pain should be evaluated for this debilitating complication.

Female↗

PubMed2002

Toll-like receptor (TLR)2 and TLR4 in human peripheral blood granulocytes: a critical role for monocytes in leukocyte lipopolysaccharide responses.

Leukocyte responsiveness to LPS is dependent upon CD14 and receptors of the Toll-like receptor (TLR) family. Neutrophils respond to LPS, but conflicting data exist regarding LPS responses of eosinophils and basophils, and expression of TLRs at the protein level in these granulocyte lineages has not been fully described. We examined the expression of TLR2, TLR4, and CD14 and found that monocytes expressed relatively high levels of cell surface TLR2, TLR4, and CD14, while neutrophils also expressed all three molecules, but at low levels. In contrast, basophils expressed TLR2 and TLR4 but not CD14, while eosinophils expressed none of these proteins. Tested in a range of functional assays including L-selectin shedding, CD11b up-regulation, IL-8 mRNA generation, and cell survival, neutrophils responded to LPS, but eosinophils and basophils did not. In contrast to previous data, we found, using monocyte depletion by negative magnetic selection, that neutrophil responses to LPS were heavily dependent upon the presence of a very low level of monocytes, and neutrophil survival induced by LPS at 22 h was monocyte dependent. We conclude that LPS has little role in the regulation of peripheral blood eosinophil and basophil function, and that, even in neutrophils, monocytes orchestrate many previously observed leukocyte LPS response patterns.

Basophils↗

PubMed2002

Lymphangioleiomyomatosis: correlation of qualitative and quantitative thin-section CT with pulmonary function tests and assessment of dependence on pleurodesis.

PURPOSE: To explore the relationship between findings at thin-section computed tomography (CT) and pulmonary function tests in lymphangioleiomyomatosis (LAM) and to evaluate the influence of pleurodesis on this relation and the effectiveness of quantitative versus qualitative CT in the assessment of disease severity. MATERIALS AND METHODS: Thirty-seven patients with LAM (17 with pleurodesis) underwent CT and pulmonary function tests. The severity of pulmonary cystic involvement was graded qualitatively by two independent readers and measured quantitatively at CT with a thresholding technique. Relationships between findings at CT and pulmonary function tests and the influence of pleurodesis on these findings were assessed with regression analysis and analysis of covariance. RESULTS: Qualitative ratings had good agreement between observers (kappa = 0.75). Quantitative CT had good repeatability and showed significant correlation with the percent predicted forced expiratory volume in 1 second (FEV(1)%) (r = 0.67, P <.001), percent predicted diffusing capacity of lung for carbon monoxide (DLCO%) (r = 0.48, P <.005), percent predicted ratio of residual volume to total lung capacity (RV/TLC%) (r = -0.65, P <.001), and percent predicted TLC (r = 0.34, P <.04). Quantitative CT results were somewhat better than qualitative CT results. The standard error of the FEV(1)% for the quantitative CT was about 85% of that for the qualitative CT. Pleurodesis had no statistically significant effect on the slope of the regression line between quantitative CT findings, FEV(1)%, and DLCO% (corrected for alveolar volume). The slope between quantitative CT and RV/TLC% was significantly (P =.044) more negative in patients with pleurodesis. CONCLUSION: Qualitative and quantitative CT findings correlate with pulmonary dysfunction over a wide range of disease severity in patients with LAM. Pleurodesis influences the relationship between CT measurements and pulmonary function test results.

Adult↗