Jeffrey L Curtis | University of Michigan Medical School (original) (raw)

Papers by Jeffrey L Curtis

Cigarette smoke (CS)einduced lung injury involves innate immune responses. The activation of inna... more Cigarette smoke (CS)einduced lung injury involves innate immune responses. The activation of innate effector cells is thought to require cross talk with dendritic cells (DCs) and macrophages, but the mediators of interaction are unknown. One candidate, CC chemokine receptor 4 (CCR4), is expressed by innate and adaptive effector cells, and its ligands are produced by DCs and macrophages. Using flow cytometry and confocal microscopy, we defined innate responses of lung myeloid DCs, macrophages, and conventional natural killer (NK) cells in mice exposed to CS over 4 days and examined the contribution of CCR4 using CCR4 knockout (CCR4 À/À ) mice. CS affected populations differently, causing an increase in F4/80 þ macrophages, a reduction in parenchymal CD11c þ CD11b þ CD103 À DCs, but no effect on mucosal CD11c þ CD11b À CD103 þ DCs. CS also induced a population of primed/activated CD69 þ NK cells and bronchoepithelial expression of the stress-related NKG2D receptoreactivating protein, retinoic acid early transcript 1. CS-exposed CCR4 À/À mice were similar to controls regarding effects on DCs and macrophages but displayed substantially impaired NK priming/activation and reduced expression of transcripts for interferon gamma, CXCL10, and retinoic acid early transcript 1. Quantitative confocal microscopy revealed that lungs of CS-exposed CCR4 À/À mice had significantly reduced contacts of NK cells with CD11c þ cells. These findings demonstrate that acute CS exposure elicits NK cell responses and suggest that CCR4 promotes NK cell priming/activation by mediating contacts with sentinel cells in the lung. (Am J Pathol 2014, 184: 454e463; http://dx.

The European respiratory journal, Jan 5, 2015

Recent studies suggest that males with chronic obstructive pulmonary disease (COPD) have more emp... more Recent studies suggest that males with chronic obstructive pulmonary disease (COPD) have more emphysema than females. It is not known if these differences persist across degrees of COPD severity. Our aim was to identify sex-specific differences in quantitative emphysema within COPD subgroups based on COPD severity.We included non-Hispanic white and African-American subjects from the COPDGene study with at least 10 pack-years of smoking and COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometry grade II or greater. We examined sex-specific differences in log-transformed emphysema (log per cent low-attenuation area (%LAA)) by GOLD spirometry grade among subjects with early-onset COPD (<55 years old) and advanced emphysema (>25% emphysema).Compared with females, males had higher log %LAA: overall (1.97±1.4 versus 1.69±1.6, β=0.32 (0.04), p=1.34×10(-14)), and among non-Hispanic white (p=8.37×10(-14)) and African-American subjects (p=0.002). Females with earl...

... American journal of respiratory and critical care medicine 2007;176:532-555. 2. Rice JP, Sacc... more ... American journal of respiratory and critical care medicine 2007;176:532-555. 2. Rice JP, SacconeNL, Rasmussen E. Definition of the phenotype. Adv Genet ... 19. Gelb AF, Hogg JC, Muller NL, Schein MJ, Kuei J, Tashkin DP, Epstein JD, Kollin J, Green RH, Zamel N, et al. ...

D10.G4.1 (D10) cells, a murine conalbumin-reactive Th2 cell line, made to overexpress the ␤ 2 int... more D10.G4.1 (D10) cells, a murine conalbumin-reactive Th2 cell line, made to overexpress the ␤ 2 integrin LFA-1 by pharmacological manipulation or by transfection become autoreactive and are capable of inducing in vivo autoimmunity. However, whether this is specific to LFA-1 and whether overexpression of other T cell integrin molecules has the same effect are unknown. We examined the functional consequences of T cell CD49d (␣ 4 integrin) overexpression by transfecting murine CD49d cDNA into D10 cells. Similar to the LFA-1-transfected cells, the CD49d-overexpressing T cells are autoreactive and proliferate in response to APCs in an MHC class II-dependent manner in the absence of nominal Ag. Additionally, CD49d overexpression is associated with increased in vitro adhesion to endothelial cells and increased in vivo splenic homing. However, in contrast to LFA-1 overexpression, increased T cell CD49d expression is not associated with autoreactive cytotoxicity or the ability to induce in vivo autoimmunity. In addition to the novel observation that CD49d overexpression is sufficient to induce T cell autoreactivity, our results also support the hypothesis that the ability to induce in vivo autoimmunity is related to T cell cytotoxicity and not to T cell proliferation function in the D10 murine adoptive transfer model of autoimmunity.

Annals of the American Thoracic Society, 2015

Respiratory research, 2015

Although T cells, especially CD8+, have been implicated in chronic obstructive pulmonary disease ... more Although T cells, especially CD8+, have been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, their role during acute exacerbations (AE-COPD) is uncertain. We recruited subjects with COPD and a history of previous AE-COPD and studied them quarterly to collect blood and spontaneously expectorated sputum while stable. During exacerbations (defined by a change in symptoms plus physician diagnosis and altered medications), we collected blood and sputum before administering antibiotics or steroids. We used flow cytometry to identify leukocytes in peripheral blood, plus Luminex® analysis or ELISA to determine levels of inflammatory biomarkers in serum and sputum supernatants. Of 33 enrolled subjects, 13 participated in multiple stable visits and had ≥1 AE-COPD visit, yielding 18 events with paired data. Flow cytometric analyses of peripheral blood demonstrated decreased CD4+ and CD8+ T cells during AE-COPD (both absolute and as a percentage of all leukocytes) and s...

Macrophages are called upon to ingest both IgG-coated targets and apoptotic cells. Important role... more Macrophages are called upon to ingest both IgG-coated targets and apoptotic cells. Important roles for tyrosine kinase Syk and leukotriene B 4 (LTB 4 ) are recognized in Fc R-mediated phagocytosis. Here we evaluated the roles of Syk and of LTB 4 in macrophage phagocytosis of apoptotic thymocytes vs. IgG-coated erythrocytes. Macrophages ingestion of apoptotic thymocytes was not influenced by exogenous or endogenous LTB 4 , nor associated with Syk activation (phosphorylation). By contrast, LTB 4 dose-dependently amplified Fc R-mediated phagocytosis as well as Syk activation. Furthermore, a role for endogenous LTB 4 in Syk activation during Fc R-mediated phagocytosis was demonstrated using pharmacologic and genetic abrogation of 5-lipoxygenase. LTB 4 was unique among 5-lipoxygenase products in this regard, since LTD 4 and 5-HETE were unable to amplify Syk activation in response to Fc R engagement. Ca 2+ chelation studies revealed that Fc R-mediated Syk activation as well as LTB 4 amplification thereof were Ca 2+ -regulated. These two parallel phagocytic processes therefore exhibit initial divergence in signal transduction events, with Syk activation being a LTB 4 -regulated event in Fc R-mediated but not apoptotic cell ingestion. As LTB 4 is an important pro-inflammatory product of macrophages, we speculate that this divergence evolved to permit Fc R-mediated phagocytosis to proceed in an inflammatory milieu while apoptotic cell clearance is non-inflammatory.

American journal of respiratory and critical care medicine, Jan 15, 2015

A35. LESSONS IN LUNG INFECTIONS, 2011

C97. ACUTE PNEUMONIA: NOVEL HOST DEFENSE MECHANISMS WITH THERAPEUTIC IMPLICATIONS, 2010

D91. CURRENT CONCEPTS IN ALLERGIC AND INFLAMMATORY DENDRITIC CELL ACTIVATION, 2009

Annals of the American Thoracic Society, Jan 24, 2015

The lung microbiome is spatially heterogenous in advanced airway diseases, but whether it varies ... more The lung microbiome is spatially heterogenous in advanced airway diseases, but whether it varies spatially in health is unknown. We postulated that the primary determinant of lung microbiome constitution in health is the balance of immigration and elimination of communities from the upper respiratory tract ("adapted island model of lung biogeography"), rather than differences in regional bacterial growth conditions. To determine if the lung microbiome is spatially varied in healthy adults. Bronchoscopy was performed on 15 healthy subjects. Specimens were sequentially collected in the lingula and right middle lobe (by bronchoalveolar lavage), then in the right upper lobe, left upper lobe and supraglottic space (by protected-specimen brush). Bacterial 16S rRNA-encoding genes were sequenced using Illumina MiSeq. There were no significant differences between specimens collected by bronchoalveolar lavage and protected specimen brush. Spatially separated intrapulmonary sites, wh...

The American journal of pathology, 2015

This Commentary highlights the article by Polverino et al, describing the development of a novel ... more This Commentary highlights the article by Polverino et al, describing the development of a novel nonhuman primate model of cigarette smoke-induced chronic obstructive pulmonary disease.

Immunopharmacology, Jan 25, 2000

The adhesive interaction between lymphocytes and lung endothelial cells presents an attractive ar... more The adhesive interaction between lymphocytes and lung endothelial cells presents an attractive arena for the development of novel therapeutic agents to modify pathologic pulmonary immune responses. The conceptual basis for choosing molecular targets to modulate this adhesive interaction derives, in large part, from results of murine experimental model systems of the pulmonary immune response. This article reviews one such model, the response of primed C57BL/6 mice to the particulate antigen sheep erythrocytes. Novel data are presented on the effect of a blocking anti-alpha(4) integrin monoclonal antibody on lung leukocyte and lymphocyte subset accumulation after intratracheal (IT) antigen challenge. Results from this model system have indicated that lymphocytes may use either the endothelial selectins or alpha(4) integrin as independent pathways to initiate recruitment into the lungs.

Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1998

The cell adhesion molecules (CAMs) required for T lymphocyte recruitment during pulmonary immune ... more The cell adhesion molecules (CAMs) required for T lymphocyte recruitment during pulmonary immune responses have not been defined. Our laboratories recently reported that intratracheal (IT) challenge of sensitized mice with SRBC induced prolonged expression of vascular P-selectin, E-selectin, and VCAM-1, particularly in areas of mononuclear leukocyte infiltration. A surge in the number of circulating T lymphocytes expressing selectin ligands preceded the peak accumulation of T cells in the lung. In addition, a significant percentage of the T cells recovered from the lung expressed selectin ligands as well. The current study demonstrates that cultured T lymphoblasts use both selectin ligands and alpha4 integrins to enter the airspace and interstitium during the response to SRBC. Fluorescently labeled T lymphoblasts, derived via activation on CD3 and growth in low dose IL-2, showed inflammation-specific recruitment into lungs harvested 24 h after cell infusion. Their flux paralleled th...

The Journal of laboratory and clinical medicine, 1993

Host defense mechanisms to the important fungal pathogen Cryptococcus neoformans are complex and ... more Host defense mechanisms to the important fungal pathogen Cryptococcus neoformans are complex and incompletely understood. From in vitro studies, we could expect CD8+ T cells to have the potential for both protective and suppressive effects on defense against cryptococci. The current study used the technique of in vivo subset depletion to determine the net effect of CD8+ T cells during actual infection. Mice depleted of CD8+ T cells by monoclonal antibody (YTS 169.4) injections were infected with the moderately virulent cryptococcal strain 613D by the intratracheal route, which mimics natural pulmonary infection. To ensure adequacy of depletion, T cell subsets were enumerated by flow cytometry in blood, spleen, lymph node, and lung. Specific elements of host defense were measured by clearance of cryptococci in vivo and by the response to cryptococcal antigens, both in vivo by delayed-type hypersensitivity (DTH) and in vitro by lymphocyte proliferation. We found that depletion of CD8+...

B55. HOST DEFENSE IN PULMONARY INFECTION AND TUBERCULOSIS, 2012

B103. COPD: MECHANISMS OF DISEASE PROGRESSION AND EXACERBATION, 2012

C24. PNEUMOCYSTIS AND OTHER FUNGAL PNEUMONIAS: PATHOGENESIS AND CLINICAL CONSEQUENCES, 2011