Downregulation of Integrin β4 Decreases the Ability of Airway Epithelial Cells to Present Antigens

Airway epithelial cells have been demonstrated to be accessory antigen presentation cells (APC) capable of activating T cells and may play an important role in the development of allergic airway inflammation of asthma. In asthmatic airways, loss of expression of the adhesion molecule integrin β4 (ITGB4) and an increase in Th2 inflammation bias has been observed in our previous study. Given that ITGB4 is engaged in multiple signaling pathways, we studied whether disruption of ITGB4-mediated cell adhesion may contribute to the adaptive immune response of epithelial cells, including their ability to present antigens, induce the activate and differentiate of T cells. We silenced ITGB4 expression in bronchial epithelial cells with an effective siRNA vector and studied the effects of ITGB4 silencing on the antigen presentation ability of airway epithelial cells. T cell proliferation and cytokine production was investigated after co-culturing with ITGB4-silenced epithelial cells. Surface expression of B7 homologs and the major histocompatibility complex (MHC) class II was also detected after ITGB4 was silenced. Our results demonstrated that silencing of ITGB4 resulted in impaired antigen presentation processes and suppressed T cell proliferation. Meanwhile, decrease in Th1 cytokine production and increase in Th17 cytokine production was induced after co-culturing with ITGB4-silenced epithelial cells. Moreover, HLA-DR was decreased and the B7 homologs expression was different after ITGB4 silencing. Overall, this study suggested that downregulation of ITGB4 expression in airway epithelial cells could impair the antigen presentation ability of these cells, which further regulate airway inflammation reaction in allergic asthma

The working alliance in a randomized controlled trial comparing online with face-to-face cognitive-behavioral therapy for depression

Background: Although numerous efficacy studies in recent years have found internet-based interventions for depression to be effective, there has been scant consideration of therapeutic process factors in the online setting. In face-to face therapy, the quality of the working alliance explains variance in treatment outcome. However, little is yet known about the impact of the working alliance in internet-based interventions, particularly as compared with face-to-face therapy. Methods: This study explored the working alliance between client and therapist in the middle and at the end of a cognitive-behavioral intervention for depression. The participants were randomized to an internet-based treatment group (n = 25) or face-to-face group (n = 28). Both groups received the same cognitive behavioral therapy over an 8-week timeframe. Participants completed the Beck Depression Inventory (BDI) post-treatment and the Working Alliance Inventory at mid- and post- treatment. Therapists completed the therapist version of the Working Alliance Inventory at post-treatment. Results: With the exception of therapists' ratings of the tasks subscale, which were significantly higher in the online group, the two groups' ratings of the working alliance did not differ significantly. Further, significant correlations were found between clients' ratings of the working alliance and therapy outcome at post-treatment in the online group and at both mid- and post-treatment in the face-to-face group. Correlation analysis revealed that the working alliance ratings did not significantly predict the BDI residual gain score in either group. Conclusions: Contrary to what might have been expected, the working alliance in the online group was comparable to that in the face-to-face group. However, the results showed no significant relations between the BDI residual gain score and the working alliance ratings in either group

Individualized and Clinically Derived Stimuli Activate Limbic Structures in Depression: An fMRI Study

In the search for neurobiological correlates of depression, a major finding is hyperactivity in limbic-paralimbic regions. However, results so far have been inconsistent, and the stimuli used are often unspecific to depression. This study explored hemodynamic responses of the brain in patients with depression while processing individualized and clinically derived stimuli.Eighteen unmedicated patients with recurrent major depressive disorder and 17 never-depressed control subjects took part in standardized clinical interviews from which individualized formulations of core interpersonal dysfunction were derived. In the patient group such formulations reflected core themes relating to the onset and maintenance of depression. In controls, formulations reflected a major source of distress. This material was thereafter presented to subjects during functional magnetic resonance imaging (fMRI) assessment.Increased hemodynamic responses in the anterior cingulate cortex, medial frontal gyrus, fusiform gyrus and occipital lobe were observed in both patients and controls when viewing individualized stimuli. Relative to control subjects, patients with depression showed increased hemodynamic responses in limbic-paralimbic and subcortical regions (e.g. amygdala and basal ganglia) but no signal decrease in prefrontal regions.This study provides the first evidence that individualized stimuli derived from standardized clinical interviewing can lead to hemodynamic responses in regions associated with self-referential and emotional processing in both groups and limbic-paralimbic and subcortical structures in individuals with depression. Although the regions with increased responses in patients have been previously reported, this study enhances the ecological value of fMRI findings by applying stimuli that are of personal relevance to each individual's depression

Molecular Etiology of Atherogenesis – In Vitro Induction of Lipidosis in Macrophages with a New LDL Model

BACKGROUND: Atherosclerosis starts by lipid accumulation in the arterial intima and progresses into a chronic vascular inflammatory disease. A major atherogenic process is the formation of lipid-loaded macrophages in which a breakdown of the endolysomal pathway results in irreversible accumulation of cargo in the late endocytic compartments with a phenotype similar to several forms of lipidosis. Macrophages exposed to oxidized LDL exihibit this phenomenon in vitro and manifest an impaired degradation of internalized lipids and enhanced inflammatory stimulation. Identification of the specific chemical component(s) causing this phenotype has been elusive because of the chemical complexity of oxidized LDL. METHODOLOGY/PRINCIPAL FINDINGS: Lipid "core aldehydes" are formed in oxidized LDL and exist in atherosclerotic plaques. These aldehydes are slowly oxidized in situ and (much faster) by intracellular aldehyde oxidizing systems to cholesteryl hemiesters. We show that a single cholesteryl hemiester incorporated into native, non-oxidized LDL induces a lipidosis phenotype with subsequent cell death in macrophages. Internalization of the cholesteryl hemiester via the native LDL vehicle induced lipid accumulation in a time- and concentration-dependent manner in "frozen" endolysosomes. Quantitative shotgun lipidomics analysis showed that internalized lipid in cholesteryl hemiester-intoxicated cells remained largely unprocessed in those lipid-rich organelles. CONCLUSIONS/SIGNIFICANCE: The principle elucidated with the present cholesteryl hemiester-containing native-LDL model, extended to other molecular components of oxidized LDL, will help in defining the molecular etiology and etiological hierarchy of atherogenic agents