TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation

NOD2, the nucleotide-binding domain and leucine-rich repeat containing gene family (NLR) member 2 is involved in mediating antimicrobial responses. Dysfunctional NOD2 activity can lead to severe inflammatory disorders, but the regulation of NOD2 is still poorly understood. Recently, proteins of the tripartite motif (TRIM) protein family have emerged as regulators of innate immune responses by acting as E3 ubiquitin ligases. We identified TRIM27 as a new specific binding partner for NOD2. We show that NOD2 physically interacts with TRIM27 via the nucleotide-binding domain, and that NOD2 activation enhances this interaction. Dependent on functional TRIM27, ectopically expressed NOD2 is ubiquitinated with K48-linked ubiquitin chains followed by proteasomal degradation. Accordingly, TRIM27 affects NOD2-mediated pro-inflammatory responses. NOD2 mutations are linked to susceptibility to Crohns disease. We found that TRIM27 expression is increased in Crohns disease patients, underscoring a physiological role of TRIM27 in regulating NOD2 signaling. In HeLa cells, TRIM27 is partially localized in the nucleus. We revealed that ectopically expressed NOD2 can shuttle to the nucleus in a Walker A dependent manner, suggesting that NOD2 and TRIM27 might functionally cooperate in the nucleus. We conclude that TRIM27 negatively regulates NOD2-mediated signaling by degradation of NOD2 and suggest that TRIM27 could be a new target for therapeutic intervention in NOD2-associated diseases.Funding Agencies|German Research Foundation (DFG)|SFB670-NG01|Swedish Society of Medicine||Regional Research Council of South-East Sweden (FORSS)||Swedish Research Council division of Medicine||Gustav V 90th anniversary foundation||Italian Telethon Foundation||DFG|SE 1122/2-1|</p

Anti-food and anti-microbial IgG subclass antibodies in inflammatory bowel disease

<p><b>Objectives:</b> Inflammatory bowel disease (IBD), particularly Crohn’s disease (CD), is associated with increased microbial-specific IgG and IgA antibodies, whereas alterations of anti-food antibodies are still disputed. The knowledge about IgG subclass antibodies in IBD is limited. In this study we analysed IgG subclass antibodies specific for nutritional and commensal antigens in IBD patients and controls.</p> <p><b>Methods:</b> Serum IgG1, IgG2, IgG3 and IgG4 specific for wheat and milk extracts, purified ovalbumin, <i>Escherichia coli</i> and <i>Bacteroides fragilis</i> lysates and mannan from <i>Saccharomyces cerevisiae</i> were analysed by ELISA in patients with CD (<i>n</i> = 56), ulcerative colitis (UC; <i>n</i> = 29), acute gastroenteritis/colitis (<i>n</i> = 12) as well as non-inflammatory controls (<i>n</i> = 62).</p> <p><b>Results:</b> Anti-<i>Saccharomyces cerevisiae</i> antibodies (ASCA) of all IgG subclasses and anti-<i>B. fragilis</i> IgG1 levels were increased in CD patients compared to UC patients and controls. The discriminant validity of ASCA IgG2 and IgG4 was comparable with that of ASCA pan-IgG and IgA, whereas it was inferior for ASCA IgG1/IgG3 and anti-<i>B. fragilis</i> IgG1. Complicated CD defined by the presence of perianal, stricturing or penetrating disease phenotypes was associated with increased ASCA IgG1/IgG3/IgG4, anti-<i>B. fragilis</i> IgG1 and anti-<i>E. coli</i> IgG1 levels. Anti-food IgG subclass levels were not different between IBD patients and controls and did not correlate with food intolerance. In contrast to anti-microbial Abs, food-specific IgG responses were predominately of the IgG4 isotype and all food-specific IgG subclass levels correlated negatively with age.</p> <p><b>Conclusion:</b> Our study supports the notion that the adaptive immune recognition of food and commensal antigens are differentially regulated.</p

Kognitive Prozesse bei der initialen Diagnosefindung und Therapieplanung in der Kieferorthopädie [Cognitive processes in inital diagnosis and treatment planning in orthodontics]

[english] Introduction: The investigation of diagnostic processes in dentistry and particularly in orthodontics is an often neglected subject of research. This study investigates cognitive processes at initial diagnosis and during treatment planning in orthodontics. We differentiated between various levels of experience: dentists without special training, assistants and specialist dentists. The aim was to identify cognitive processes and use this information for the improvement of education. Methods: A case vignette (complete, evaluated diagnostic record of a patient with patient’s history, clinical findings, study model, cephalogram, panoramic x-ray, photographs) was presented to 17 test persons (5 dentists, 5 assistants and 7 specialist dentists). With the help of think-aloud protocols, statements were systematised and quantified to enable statistical analysis. Results: The cognitive process is a complex and variable interaction of different processes. Reduction to a single known cognitive model was not possible. At a high cognitive load, there were no significant differences between groups for processing, but significant differences were found in the order in which the diagnostic records were considered. With increasing experience, less information (15%) was considered. The study model takes up a substantial proportion of diagnosis and treatment planning in terms of time (&gt;30%) and content. Discussion: The initial orthodontic diagnosis and treatment planning is a highly individual process. An integrated model of analytical and non-analytical approaches can be adopted for orthodontics. Target for the improvement of education should be stricter systematics and reduction of the cognitive load. To build individual strategies it may also be helpful to incorporate more case-based exercises. <br>[german] Einführung: Die Untersuchung diagnostischer Prozesse nach kognitiven Gesichtspunkten ist speziell in der Zahnmedizin und Kieferorthopädie bisher wenig betrachtet worden. In dieser Studie werden die kognitiven Prozesse bei der initialen Diagnostik und Therapieplanung in der Kieferorthopädie untersucht. Es wurden verschiedene Erfahrungslevel von Zahnärzten ohne spezielle Ausbildung, Weiterbildungsassistenten und Fachzahnärzten differenziert. Ziel war es, die gedanklichen Prozesse zu erkennen und Konsequenzen für eine Verbesserung der Ausbildung abzuleiten. Methode: Eine Fallvignette (komplette, ausgewertete diagnostische Unterlagen eines Patienten mit Anamnese, klinischem Befund, Studienmodell, Fernröntgenseitbild, Orthopantomogramm, Fotos) wurde 17 Probanden (5 Zahnärzte, 5 Weiterbildungsassistenten und 7 Fachzahnärzte) vorgelegt. Anhand von Think-aloud-Protokollen der Bearbeitung der Fallvignette wurden die Aussagen systematisiert und quantifiziert und damit einer statistischen Betrachtung zugänglich gemacht. Ergebnis: Der kognitive Prozess ist ein komplexes und variables Zusammenwirken verschiedener Abläufe. Eine Reduktion auf ein bekanntes kognitives Modell war nicht möglich. Bei einer hohen Cognitive Load zeigten sich in der Zeit für die Bearbeitung keine signifikanten Unterschiede zwischen den Gruppen, wohl aber erhebliche Differenzen in der Reihenfolge der Betrachtung der Befunde. Mit steigender Berufserfahrung werden weniger Informationen (15%) abgerufen. Sowohl zeitlich (&gt;30%) als auch inhaltlich hat das Studienmodell wesentlichen Anteil an der Diagnostik und Therapieplanung. Diskussion: Die initiale kieferorthopädische Diagnostik und Therapieplanung ist ein hochindividueller Prozess. Es kann ein integriertes Modell aus analytischem und nichtanalytischem Vorgehen für die Kieferorthopädie angenommen werden. Verbesserungen in der Wissensvermittlung sollten eine strengere Systematisierung und Reduktion der kognitiven Belastung zum Ziel haben. Zum Aufbau individueller Strategien könnte auch der vermehrte Einsatz fallbasierter Übungen beitragen