Carla M. Sevin

Human TH17 cells express a functional IL-13 receptor and IL-13 attenuates IL-17A production.

BACKGROUND IL-13 is a central mediator of airway responsiveness and mucus expression in patients with allergic airway inflammation, and IL-13 is currently a therapeutic target for asthma. However, little is known about how IL-13 regulates human CD4(+) T-cell lineages because IL-13 receptor (IL-13R) α1, a subunit of IL-13R, has not previously been reported to exist on human T cells. OBJECTIVE We sought to determine whether human CD4(+) T(H)17 cells express IL-13Rα1 and whether IL-13 regulates T(H)17 cytokine production. METHODS Naive human CD4(+) cells were isolated from whole blood, activated with anti-CD3 and anti-CD28, and polarized to T(H)1, T(H)2, T(H)17, or induced regulatory T cells in the presence of IL-13 (0-10 ng/mL). Cell supernatants, total RNA, or total protein was examined 4 days after T(H)17 polarization. RESULTS T(H)17 cells, but not T(H)0, T(H)1, T(H)2, or induced regulatory T cells, expressed IL-13Rα1. IL-13 attenuated IL-17A production, as well as expression of retinoic acid-related orphan receptor, runt-related transcription factor-1, and interferon regulatory factor 4 in T(H)17-polarized cells. IL-13 neither inhibited IFN-γ production from T(H)1 cells nor inhibited IL-4 production from T(H)2 cells. Furthermore, attenuation of IL-17A production only occurred when IL-13 was present within 24 hours of T-cell activation or at the time of restimulation. CONCLUSIONS IL-13Rα1 is expressed on human CD4(+) T(H)17 cells, and IL-13 attenuates IL-17A production at polarization and restimulation. Although IL-13 is an attractive therapeutic target for decreasing symptoms associated with asthma, these results suggest that therapies inhibiting IL-13 production could have adverse side effects by increasing IL-17A production.

Blockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity.

RATIONALE Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function. OBJECTIVES To determine the effects of PD-1 pathway blockade on sarcoidosis CD4(+) T-cell proliferative capacity. METHODS Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage-derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens. MEASUREMENTS AND MAIN RESULTS Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1(+) CD4(+) T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1(+) CD4(+) T cells with spontaneous clinical resolution but not with disease progression. CONCLUSIONS Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4(+) T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a viable therapeutic target to optimize clinical outcomes.

Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL-23 receptor signaling and IL-17A production in patients with severe asthma

BACKGROUND Women have an increased prevalence of severe asthma compared with men. IL-17A is associated with severe asthma and requires IL-23 receptor (IL-23R) signaling, which is negatively regulated by let-7f microRNA. OBJECTIVE We sought to Determine the mechanism by which 17β-estradiol (E2) and progesterone (P4) increase IL-17A production. METHODS IL-17A production was determined by using flow cytometry in TH17 cells from women (n = 14) and men (n = 15) with severe asthma. Cytokine levels were measured by using ELISA, and IL-23R and let-7f expression was measured by using quantitative PCR in TH17-differentiated cells from healthy women (n = 13) and men (n = 14). In sham-operated or ovariectomized female mice, 17β-E2, P4, 17β-E2+P4, or vehicle pellets were administered for 3 weeks before ex vivo TH17 cell differentiation. Airway neutrophil infiltration and CXCL1 (KC) expression were also determined in ovalbumin (OVA)-challenged wild-type female recipient mice with an adoptive transfer of OVA-specific TH17 cells from female and male mice. RESULTS In patients with severe asthma and healthy control subjects, IL-17A production was increased in TH17 cells from women compared with men. IL-23R expression was increased and let-7f expression was decreased in TH17-differentiated cells from women compared with men. In ovariectomized mice IL-17A and IL-23R expression was increased and Let-7f expression was decreased in TH17 cells from mice administered 17β-E2+P4 compared with those administered vehicle. Furthermore, transfer of female OVA-specific TH17 cells increased acute neutrophil infiltration in the lungs of OVA-challenged recipient mice compared with transfer of male OVA-specific TH17 cells. CONCLUSIONS 17β-E2+P4 increased IL-17A production from TH17 cells, providing a potential mechanism for the increased prevalence of severe asthma in women compared with men.

Infections and asthma: new insights into old ideas.

Cite this as: C. M. Sevin and R. S. Peebles Jr, Clinical & Experimental Allergy, 2010 (40) 1142–1154.

Deficiency of gp91phox Inhibits Allergic Airway Inflammation

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a multienzyme complex, is the major source for production of reactive oxygen species (ROS). ROS are increased in allergic diseases, such as asthma, but the role of ROS in disease pathogenesis remains uncertain. We hypothesized that mice unable to generate ROS via the NADPH oxidase pathway would have decreased allergic airway inflammation. To test this hypothesis, we studied gp91phox(-/-) mice in a model of allergic airway inflammation after sensitization and challenge with ovalbumin. Serum, bronchoalveolar lavage fluid, and lungs were then examined for evidence of allergic inflammation. We found that mice lacking a functional NADPH oxidase complex had significantly decreased ROS production and allergic airway inflammation, compared with wild-type (WT) control animals. To determine the mechanism by which allergic inflammation was inhibited by gp91phox deficiency, we cultured bone marrow-derived dendritic cells from WT and gp91phox(-/-) mice and activated them with LPS. IL-12 expression was significantly increased in the gp91phox(-/-) bone marrow-derived dendritic cells, suggesting that the cytokine profile produced in the absence of gp91phox enhanced the conditions leading to T helper (Th) type 1 differentiation, while inhibiting Th2 polarization. Splenocytes from sensitized gp91phox(-/-) animals produced significantly less IL-13 in response to ovalbumin challenge in vitro compared with splenocytes from sensitized WT mice, suggesting that NADPH oxidase promotes allergic sensitization. In contrast, inflammatory cytokines produced by T cells cultured from WT and gp91phox(-/-) mice under Th0, Th1, Th2, and Th17 conditions were not significantly different. This study demonstrates the importance of NADPH oxidase activity and ROS production in a murine model of asthma.

Peer Support as a Novel Strategy to Mitigate Post-Intensive Care Syndrome.

ABSTRACT Post‐intensive care syndrome, a condition defined by new or worsening impairment in cognition, mental health, and physical function after critical illness, has emerged in the past decade as a common and life‐altering consequence of critical illness. New strategies are urgently needed to mitigate the risk of neuropsychological and functional impairment common after critical illness and to prepare and support survivors on their road toward recovery. The present state of critical care survivorship is described, and postdischarge care delivery in the United States and the potential impact of the present‐day fragmented model of care delivery are detailed. A novel strategy that uses peer support groups could more effectively meet the needs of survivors of critical illness and mitigate post‐intensive care syndrome.

Mechanisms of allergy and clinical immunologyEstrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL-23 receptor signaling and IL-17A production in patients with severe asthma

BACKGROUND Women have an increased prevalence of severe asthma compared with men. IL-17A is associated with severe asthma and requires IL-23 receptor (IL-23R) signaling, which is negatively regulated by let-7f microRNA. OBJECTIVE We sought to Determine the mechanism by which 17β-estradiol (E2) and progesterone (P4) increase IL-17A production. METHODS IL-17A production was determined by using flow cytometry in TH17 cells from women (n = 14) and men (n = 15) with severe asthma. Cytokine levels were measured by using ELISA, and IL-23R and let-7f expression was measured by using quantitative PCR in TH17-differentiated cells from healthy women (n = 13) and men (n = 14). In sham-operated or ovariectomized female mice, 17β-E2, P4, 17β-E2+P4, or vehicle pellets were administered for 3 weeks before ex vivo TH17 cell differentiation. Airway neutrophil infiltration and CXCL1 (KC) expression were also determined in ovalbumin (OVA)-challenged wild-type female recipient mice with an adoptive transfer of OVA-specific TH17 cells from female and male mice. RESULTS In patients with severe asthma and healthy control subjects, IL-17A production was increased in TH17 cells from women compared with men. IL-23R expression was increased and let-7f expression was decreased in TH17-differentiated cells from women compared with men. In ovariectomized mice IL-17A and IL-23R expression was increased and Let-7f expression was decreased in TH17 cells from mice administered 17β-E2+P4 compared with those administered vehicle. Furthermore, transfer of female OVA-specific TH17 cells increased acute neutrophil infiltration in the lungs of OVA-challenged recipient mice compared with transfer of male OVA-specific TH17 cells. CONCLUSIONS 17β-E2+P4 increased IL-17A production from TH17 cells, providing a potential mechanism for the increased prevalence of severe asthma in women compared with men.

A Clinic Model: Post-Intensive Care Syndrome and Post-Intensive Care Syndrome-Family.

ABSTRACT The number of patients surviving critical illness in the United States has increased with advancements in medicine. Post‐intensive care syndrome and post‐intensive care syndrome‐family are terms developed by the Society of Critical Care Medicine in order to address the cognitive, psychological, and physical sequelae emerging in patients and their families after discharge from the intensive care unit. In the United Kingdom and Europe, intensive care unit follow‐up clinics have been used to address the complications of post‐intensive care syndrome for some time. However, the interprofessional clinic at Vanderbilt University Medical Center is among the first in the United States to address the wide variety of problems experienced by intensive care survivors and to provide patients and their families with care after discharge from the intensive care unit.

Microscopic anatomy of the pleura.

This article describes the anatomy of the pleura, which is made up of five layers. Blood supply and lymphatics are described, as are pleural fluid, mesothelial cells, and Kampmeier foci.

Medication management to ameliorate post-intensive care syndrome

M rates of critically ill patients have decreased markedly in recent years thanks to advancements in care.1 Given the improved survival rates of critically ill patients, investigators have broadened their focus from short-term mortality to long-term mortality and morbidities that are often underrecognized by intensive care unit (ICU) practitioners. The Society of Critical Care Medicine (SCCM) has defined post–intensive care syndrome (PICS) as a new or worsening decrement in mental, cognitive, or physical health following critical illness that persists beyond the acute hospitalization.2 Many medication-related risk factors are associated with development of cognitive impairment in critically ill patients, including glucose dysregulation,3,4 delirium,5 and medications.6 Medications have also been associated with acute neuromuscular weakness following an ICU admission.7 In the past decade, the increased risk of adverse drug events (ADEs) during transitions of care has become widely known. This column focuses on how medication management strategies in the ICU, after the ICU, and after hospitalization may prevent or help manage PICS.