TH17 cells in asthma and COPD Alcorn, John F; Crowe, Christopher R; Kolls, Jay K
Annual review of physiology,
2010, Letnik:
72
Journal Article
Recenzirano
Asthma and chronic obstructive pulmonary disease (COPD) represent two classes of chronic obstructive lung disorders that may share some similar immunologic mechanisms of disease. Asthma is a complex ...human disease characterized by airway hyperresponsiveness (AHR) and inflammation, whereas COPD is marked by progressive emphysematic changes in the lung. Recently it has been shown that advanced COPD is characterized by lymphoid follicles, drawing attention to immunological mechanisms in COPD. Despite numerous studies in mice to elucidate the immunologic mechanisms of asthma, sufficient current treatment options are limited. Clinically, many asthma patients fail to satisfactorily respond to standard steroid therapy, and this type of steroid-resistant, severe asthma has been linked to the presence of neutrophilic inflammation in the lung. The role of neutrophils, macrophages, and their secreted proteases in COPD needs to be better defined. Recently, the T lymphocyte subset T(H)17 was shown to play a role in regulating neutrophilic and macrophage inflammation in the lung, suggesting a potential role for T(H)17 cells in severe, steroid-insensitive asthma and COPD.
Semi-quantitative IHC is a powerful method for investigating protein expression and localization within tissues. The semi-quantitative immunohistochemistry (IHC) involves using software such as free ...software ImageJ Fiji to conduct deconvolution and downstream analysis. Currently, there is lack of an integrated protocol that includes a detailed procedure of how to measure or compare protein expression. Publications that use semi-quantification methods to quantify protein expression often don't provide enough details in their methods section, which makes it difficult for the reader to reproduce their data. The current protocol for the first time provides a detailed, step-by-step instruction of conducting semi-quantitative analysis of IHC images using ImageJ Fiji software so that researchers would be able to follow this single protocol to conduct their research. The protocol uses semi-quantitative IHC of organic anion transporting polypeptide (OATP1B1) as an example, and gives detailed steps on how to deconvolute IHC images stained with hematoxylin and 3, 3 - diaminobenzidine (DAB) and how to quantify their expression using ImageJ Fiji. The protocol includes clear steps for a reader so that this method can be applied to many different proteins. We anticipate this method will provide a practical guidance to the reader and make semi-quantification of proteins an easier task to include in publications.
Staphylococcus aureus is a significant cause of hospital and community acquired pneumonia and causes secondary infection after influenza A. Recently, patients with hyper-IgE syndrome, who often ...present with S. aureus infections of the lung and skin, were found to have mutations in STAT3, required for Th17 immunity, suggesting a potential critical role for Th17 cells in S. aureus pneumonia. Indeed, IL-17R(-/-) and IL-22(-/-) mice displayed impaired bacterial clearance of S. aureus compared with that of wild-type mice. Mice challenged with influenza A PR/8/34 H1N1 and subsequently with S. aureus had increased inflammation and decreased clearance of both virus and bacteria. Coinfection resulted in greater type I and II IFN production in the lung compared with that with virus infection alone. Importantly, influenza A coinfection resulted in substantially decreased IL-17, IL-22, and IL-23 production after S. aureus infection. The decrease in S. aureus-induced IL-17, IL-22, and IL-23 was independent of type II IFN but required type I IFN production in influenza A-infected mice. Furthermore, overexpression of IL-23 in influenza A, S. aureus-coinfected mice rescued the induction of IL-17 and IL-22 and markedly improved bacterial clearance. These data indicate a novel mechanism by which influenza A-induced type I IFNs inhibit Th17 immunity and increase susceptibility to secondary bacterial pneumonia.
Acute lung injury due to influenza infection is associated with high mortality, an increase in neutrophils in the airspace, and increases in tissue myeloperoxidase (MPO). Because IL-17A and IL-17F, ...ligands for IL-17 receptor antagonist (IL-17RA), have been shown to mediate neutrophil migration into the lung in response to LPS or Gram-negative bacterial pneumonia, we hypothesized that IL-17RA signaling was critical for acute lung injury in response to pulmonary influenza infection. IL-17RA was critical for weight loss and both neutrophil migration and increases in tissue myeloperoxidase (MPO) after influenza infection. However, IL-17RA was dispensable for the recruitment of CD8(+) T cells specific for influenza hemagglutinin or nucleocapsid protein. Consistent with this, IL-17RA was not required for viral clearance. However, in the setting of influenza infection, IL-17RA(-/-) mice showed significantly reduced levels of oxidized phospholipids, which have previously been shown to be an important mediator in several models of acute lung injury, including influenza infection and gastric acid aspiration. Taken together, these data support targeting IL-17 or IL-17RA in acute lung injury due to acute viral infection.
Vitamin D deficiency is widespread and has been associated with many chronic diseases, including autoimmune disorders. A study was undertaken to explore the impact of low vitamin D levels on ...autoantibody production in healthy individuals, as well as B cell hyperactivity and interferon α (IFNα) activity in patients with systemic lupus erythematosus (SLE).
Serum samples from 32 European American female patients with SLE and 32 matched controls were tested for 25-hydroxyvitamin D (25(OH)D) levels, lupus-associated autoantibodies and serum IFNα activity. Isolated peripheral blood mononuclear cells were tested for intracellular phospho-ERK 1/2 as a measure of B cell activation status.
Vitamin D deficiency (25(OH)D <20 ng/ml) was significantly more frequent among patients with SLE (n=32, 69%) and antinuclear antibody (ANA)-positive controls (n=14, 71%) compared with ANA-negative controls (n=18, 22%) (OR 7.7, 95% CI 2.0 to 29.4, p=0.003 and OR 8.8, 95% CI 1.8 to 43.6, p=0.011, respectively). Patients with high B cell activation had lower mean (SD) 25(OH)D levels than patients with low B cell activation (17.2 (5.1) vs 24.2 (3.9) ng/ml; p=0.009). Patients with vitamin D deficiency also had higher mean (SD) serum IFNα activity than patients without vitamin D deficiency (3.5 (6.6) vs 0.3 (0.3); p=0.02).
The observation that ANA-positive healthy controls are significantly more likely to be deficient in vitamin D than ANA-negative healthy controls, together with the finding that vitamin D deficiency is associated with certain immune abnormalities in SLE, suggests that vitamin D plays an important role in autoantibody production and SLE pathogenesis.
Health care price transparency is gaining momentum as a tangible policy intervention that can unleash market principles to increase competition, help begin to decrease U.S. health care expenditures, ...and provide Americans with access to affordable, high-quality health care. Indeed, pricing reform is required to facilitate patient shopping in health care. In this narrative policy review, we offer a brief history of health care price transparency efforts and an overview of the health care price transparency literature. Further, we highlight the current rules and legislative initiatives aimed at achieving the full potential of health care price transparency. Lastly, we offer key takeaways and highlight suggestions for future policy directions, including the need to ensure hospital and insurance compliance through more appropriate penalties and incentives, importance of reducing regulation to promote financial upside that can be obtained by both patients and providers who actively promote shopping for lower cost, higher quality health care goods and services, and the need for transparent and easily found quality metrics, including outcomes most important to patients, driven by physicians "on the ground" with patient input.
NAFLD (non-alcoholic fatty liver disease) involves significant changes in liver metabolism characterized by oxidative stress, lipid accumulation and fibrogenesis. Mitochondrial dysfunction and ...bioenergetic defects also contribute to NAFLD. In the present study, we examined whether differences in mtDNA influence NAFLD. To determine the role of mitochondrial and nuclear genomes in NAFLD, MNX (mitochondrial-nuclear exchange) mice were fed an atherogenic diet. MNX mice have mtDNA from C57BL/6J mice on a C3H/HeN nuclear background and vice versa. Results from MNX mice were compared with wild-type C57BL/6J and C3H/HeN mice fed a control or atherogenic diet. Mice with the C57BL/6J nuclear genome developed more macrosteatosis, inflammation and fibrosis compared with mice containing the C3H/HeN nuclear genome when fed the atherogenic diet. These changes were associated with parallel alterations in inflammation and fibrosis gene expression in wild-type mice, with intermediate responses in MNX mice. Mice with the C57BL/6J nuclear genome had increased State 4 respiration, whereas MNX mice had decreased State 3 respiration and RCR (respiratory control ratio) when fed the atherogenic diet. Complex IV activity and most mitochondrial biogenesis genes were increased in mice with the C57BL/6J nuclear or mitochondrial genome, or both fed the atherogenic diet. These results reveal new interactions between mitochondrial and nuclear genomes and support the concept that mtDNA influences mitochondrial function and metabolic pathways implicated in NAFLD.
CONTEXT Electroconvulsive therapy (ECT) is highly effective for treatment of
major depression, but naturalistic studies show a high rate of relapse after
discontinuation of ECT. OBJECTIVE To ...determine the efficacy of continuation pharmacotherapy with nortriptyline
hydrochloride or combination nortriptyline and lithium carbonate in preventing
post-ECT relapse. DESIGN Randomized, double-blind, placebo-controlled trial conducted from 1993
to 1998, stratified by medication resistance or presence of psychotic depression
in the index episode. SETTING Two university-based hospitals and 1 private psychiatric hospital. PATIENTS Of 290 patients with unipolar major depression recruited through clinical
referral who completed an open ECT treatment phase, 159 patients met remitter
criteria; 84 remitting patients were eligible and agreed to participate in
the continuation study. INTERVENTIONS Patients were randomly assigned to receive continuation treatment for
24 weeks with placebo (n = 29), nortriptyline (target steady-state level,
75-125 ng/mL) (n = 27), or combination nortriptyline and lithium (target steady-state
level, 0.5-0.9 mEq/L) (n = 28). MAIN OUTCOME MEASURE Relapse of major depressive episode, compared among the 3 continuation
groups. RESULTS Nortriptyline-lithium combination therapy had a marked advantage in
time to relapse, superior to both placebo and nortriptyline alone. Over the
24-week trial, the relapse rate for placebo was 84% (95% confidence interval
CI, 70%-99%); for nortriptyline, 60% (95% CI, 41%-79%); and for nortriptyline-lithium,
39% (95% CI, 19%-59%). All but 1 instance of relapse with nortriptyline-lithium
occurred within 5 weeks of ECT termination, while relapse continued throughout
treatment with placebo or nortriptyline alone. Medication-resistant patients,
female patients, and those with more severe depressive symptoms following
ECT had more rapid relapse. CONCLUSIONS Our study indicates that without active treatment, virtually all remitted
patients relapse within 6 months of stopping ECT. Monotherapy with nortriptyline
has limited efficacy. The combination of nortriptyline and lithium is more
effective, but the relapse rate is still high, particularly during the first
month of continuation therapy.
The doctoral journey is as much about identity transitions as it is about becoming an expert in a field of study. However, transitioning from past and professional lives and identities to scholarly ...identities is not an easy process. Three doctoral students at various stages of completion engaged in self-study research to explore their emerging identities as doctoral student practitioners. Drawing on self-study and doctoral student identity research, as well as findings from our individual analyses, we explore how self-study can be used as an authentic and positive experience to help doctoral students understand their scholarly identity development. After describing the benefits of self-study research for doctoral student success, we provide practical guidelines for how to implement self-study research into existing doctoral programs.
The Professional Identity Essay (PIE) is a theory and evidence-based Medical Professional Identity Formation (MPIF) measure. We describe trajectories of PIE-measured MPIF over a 4-year US medical ...school curriculum.
Students write PIEs at medical school orientation, clinical clerkships orientation, and post-advanced (near graduation) clerkship. A trained evaluator assigns an overall stage score to narrative responses to nine PIE prompts (inter-rater ICC 0.83, 95% CI 0.57 - 0.96, intra-rater ICC 0.85). Distribution of PIE stage scores across time points were analyzed in the aggregate and individual students were classified as Increase, Stable (no score change) or Decrease based on the trajectories of PIE stage scores over time.
202 students completed 592 PIEs from 2018-2023. There was a significant change in the proportion of PIEs in stages over time (
84.40,
< 0.001), 47% (
= 95) students were categorized in the Increase trajectory, 45.5% (
= 92) as Stable and 7.4% (
= 15) as Decrease. Older age and time-predicted stage scores change within trajectories (
< 0.05).
Medical students' PIE stage scores increase over time with three distinctive trajectories. Further study is needed to explore the utility of this method for formative assessment, program evaluation, and MPIF research.
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