IL-10 producing regulatory B cells are decreased in blood from smokers and COPD patients.

BACKGROUND: Two opposing B cell subsets have been defined based on their cytokine profile: IL-6 producing effector B cells (B-effs) versus IL-10 producing regulatory B cells (B-regs) that respectively positively or negatively regulate immune responses. B-regs are decreased and/or impaired in many autoimmune diseases and inflammatory conditions. Since there is increasing evidence that links B cells and B cell-rich lymphoid follicles to the pathogenesis of COPD, the aim of this study was to investigate the presence and function of B-regs in COPD. METHODS: First, presence of IL-10 producing regulatory B cells in human lung tissue was determined by immunohistochemistry. Secondly, quantification of IL-10 + B-regs and IL-6 + B-effs in peripheral blood mononuclear cells (PBMCs) from healthy controls, smokers without airflow limitation, and COPD patients (GOLD stage I-IV) was performed by flow cytometry. Thirdly, we exposed blood-derived B cells from COPD patients in vitro to cigarette smoke extract (CSE) and quantified IL-10 + B-regs and IL-6 + B-effs. Furthermore, we aimed at restoring the perturbed IL10 production by blocking BAFF. Fourthly, we determined mRNA expression of transcription factors involved in IL-10 production in FACS sorted memory- and naive B cells upon exposure to medium or CSE. RESULTS: The presence of IL-10 producing regulatory B cells in parenchyma and lymphoid follicles in lungs was confirmed by immunohistochemistry. The percentage of IL-10 + B-regs was significantly decreased in blood-derived memory B cell subsets from smokers without airflow limitation and patients with COPD, compared to never smokers. Furthermore, the capacity of B cells to produce IL-10 was reduced upon in vitro exposure to CSE and this could not be restored by BAFF-blockade. Finally, upon CSE exposure, mRNA levels of the transcription factors IRF4 and HIF-1α, were decreased in memory B cells. CONCLUSION: Decreased numbers and impaired function of B-regs in smokers and patients with COPD might contribute to the initiation and progression of the disease.

Effect of ACE1 polymorphism rs1799752 on protein levels of ACE2, the SARS-CoV-2 entry receptor, in alveolar lung epithelium.

Increased protein levels of ACE2 in alveolar epithelium of subjects who are homozygous for the ACE1 insertion of rs1799752 might facilitate host cell entry of #SARSCoV2 and explain the higher prevalence of #COVID19 in certain regions https://bit.ly/3k6aAE8.

Expression of ACE2, the SARS-CoV-2 Receptor, in Lung Tissue of Patients With Type 2 Diabetes.

Increased expression of pulmonary ACE2, the SARS-CoV-2 receptor, could contribute to increased infectivity of COVID-19 in patients with diabetes, but ACE2 expression has not been studied in lung tissue of subjects with diabetes. We therefore studied ACE2 mRNA and protein expression in lung tissue samples of subjects with and without diabetes that were collected between 2002 and 2020 from patients undergoing lobectomy for lung tumors. For RT-PCR analyses, samples from 15 subjects with diabetes were compared with 91 randomly chosen control samples. For immunohistochemical staining, samples from 26 subjects with diabetes were compared with 66 randomly chosen control samples. mRNA expression of ACE2 was measured by quantitative RT-PCR. Protein levels of ACE2 were visualized by immunohistochemistry on paraffin-embedded lung tissue samples and quantified in alveolar and bronchial epithelium. Pulmonary ACE2 mRNA expression was not different between subjects with or without diabetes. In contrast, protein levels of ACE2 were significantly increased in both alveolar tissue and bronchial epithelium of patients with diabetes compared with control subjects, independent of smoking, chronic obstructive pulmonary disease, BMI, renin-angiotensin-aldosterone system inhibitor use, and other potential confounders. To conclude, we show increased bronchial and alveolar ACE2 protein expression in patients with diabetes. Further research is needed to elucidate whether upregulation of ACE2 expression in airways and lungs has consequences on infectivity and clinical outcomes of COVID-19.

Psychopathy and Corticostriatal Connectivity: The Link to Criminal Behavior in Methamphetamine Dependence.

Methamphetamine use and psychopathy are associated with criminal behavior; however, it is unclear how methamphetamine use and psychopathy interact to promote violent, economic and drug offenses. Abnormalities in corticostriatal functional connectivity are exhibited in both psychopathic and methamphetamine dependent individuals, which may contribute to criminal behavior through maladaptive and impulsive decision-making processes. This study shows that psychopathic traits contribute to weaker corticostriatal connectivity in methamphetamine dependence and contributes to an increase in criminal behavior. As the propensity to engage in criminal activity is dependent on a number of factors, a hierarchical regression identifies the contribution of the impulsive antisocial domain of psychopathy, anxiety, years of methamphetamine use and corticostriatal connectivity on different types of criminal offenses. Methamphetamine use and psychopathic traits reduce treatment responsiveness and increase the likelihood of recidivism, and it is therefore important to understand the factors underlying the propensity to engage in criminal behavior.

Heterotelechelic polymer prodrug nanoparticles: Adaptability to different drug combinations and influence of the dual functionalization on the cytotoxicity.

Well-defined, heterotelechelic polymer prodrugs for combination therapy were synthesized by using a combination of the "drug-initiated" nitroxide-mediated polymerization from a gemcitabine-alkoxyamine initiator and the nitroxide exchange reaction using TEMPO-bearing drugs to end-cap the drug-polymer chain-end by a second drug. This methodology was successfully applied to two different clinically relevant combinations, gemcitabine/doxorubicin (Gem/Dox) and gemcitabine/lapatinib (Gem/Lap), showing a certain degree of universality of the synthetic methodology. It also represented the first nanocarrier for the co-delivery of Gem and Lap ever reported. Well-controlled, low molar mass heterotelechelic polymers (Mn = 2100-4090 g.mol-1, Ð = 1.18-1.38) with ~1:1 drug ratios and high overall drug loadings up to 40 wt% were obtained. They were formulated into nanoparticles by nanoprecipitation and exhibited average diameters in the 34-154 nm range, with narrow particle size distributions (PSD = 0.01-0.22) and excellent colloidal stability over time. Their biological evaluation in terms of drug release and cytotoxicity was performed and compared to that of different monofunctional polymer prodrug formulations. We showed that heterobifunctional polymer prodrugs induced cytotoxicity to MCF-7 cells, with IC50 values in the 120-300 nM range depending on the combination tested. Interestingly, whereas Gem/Dox combination did not lead to noticeable improvement over monofunctional therapies, co-nanoprecipitation of Gem/Lap prodrugs led to synergistic effect.