Targeting caspase-8/c-FLIP heterodimer in complex II promotes DL-mediated cell death.

Death receptor (DR) networks are controlled by the assembly of the Death-Inducing Signaling Complex (DISC) and complex II. The family of small molecules FLIPins (FLIP interactors) were developed to target the caspase-8/c-FLIP heterodimer. FLIPin compounds were shown to promote apoptosis and caspase-8 activation at the DISC upon stimulation with death ligands (DLs) such as CD95L and TRAIL.

Feasibility and acceptability pilot study of an online weight loss program in rural, underserved communities.

Background: The purpose of this intervention was to investigate the feasibility, acceptability, and preliminary effectiveness of an online weight loss program, EMPOWER, in rural, underserved communities.

Methods: Adults with a body mass index (BMI) ≥ 25 kg/m living in rural counties were recruited through collaboration with University of Illinois Extension. The intervention lasted 1 year including online educations sessions, nutrition and lifestyle coaching, and diet and weight monitoring a novel web application, MealPlot.

Targeting type I DED interactions at the DED filament serves as a sensitive switch for cell fate decisions.

Activation of procaspase-8 in the death effector domain (DED) filaments of the death-inducing signaling complex (DISC) is a key step in apoptosis. In this study, a rationally designed cell-penetrating peptide, DEDid, was engineered to mimic the h2b helical region of procaspase-8-DED2 containing a highly conservative FL motif. Furthermore, mutations were introduced into the DEDid binding site of the procaspase-8 type I interface.

Leucine-Rich Glioma-Inactivated 1 (LGI1) Protein Stimulates Proliferation and IL-10 Production in Peripheral Blood Mononuclear Cells of Patients with LGI1 Antibody-Mediated Autoimmune Encephalitis In Vitro.

Limbic encephalitis (LE) due to anti-leucine-rich glioma-inactivated 1 (LGI1) antibodies is an autoimmune disease characterized by distinct clinical features unique to LGI1 LE, such as faciobrachial dystonic seizures. However, it is unclear whether an additional disease-related LGI1 antigen-specific T cell response is involved in the pathogenesis of this disease. To address this question, we studied the effect of recombinant LGI1 on the proliferation and effector-specific cytokine production (IFN-γ, IL-5, IL-10, and IL-17) of peripheral blood mononuclear cells (PBMCs) from patients with LGI1 LE and healthy controls.

Proteomic and transcriptomic profiling of brainstem, cerebellum and olfactory tissues in early- and late-phase COVID-19.

Neurological symptoms, including cognitive impairment and fatigue, can occur in both the acute infection phase of coronavirus disease 2019 (COVID-19) and at later stages, yet the mechanisms that contribute to this remain unclear. Here we profiled single-nucleus transcriptomes and proteomes of brainstem tissue from deceased individuals at various stages of COVID-19. We detected an inflammatory type I interferon response in acute COVID-19 cases, which resolves in the late disease phase.

Patterns of allergic sensitization in adults with severe asthma: the ATLAS non-interventional study.

Objectives: Severe asthma is heterogeneous, with childhood-onset asthma believed more likely to be allergic, whereas adult-onset asthma is considered typically non-allergic. However, the allergic diagnosis is typically by exclusion: if patients do not react to an allergen panel, which is not standardized and often limited to few allergens, they are considered non-allergic. The overall aim of the ATLAS study was to characterize the sensitization to allergens in severe asthma (independent of phenotype).

Plasma concentrations of anti-inflammatory cytokine TGF-β are associated with hippocampal structure related to explicit memory performance in older adults.

Human cognitive abilities, and particularly hippocampus-dependent memory performance typically decline with increasing age. Immunosenescence, the age-related disintegration of the immune system, is increasingly coming into the focus of research as a considerable factor contributing to cognitive decline. In the present study, we investigated potential associations between plasma levels of pro- and anti-inflammatory cytokines and learning and memory performance as well as hippocampal anatomy in young and older adults.

Zinc aspartate induces proliferation of resting and antigen-stimulated human PBMC under high-density cell culture condition.

Background: Zinc, one of the most important essential trace elements in the human body, regulates a wide range of cellular functions of immune cells, such as proliferation, differentiation and survival. Zinc deficiency affects both the innate and adaptive immune system. Zinc supplementation was discussed as possible therapy for infectious diseases and T cell-mediated autoimmune diseases.

[General knowledge of frequently applied test procedures in rheumatological and immunological diagnostics and research].

Knowledge of test procedures is essential for an optimal approach in rheumatological and immunological diagnostics as well as for a correct interpretation of the findings. In practice, they are a basis for the independent provision of diagnostic laboratory services. For scientific questions they have become indispensable tools in many areas.

Antibody Properties Associate with Clinical Phenotype in LGI1 Encephalitis.

Autoimmune encephalitis (AE) associated with autoantibodies against leucine-rich glioma-inactivated protein-1 (LGI1) can present with faciobrachial dystonic seizures (FBDS) and/or limbic encephalitis (LE). The reasons for this heterogeneity in phenotypes are unclear. We performed autoantibody (abs) characterization per patient, two patients suffering from LE and two from FBDS, using isolated antibodies specified with single amino acid epitope mapping.

IL-13 determines specific IgE responses and SARS-CoV-2 immunity after mild COVID-19 and novel mRNA vaccination.

After recovery, mild and severe COVID-19 diseases are associated with long-term effects on the host immune system, such as prolonged T-cell activation or accumulation of autoantibodies. In this study, we show that mild SARS-CoV-2 infections, but not SARS-CoV-2 spike mRNA vaccinations, cause durable atopic risk factors such as a systemic Th2- and Th17-type environment as well as activation of B cells responsive of IgE against aeroallergens from house dust mite and mold. At an average of 100 days post mild SARS-CoV-2 infections, anti-mold responses were associated with low IL-13 levels and increased pro-inflammatory IL-6 titers.

Homologous and Heterologous Anti-COVID-19 Vaccination Does Not Induce New-Onset Formation of Autoantibodies Typically Accompanying Lupus Erythematodes, Rheumatoid Arthritis, Celiac Disease and Antiphospholipid Syndrome.

The COVID-19 pandemics has caused the death of almost six million people worldwide. In order to establish collective immunity, the first vaccines that were approved in Germany were the vector virus-based vaccine Vaxzevria and the mRNA vaccines Comirnaty and Spikevax, respectively. As it was reported that SARS-CoV-2 can trigger autoimmunity, it is of significant interest to investigate whether COVID-19 vaccines evoke the formation of autoantibodies and subsequent autoimmunity.

Ionic mitigation of CD4 T cell metabolic fitness, Th1 central nervous system autoimmunity and Th2 asthmatic airway inflammation by therapeutic zinc.

T helper (Th) cells provide immunity to pathogens but also contribute to detrimental immune responses during allergy and autoimmunity. Th2 cells mediate asthmatic airway inflammation and Th1 cells are involved in the pathogenesis of multiple sclerosis. T cell activation involves complex transcriptional networks and metabolic reprogramming, which enable proliferation and differentiation into Th1 and Th2 cells.

Robust induction of neutralizing antibodies against the SARS-CoV-2 Delta variant after homologous Spikevax or heterologous Vaxzevria-Spikevax vaccination.

Sera of vaccines were assessed by surrogate virus neutralization tests for their capacity to neutralize the SARS-CoV-2 Delta variant. Homologous prime-boost immunization with Moderna's Spikevax as well as heterologous immunization with AstraZeneca's Vaxzevria followed by Moderna's Spikevax were identified as highly potent vaccination regimens for the induction of Delta-neutralizing antibodies.

Albumin Substitution in Decompensated Liver Cirrhosis: Don't Forget Zinc.

Decompensated liver cirrhosis has a dismal prognosis, with patients surviving on average for 2-4 years after the first diagnosis of ascites. Albumin is an important tool in the therapy of cirrhotic ascites. By virtue of its oncotic properties, it reduces the risk of cardiovascular dysfunction after paracentesis.

Fate of Phytometabolites of Antibiotics during Digestion and Implications for Human Health.

Antibiotics are released into the environment as their global consumption increases. Uptake, accumulation, and metabolism of antibiotics by food crops is an emerging health concern as the associated risks of consuming food crops containing antibiotics are still largely unknown. This study investigated the fate of sulfamethazine, sulfamethoxazole, and their phytometabolites during digestion of the model plant.

Pitavastatin Is a Highly Potent Inhibitor of T-Cell Proliferation.

Repositioning of approved drugs is an alternative time- and cost-saving strategy to classical drug development. Statins are 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase inhibitors that are usually used as cholesterol-lowering medication, and they also exhibit anti-inflammatory effects. In the present study, we observed that the addition of Pitavastatin at nanomolar concentrations inhibits the proliferation of CD3/CD28 antibody-stimulated human T cells of healthy donors in a dose-dependent fashion.

Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage.

Janus kinase inhibitors (JAKis) represent a new strategy in rheumatoid arthritis (RA) therapy. Still, data directly comparing different JAKis are rare. In the present in vitro study, we investigated the immunomodulatory potential of four JAKis (tofacitinib, baricitinib, upadacitinib, and filgotinib) currently approved for RA treatment by the European Medicines Agency.

Zinc Aspartate Induces IL-16 Secretion and Apoptosis in Human T Cells.

T cell activation mediates immunity to pathogens. On the flipside, T cells are also involved in pathological immune responses during chronic autoimmune diseases. We recently reported that zinc aspartate, a registered drug with high bioavailability, dose-dependently inhibits T cell activation and Th1/Th2/Th17 cytokine production of stimulated human and mouse T cells.

Screening of FDA-Approved Drug Library Identifies Adefovir Dipivoxil as Highly Potent Inhibitor of T Cell Proliferation.

Repositioning of approved drugs for identifying new therapeutic purposes is an alternative, time and cost saving strategy to classical drug development. Here, we screened a library of 786 FDA-approved drugs to find compounds, which can potentially be repurposed for treatment of T cell-mediated autoimmune diseases. Investigating the effect of these diverse substances on mitogen-stimulated proliferation of both, freshly stimulated and pre-activated (48 h) peripheral blood mononuclear cells (PBMCs), we discovered Adefovir Dipivoxil (ADV) as very potent compound, which inhibits T cell proliferation in a nanomolar range.