Argonaute Autoantibodies as Biomarkers in Autoimmune Neurologic Diseases

OBJECTIVE: To identify and characterize autoantibodies (Abs) as novel biomarkers for an autoimmune context in patients with central and peripheral neurologic diseases. METHODS: Two distinct approaches (immunoprecipitation/mass spectrometry-based proteomics and protein microarrays) and patients' sera and CSF were used. The specificity of the identified target was confirmed by cell-based assay (CBA) in 856 control samples. RESULTS: Using the 2 methods as well as sera and CSF of patients with central and peripheral neurologic involvement, we identified Abs against the family of Argonaute proteins (mainly AGO1 and AGO2), which were already reported in systemic autoimmunity. AGO-Abs were mostly of immunoglobulin G 1 subclass and conformation dependent. Using CBA, AGO-Abs were detected in 21 patients with a high suspicion of autoimmune neurologic diseases (71.4% were women; median age 57 years) and only in 4/856 (0.5%) controls analyzed by CBA (1 diagnosed with small-cell lung cancer and the other 3 with Sjögren syndrome). Among the 21 neurologic patients identified, the main clinical presentations were sensory neuronopathy (8/21, 38.1%) and limbic encephalitis (6/21, 28.6%). Fourteen patients (66.7%) had autoimmune comorbidities and/or co-occurring Abs, whereas AGO-Abs were the only autoimmune biomarker for the remaining 7/21 (33.3%). Thirteen (61.9%) patients were treated with immunotherapy; 8/13 (61.5%) improved, and 3/13 (23.1%) remained stable, suggesting an efficacy of these treatments. CONCLUSIONS: AGO-Abs might be potential biomarkers of autoimmunity in patients with central and peripheral nonparaneoplastic neurologic diseases. In 7 patients, AGO-Abs were the only biomarkers; thus, their identification may be useful to suspect the autoimmune character of the neurologic disorder. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that AGO-Abs are more frequent in patients with autoimmune neurologic diseases than controls

Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation

Background: The homozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell (DC) and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function. Objective: We sought to describe the effect on hematopoiesis and immunity of the compound heterozygous R83C/R291Q mutation of IRF8, which is present in a patient with recurrent viral infection, granuloproliferation, and intracerebral calcification. Methods: Variant IRF8 alleles were identified by means of exome sequencing, and their function was tested by using reporter assays. The cellular phenotype was studied in detail by using flow cytometry, functional immunologic assay transcriptional profiling, and antigen receptor profiling. Results: Both mutations affected conserved residues, and R291Q is orthologous to R294, which is mutated in the BXH2 IRF8-deficient mouse. R83C showed reduced nuclear translocation, and neither mutant was able to regulate the Ets/IRF composite element or interferon-stimulated response element, whereas R291Q retained BATF/JUN interactions. DC deficiency and monocytopenia were observed in blood, dermis, and lung lavage fluid. Granulocytes were consistently increased, dysplastic, and hypofunctional. Natural killer cell development and maturation were arrested. TH1, TH17, and CD8+ memory T-cell differentiation was significantly reduced, and T cells did not express CXCR3. B-cell development was impaired, with fewer memory cells, reduced class-switching, and lower frequency and complexity of somatic hypermutation. Cell-specific gene expression was widely disturbed in interferon- and IRF8-regulated transcripts. Conclusions: This analysis defines the clinical features of human biallelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by DC and monocyte deficiency combined with widespread immune dysregulation

Telefonbasierte Kommunikationsausbildung in Zeiten von COVID-19

Introduction: In the wake of the COVID-19 pandemic, alternatives to established and proven formats had to be found in university teaching within a very short time. In the case of the SkillsLab at the Dorothea Erxleben Lernzentrum Halle (Saale) at the Martin Luther University Halle (Saale)-Wittenberg, this meant in relation to the communication courses that a considerable proportion of the simulation participants of advanced age or with pre-existing conditions were suddenly no longer available for conversation simulations in teaching.Project description: In the course of the seminar "Conversation with relatives - dealing with relatives" in the 8th semester, the conversation simulation was therefore adapted at short notice and converted into a telephone conversation. Thus, the simulation subjects were able to participate remotely and the students had the opportunity to test their doctor-patient conversation skills with regard to telephone calls in a safe environment. Results: The focus on nonverbal techniques and the departure from the usual face-to-face setting was perceived by students and simulation subjects alike as a positive stimulus and particularly challenging. The lack of visual impressions had made empathic conversation more difficult. Discussion and Conclusions: The positive experiences from this project should be used to expand the communication curriculum in the future to include telephone-based conversations with simulation subjects. Ideally, it would then be possible for the simulation persons to be present in the future after the conversation for feedback mediation and group discussion.Einleitung: Im Zuge der COVID-19 Pandemie mussten in der universitären Lehre in kürzester Zeit Alternativen zu etablierten und bewährten Formaten gefunden werden. Im Falle des SkillsLabs im Dorothea Erxleben Lernzentrum Halle (Saale) an der Martin-Luther-Universität Halle (Saale)-Wittenberg bedeutete dies bezogen auf die Kommunikationskurse, dass ein beachtlicher Teil der Simulationspersonen im höheren Alter oder mit Vorerkrankungen plötzlich nicht mehr für Gesprächssimulationen in der Lehre zur Verfügung stand.Projektbeschreibung: Im Zuge des Seminares "Angehörigengespräch - Umgang mit Angehörigen" im 8. Fachsemester wurde die Gesprächssimulation deshalb kurzfristig angepasst und in ein Telefonat umgewandelt. Somit wurde es den Simulationspersonen ermöglicht aus der Ferne mitzuarbeiten und die Studierenden hatten die Möglichkeit in sicherer Umgebung ihre Arzt-Patienten-Gesprächsführung in Bezug auf Telefonate zu erproben. Ergebnisse: Der Fokus auf nonverbalen Techniken und das Verlassen des üblichen Face-to-Face Settings wurde gleichermaßen durch die Studierenden und die Simulationspersonen als ein positiver Impuls und besondere Herausforderung wahrgenommen. Das Fehlen der optischen Eindrücke habe eine empathische Gesprächsführung schwieriger gemacht. Diskussion und Schlussfolgerungen: Die positiven Erfahrungen aus diesem Projekt sollen genutzt werden um das Kommunikationscurriculum zukünftig um telefongestützte Gespräche mit Simulationspersonen zu erweitern. Im Idealfall ist es dann möglich, dass die Simulationspersonen zukünftig nach dem Gespräch zur Feedbackvermittlung und zur Gruppendiskussion anwesend sein können